WorldWideScience

Sample records for global metabolic regulation

  1. Quantitative analysis of proteome and lipidome dynamics reveals functional regulation of global lipid metabolism

    DEFF Research Database (Denmark)

    Casanovas, Albert; Sprenger, Richard R; Tarasov, Kirill

    2015-01-01

    Elucidating how and to what extent lipid metabolism is remodeled under changing conditions is essential for understanding cellular physiology. Here, we analyzed proteome and lipidome dynamics to investigate how regulation of lipid metabolism at the global scale supports remodeling of cellular...

  2. Linking high-resolution metabolic flux phenotypes and transcriptional regulation in yeast modulated by the global regulator Gcn4p

    DEFF Research Database (Denmark)

    Moxley, Joel F.; Jewett, Michael Christopher; Antoniewicz, Maciek R.

    2009-01-01

    . However, the potential of systems biology approaches is limited by difficulties in integrating metabolic measurements across the functional levels of the cell despite their being most closely linked to cellular phenotype. To address this limitation, we developed a model-based approach to correlate m......RNA and metabolic flux data that combines information from both interaction network models and flux determination models. We started by quantifying 5,764 mRNAs, 54 metabolites, and 83 experimental C-13-based reaction fluxes in continuous cultures of yeast under stress in the absence or presence of global regulator...... of metabolic flux (i.e., use of different reaction pathways) by transcriptional regulation and metabolite interaction density (i.e., level of pairwise metabolite-protein interactions) as a key biosynthetic control determinant. Furthermore, this model predicted flux rewiring in studies of follow...

  3. Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism.

    Science.gov (United States)

    Cuyàs, E; Fernández-Arroyo, S; Verdura, S; García, R Á-F; Stursa, J; Werner, L; Blanco-González, E; Montes-Bayón, M; Joven, J; Viollet, B; Neuzil, J; Menendez, J A

    2018-02-15

    The anti-diabetic biguanide metformin may exert health-promoting effects via metabolic regulation of the epigenome. Here we show that metformin promotes global DNA methylation in non-cancerous, cancer-prone and metastatic cancer cells by decreasing S-adenosylhomocysteine (SAH), a strong feedback inhibitor of S-adenosylmethionine (SAM)-dependent DNA methyltransferases, while promoting the accumulation of SAM, the universal methyl donor for cellular methylation. Using metformin and a mitochondria/complex I (mCI)-targeted analog of metformin (norMitoMet) in experimental pairs of wild-type and AMP-activated protein kinase (AMPK)-, serine hydroxymethyltransferase 2 (SHMT2)- and mCI-null cells, we provide evidence that metformin increases the SAM:SAH ratio-related methylation capacity by targeting the coupling between serine mitochondrial one-carbon flux and CI activity. By increasing the contribution of one-carbon units to the SAM from folate stores while decreasing SAH in response to AMPK-sensed energetic crisis, metformin can operate as a metabolo-epigenetic regulator capable of reprogramming one of the key conduits linking cellular metabolism to the DNA methylation machinery.

  4. Structure analysis of the global metabolic regulator Crc from Pseudomonas aeruginosa.

    Science.gov (United States)

    Wei, Yong; Zhang, Heng; Gao, Zeng-Qiang; Xu, Jian-Hua; Liu, Quan-Sheng; Dong, Yu-Hui

    2013-01-01

    The global metabolic regulator catabolite repression control (Crc) has recently been found to modulate the susceptibility to antibiotics and virulence in the opportunistic pathogen Pseudomonas aeruginosa and been suggested as a nonlethal target for novel antimicrobials. In P. aeruginosa, Crc couples with the CA motifs from the small RNA CrcZ to form a post-transcriptional regulator system and is removed from the 5'-end of the target mRNAs. In this study, we first reported the crystal structure of Crc from P. aeruginosa refined to 2.20 Å. The structure showed that it consists of two halves with similar overall topology and there are 11 β strands surrounded by 13 helices, forming a four-layered α/β-sandwich. The circular dichroism spectroscopy revealed that it is thermostable in solution and shares similar characteristics to that in crystal. Comprehensive structural analysis and comparison with the homologies of Crc showed high similarity with several known nucleases and consequently may be classified into a member exodeoxyribonuclease III. However, it shows distinct substrate specificity (RNA as the preferred substrate) compared to these DNA endonucleases. Structural comparisons also revealed potential RNA recognition and binding region mainly consisting of five flexible loops. Our structure study provided the basis for the future application of Crc as a target to develop new antibiotics. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

  5. The Global Regulator Spx Functions in the Control of Organosulfur Metabolism in Bacillus subtilis†

    Science.gov (United States)

    Choi, Soon-Yong; Reyes, Dindo; Leelakriangsak, Montira; Zuber, Peter

    2006-01-01

    Spx is a global transcriptional regulator of the oxidative stress response in Bacillus subtilis. Its target is RNA polymerase, where it contacts the α subunit C-terminal domain. Recently, evidence was presented that Spx participates in sulfate-dependent control of organosulfur utilization operons, including the ytmI, yxeI, ssu, and yrrT operons. The yrrT operon includes the genes that function in cysteine synthesis from S-adenosylmethionine through intermediates S-adenosylhomocysteine, ribosylhomocysteine, homocysteine, and cystathionine. These operons are also negatively controlled by CymR, the repressor of cysteine biosynthesis operons. All of the operons are repressed in media containing cysteine or sulfate but are derepressed in medium containing the alternative sulfur source, methionine. Spx was found to negatively control the expression of these operons in sulfate medium, in part, by stimulating the expression of the cymR gene. In addition, microarray analysis, monitoring of yrrT-lacZ fusion expression, and in vitro transcription studies indicate that Spx directly activates yrrT operon expression during growth in medium containing methionine as sole sulfur source. These experiments have uncovered additional roles for Spx in the control of gene expression during unperturbed, steady-state growth. PMID:16885442

  6. Metabolic regulation of yeast

    Science.gov (United States)

    Fiechter, A.

    1982-12-01

    Metabolic regulation which is based on endogeneous and exogeneous process variables which may act constantly or time dependently on the living cell is discussed. The observed phenomena of the regulation are the result of physical, chemical, and biological parameters. These parameters are identified. Ethanol is accumulated as an intermediate product and the synthesis of biomass is reduced. This regulatory effect of glucose is used for the aerobic production of ethanol. Very high production rates are thereby obtained. Understanding of the regulation mechanism of the glucose effect has improved. In addition to catabolite repression, several other mechanisms of enzyme regulation have been described, that are mostly governed by exogeneous factors. Glucose also affects the control of respiration in a third class of yeasts which are unable to make use of ethanol as a substrate for growth. This is due to the lack of any anaplerotic activity. As a consequence, diauxic growth behavior is reduced to a one-stage growth with a drastically reduced cell yield. The pulse chemostat technique, a systematic approach for medium design is developed and medium supplements that are essential for metabolic control are identified.

  7. [Regulation of terpene metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1989-11-09

    Terpenoid oils, resins, and waxes from plants are important renewable resources. The objective of this project is to understand the regulation of terpenoid metabolism using the monoterpenes (C[sub 10]) as a model. The pathways of monoterpene biosynthesis and catabolism have been established, and the relevant enzymes characterized. Developmental studies relating enzyme levels to terpene accumulation within the oil gland sites of synthesis, and work with bioregulators, indicate that monoterpene production is controlled by terpene cyclases, the enzymes catalyzing the first step of the monoterpene pathway. As the leaf oil glands mature, cyclase levels decline and monoterpene biosynthesis ceases. Yield then decreases as the monoterpenes undergo catabolism by a process involving conversion to a glycoside and transport from the leaf glands to the root. At this site, the terpenoid is oxidatively degraded to acetate that is recycled into other lipid metabolites. During the transition from terpene biosynthesis to catabolism, the oil glands undergo dramatic ultrastructural modification. Degradation of the producing cells results in mixing of previously compartmentized monoterpenes with the catabolic enzymes, ultimately leading to yield decline. This regulatory model is being applied to the formation of other terpenoid classes (C[sub 15] C[sub 20], C[sub 30], C[sub 40]) within the oil glands. Preliminary investigations on the formation of sesquiterpenes (C[sub 15]) suggest that the corresponding cyclases may play a lesser role in determining yield of these products, but that compartmentation effects are important. From these studies, a comprehensive scheme for the regulation of terpene metabolism is being constructed. Results from this project wail have important consequences for the yield and composition of terpenoid natural products that can be made available for industrial exploitation.

  8. [Regulation of terpene metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1991-01-01

    During the last grant period, we have completed studies on the key pathways of monoterpene biosynthesis and catabolism in sage and peppermint, and have, by several lines of evidence, deciphered the rate-limiting step of each pathway. We have at least partially purified and characterized the relevant enzymes of each pathway. We have made a strong case, based on analytical, in vivo, and in vitro studies, that terpene accumulation depends upon the balance between biosynthesis and catabolism, and provided supporting evidence that these processes are developmentally-regulated and very closely associated with senescence of the oil glands. Oil gland ontogeny has been characterized at the ultrastructural level. We have exploited foliar-applied bioregulators to delay gland senescence, and have developed tissue explant and cell culture systems to study several elusive aspects of catabolism. We have isolated pure gland cell clusters and localized monoterpene biosynthesis and catabolism within these structures, and have used these preparations as starting materials for the purification to homogeneity of target regulatory'' enzymes. We have thus developed the necessary background knowledge, based on a firm understanding of enzymology, as well as the necessary experimental tools for studying the regulation of monoterpene metabolism at the molecular level. Furthermore, we are now in a position to extend our systematic approach to other terpenoid classes (C[sub 15]-C[sub 30]) produced by oil glands.

  9. Global Metabolic Regulation of the Snow Alga Chlamydomonas nivalis in Response to Nitrate or Phosphate Deprivation by a Metabolome Profile Analysis.

    Science.gov (United States)

    Lu, Na; Chen, Jun-Hui; Wei, Dong; Chen, Feng; Chen, Gu

    2016-05-10

    In the present work, Chlamydomonas nivalis, a model species of snow algae, was used to illustrate the metabolic regulation mechanism of microalgae under nutrient deprivation stress. The seed culture was inoculated into the medium without nitrate or phosphate to reveal the cell responses by a metabolome profile analysis using gas chromatography time-of-flight mass spectrometry (GC/TOF-MS). One hundred and seventy-one of the identified metabolites clustered into five groups by the orthogonal partial least squares discriminant analysis (OPLS-DA) model. Among them, thirty of the metabolites in the nitrate-deprived group and thirty-nine of the metabolites in the phosphate-deprived group were selected and identified as "responding biomarkers" by this metabolomic approach. A significant change in the abundance of biomarkers indicated that the enhanced biosynthesis of carbohydrates and fatty acids coupled with the decreased biosynthesis of amino acids, N-compounds and organic acids in all the stress groups. The up- or down-regulation of these biomarkers in the metabolic network provides new insights into the global metabolic regulation and internal relationships within amino acid and fatty acid synthesis, glycolysis, the tricarboxylic acid cycle (TCA) and the Calvin cycle in the snow alga under nitrate or phosphate deprivation stress.

  10. Metabolic regulation of inflammation.

    Science.gov (United States)

    Gaber, Timo; Strehl, Cindy; Buttgereit, Frank

    2017-05-01

    Immune cells constantly patrol the body via the bloodstream and migrate into multiple tissues where they face variable and sometimes demanding environmental conditions. Nutrient and oxygen availability can vary during homeostasis, and especially during the course of an immune response, creating a demand for immune cells that are highly metabolically dynamic. As an evolutionary response, immune cells have developed different metabolic programmes to supply them with cellular energy and biomolecules, enabling them to cope with changing and challenging metabolic conditions. In the past 5 years, it has become clear that cellular metabolism affects immune cell function and differentiation, and that disease-specific metabolic configurations might provide an explanation for the dysfunctional immune responses seen in rheumatic diseases. This Review outlines the metabolic challenges faced by immune cells in states of homeostasis and inflammation, as well as the variety of metabolic configurations utilized by immune cells during differentiation and activation. Changes in cellular metabolism that contribute towards the dysfunctional immune responses seen in rheumatic diseases are also briefly discussed.

  11. [Regulation of terpene metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1992-01-01

    This report describes accomplishments over the past year on understanding of terpene synthesis in mint plants and sage. Specifically reported are the fractionation of 4-S-limonene synthetase, the enzyme responsible for the first committed step to monoterpene synthesis, along with isolation of the corresponding RNA and DNA cloning of its gene; the localization of the enzyme within the oil glands, regulation of transcription and translation of the synthetase, the pathway to camphor biosynthesis,a nd studies on the early stages and branch points of the isoprenoid pathway.

  12. Understanding Regulation of Metabolism through Feasibility Analysis

    NARCIS (Netherlands)

    Nikerel, I.E.; Berkhout, J.; Hu, F.; Teusink, B.; Reinders, M.J.T.; De Ridder, D.

    2012-01-01

    Understanding cellular regulation of metabolism is a major challenge in systems biology. Thus far, the main assumption was that enzyme levels are key regulators in metabolic networks. However, regulation analysis recently showed that metabolism is rarely controlled via enzyme levels only, but

  13. Regulation of metabolic networks by small molecule metabolites

    Directory of Open Access Journals (Sweden)

    Kanehisa Minoru

    2007-03-01

    Full Text Available Abstract Background The ability to regulate metabolism is a fundamental process in living systems. We present an analysis of one of the mechanisms by which metabolic regulation occurs: enzyme inhibition and activation by small molecules. We look at the network properties of this regulatory system and the relationship between the chemical properties of regulatory molecules. Results We find that many features of the regulatory network, such as the degree and clustering coefficient, closely match those of the underlying metabolic network. While these global features are conserved across several organisms, we do find local differences between regulation in E. coli and H. sapiens which reflect their different lifestyles. Chemical structure appears to play an important role in determining a compounds suitability for use in regulation. Chemical structure also often determines how groups of similar compounds can regulate sets of enzymes. These groups of compounds and the enzymes they regulate form modules that mirror the modules and pathways of the underlying metabolic network. We also show how knowledge of chemical structure and regulation could be used to predict regulatory interactions for drugs. Conclusion The metabolic regulatory network shares many of the global properties of the metabolic network, but often varies at the level of individual compounds. Chemical structure is a key determinant in deciding how a compound is used in regulation and for defining modules within the regulatory system.

  14. Metabolic Regulation of a Bacterial Cell System with Emphasis on Escherichia coli Metabolism

    Science.gov (United States)

    Shimizu, Kazuyuki

    2013-01-01

    It is quite important to understand the overall metabolic regulation mechanism of bacterial cells such as Escherichia coli from both science (such as biochemistry) and engineering (such as metabolic engineering) points of view. Here, an attempt was made to clarify the overall metabolic regulation mechanism by focusing on the roles of global regulators which detect the culture or growth condition and manipulate a set of metabolic pathways by modulating the related gene expressions. For this, it was considered how the cell responds to a variety of culture environments such as carbon (catabolite regulation), nitrogen, and phosphate limitations, as well as the effects of oxygen level, pH (acid shock), temperature (heat shock), and nutrient starvation. PMID:25937963

  15. Understanding Regulation of Metabolism through Feasibility Analysis

    Science.gov (United States)

    Nikerel, Emrah; Berkhout, Jan; Hu, Fengyuan; Teusink, Bas; Reinders, Marcel J. T.; de Ridder, Dick

    2012-01-01

    Understanding cellular regulation of metabolism is a major challenge in systems biology. Thus far, the main assumption was that enzyme levels are key regulators in metabolic networks. However, regulation analysis recently showed that metabolism is rarely controlled via enzyme levels only, but through non-obvious combinations of hierarchical (gene and enzyme levels) and metabolic regulation (mass action and allosteric interaction). Quantitative analyses relating changes in metabolic fluxes to changes in transcript or protein levels have revealed a remarkable lack of understanding of the regulation of these networks. We study metabolic regulation via feasibility analysis (FA). Inspired by the constraint-based approach of Flux Balance Analysis, FA incorporates a model describing kinetic interactions between molecules. We enlarge the portfolio of objectives for the cell by defining three main physiologically relevant objectives for the cell: function, robustness and temporal responsiveness. We postulate that the cell assumes one or a combination of these objectives and search for enzyme levels necessary to achieve this. We call the subspace of feasible enzyme levels the feasible enzyme space. Once this space is constructed, we can study how different objectives may (if possible) be combined, or evaluate the conditions at which the cells are faced with a trade-off among those. We apply FA to the experimental scenario of long-term carbon limited chemostat cultivation of yeast cells, studying how metabolism evolves optimally. Cells employ a mixed strategy composed of increasing enzyme levels for glucose uptake and hexokinase and decreasing levels of the remaining enzymes. This trade-off renders the cells specialized in this low-carbon flux state to compete for the available glucose and get rid of over-overcapacity. Overall, we show that FA is a powerful tool for systems biologists to study regulation of metabolism, interpret experimental data and evaluate hypotheses. PMID

  16. Fibroblast Growth Factor Signaling in Metabolic Regulation.

    Science.gov (United States)

    Nies, Vera J M; Sancar, Gencer; Liu, Weilin; van Zutphen, Tim; Struik, Dicky; Yu, Ruth T; Atkins, Annette R; Evans, Ronald M; Jonker, Johan W; Downes, Michael Robert

    2015-01-01

    The prevalence of obesity is a growing health problem. Obesity is strongly associated with several comorbidities, such as non-alcoholic fatty liver disease, certain cancers, insulin resistance, and type 2 diabetes, which all reduce life expectancy and life quality. Several drugs have been put forward in order to treat these diseases, but many of them have detrimental side effects. The unexpected role of the family of fibroblast growth factors in the regulation of energy metabolism provides new approaches to the treatment of metabolic diseases and offers a valuable tool to gain more insight into metabolic regulation. The known beneficial effects of FGF19 and FGF21 on metabolism, together with recently discovered similar effects of FGF1 suggest that FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic conditions. To facilitate the development of new therapies with improved targeting and minimal side effects, a better understanding of the molecular mechanism of action of FGFs is needed. In this review, we will discuss what is currently known about the physiological roles of FGF signaling in tissues important for metabolic homeostasis. In addition, we will discuss current concepts regarding their pharmacological properties and effector tissues in the context of metabolic disease. Also, the recent progress in the development of FGF variants will be reviewed. Our goal is to provide a comprehensive overview of the current concepts and consensuses regarding FGF signaling in metabolic health and disease and to provide starting points for the development of FGF-based therapies against metabolic conditions.

  17. Regulation of trehalose metabolism in Saccharomyces

    International Nuclear Information System (INIS)

    Panek, A.D.; Costa-Carvalho, V.L.A.; Ortiz, C.H.D.; Dellamora-Ortiz, G.M.; Paschoalin, V.M.F.; Panek, A.C.

    1984-01-01

    The regulation of trehalose metabolism in Saccharomyces is studied by construction of mutants with specific lesions, cloning of genes involved in the regulation of trehalose synthase and of trehalase, as well as, isolation and purification of enzymes from the various mutants constructed. (M.A.C.) [pt

  18. [Aging and metabolism: changes and regulation].

    Science.gov (United States)

    Ortiz, Genaro Gabriel; Arias-Merino, Elva D; Velázquez-Brizuela, Irma E; Pacheco-Moisés, Fermín P; Flores-Alvarado, Luis J; Torres-Sánchez, Erandis D; Cortés-Enríquez, Fernando; González-Renovato, Erika D; Ortiz-Velázquez, Irma G

    2012-09-01

    Studies about the effects of aging in the physiology and metabolism are increasingly, one of its objectives is to help implement programs to improve the quality of life and prevent disability in elderly. It is relevant to mention that, during aging, there is a natural metabolic deceleration, a series of changes in the regulation of energy are produced, which contributes to loss of weight and fat; the changes in the regulation of caloric intake contribute to increase the susceptibility to energy imbalance both positive and negative, which is associated with a deterioration in health. However, to grow old, is not a death sentence for metabolism, on the other hand, it can be controlled by maintaining an active lifestyle, coupled with this, research has shown that the metabolism'can be regulated by a synchronized clock (circadian rhythms), which is mediated by regulatory proteins, this relationship ensures the proper functioning of the cells and therefore good health. The aim of this review is to provide updated information on the energy- metabolism-regulation and its relationship with the great variety of components involved in energy expenditure that accompany aging, to analyze the regulation of this system to improve the quality of life and maintenance of health in old age.

  19. Fibroblast growth factor signaling in metabolic regulation

    Directory of Open Access Journals (Sweden)

    Vera eNies

    2016-01-01

    Full Text Available The prevalence of obesity is a growing health problem. Obesity is strongly associated with several comorbidities, such as non-alcoholic fatty liver disease, certain cancers, insulin resistance and type 2 diabetes, which all reduce life expectancy and life quality. Several drugs have been put forward in order to treat these diseases, but many of them have detrimental side effects. The unexpected role of the family of fibroblast growth factors in the regulation of energy metabolism provides new approaches to the treatment of metabolic diseases, and offers a valuable tool to gain more insight into metabolic regulation. The known beneficial effects of FGF19 and FGF21 on metabolism, together with recently discovered similar effects of FGF1 suggest that FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic conditions. To facilitate the development of new therapies with improved targeting and minimal side effects, a better understanding of the molecular mechanism of action of FGFs is needed.In this review we will discuss what is currently known about the physiological roles of FGF signaling in tissues important for metabolic homeostasis. In addition, we will discuss current concepts regarding their pharmacological properties and effector tissues in the context of metabolic disease. Also the recent progress in the development of FGF variants will be reviewed. Our goal is to provide a comprehensive overview of the current concepts and consensuses regarding FGF signaling in metabolic health and disease, and to provide starting points for the development of FGF-based therapies against metabolic conditions.

  20. The Global Epidemic of the Metabolic Syndrome.

    Science.gov (United States)

    Saklayen, Mohammad G

    2018-02-26

    Metabolic syndrome, variously known also as syndrome X, insulin resistance, etc., is defined by WHO as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Though there is some variation in the definition by other health care organization, the differences are minor. With the successful conquest of communicable infectious diseases in most of the world, this new non-communicable disease (NCD) has become the major health hazard of modern world. Though it started in the Western world, with the spread of the Western lifestyle across the globe, it has become now a truly global problem. The prevalence of the metabolic syndrome is often more in the urban population of some developing countries than in its Western counterparts. The two basic forces spreading this malady are the increase in consumption of high calorie-low fiber fast food and the decrease in physical activity due to mechanized transportations and sedentary form of leisure time activities. The syndrome feeds into the spread of the diseases like type 2 diabetes, coronary diseases, stroke, and other disabilities. The total cost of the malady including the cost of health care and loss of potential economic activity is in trillions. The present trend is not sustainable unless a magic cure is found (unlikely) or concerted global/governmental/societal efforts are made to change the lifestyle that is promoting it. There are certainly some elements in the causation of the metabolic syndrome that cannot be changed but many are amenable for corrections and curtailments. For example, better urban planning to encourage active lifestyle, subsidizing consumption of whole grains and possible taxing high calorie snacks, restricting media advertisement of unhealthy food, etc. Revitalizing old fashion healthier lifestyle, promoting old-fashioned foods using healthy herbs rather than oil and sugar, and educating people about choosing healthy/wholesome food over junks

  1. Regulation of Metabolic Activity by p53

    Directory of Open Access Journals (Sweden)

    Jessica Flöter

    2017-05-01

    Full Text Available Metabolic reprogramming in cancer cells is controlled by the activation of multiple oncogenic signalling pathways in order to promote macromolecule biosynthesis during rapid proliferation. Cancer cells also need to adapt their metabolism to survive and multiply under the metabolically compromised conditions provided by the tumour microenvironment. The tumour suppressor p53 interacts with the metabolic network at multiple nodes, mostly to reduce anabolic metabolism and promote preservation of cellular energy under conditions of nutrient restriction. Inactivation of this tumour suppressor by deletion or mutation is a frequent event in human cancer. While loss of p53 function lifts an important barrier to cancer development by deleting cell cycle and apoptosis checkpoints, it also removes a crucial regulatory mechanism and can render cancer cells highly sensitive to metabolic perturbation. In this review, we will summarise the major concepts of metabolic regulation by p53 and explore how this knowledge can be used to selectively target p53 deficient cancer cells in the context of the tumour microenvironment.

  2. Linking metabolomics data to underlying metabolic regulation

    Directory of Open Access Journals (Sweden)

    Thomas eNägele

    2014-11-01

    Full Text Available The comprehensive experimental analysis of a metabolic constitution plays a central role in approaches of organismal systems biology.Quantifying the impact of a changing environment on the homeostasis of cellular metabolism has been the focus of numerous studies applying various metabolomics techniques. It has been proven that approaches which integrate different analytical techniques, e.g. LC-MS, GC-MS, CE-MS and H-NMR, can provide a comprehensive picture of a certain metabolic homeostasis. Identification of metabolic compounds and quantification of metabolite levels represent the groundwork for the analysis of regulatory strategies in cellular metabolism. This significantly promotes our current understanding of the molecular organization and regulation of cells, tissues and whole organisms.Nevertheless, it is demanding to elicit the pertinent information which is contained in metabolomics data sets.Based on the central dogma of molecular biology, metabolite levels and their fluctuations are the result of a directed flux of information from gene activation over transcription to translation and posttranslational modification.Hence, metabolomics data represent the summed output of a metabolic system comprising various levels of molecular organization.As a consequence, the inverse assignment of metabolomics data to underlying regulatory processes should yield information which-if deciphered correctly-provides comprehensive insight into a metabolic system.Yet, the deduction of regulatory principles is complex not only due to the high number of metabolic compounds, but also because of a high level of cellular compartmentalization and differentiation.Motivated by the question how metabolomics approaches can provide a representative view on regulatory biochemical processes, this article intends to present and discuss current metabolomics applications, strategies of data analysis and their limitations with respect to the interpretability in context of

  3. Insights from the cold transcriptome and metabolome of Dendrobium officinale: global reprogramming of metabolic and gene regulation networks during cold acclimation

    Directory of Open Access Journals (Sweden)

    Zhi-Gang Wu

    2016-11-01

    Full Text Available Plant cold acclimation (CA is a genetically complex phenomenon involving gene regulation and expression. Little is known about the cascading pattern of gene regulatroy network and the link between genes and metabolites during CA. Dendrobium officinale (DOKM is an important medicinal and ornamental plant and hypersensitive to low temperature. Here, we used the large scale metabolomic and transcriptomic technologies to reveal the response to CA in DOKM seedlings based on the physiological profile analyses. Lowering temperature from 4 oC to -2 oC resulted in significant increase(P<0.01)in antioxidant activities and electrolyte leakage during 24 h. The fitness CA piont of 0 oC and control (20 oC during 20 h were firstly obtained according to physiological analyses. Subsequently, massive transcriptome and metabolome reprogramming occurred during CA. The gene to metabolite network demonstrated that the CA associated processes are highly energy demanding through activating hydrolysis of sugars, amino acids catabolism and citrate cycle. The expression levels of 2,767 genes were significantly affected by CA, including 153-fold upregulation of CBF transcription factor, 56-fold upregulation of MAPKKK16 protein kinase. Moreover, the gene interaction and regulation network analysis revealed that the CA as an active process, was regulated at the transcriptional, post-transcriptional, translational and post-translational levels. Our findings highligted a comprehensive regulatory mechanism including cold signal transduction, transcriptional regulation and gene expression, which contributes a deeper understanding of the highly complex regulatory program during CA in DOKM. Some marker genes identified in DOKM seedlings will allow us to understand the role of each individual during CA by further functional analyses.

  4. Regulation of metabolism by the Mediator complex.

    Science.gov (United States)

    Youn, Dou Yeon; Xiaoli, Alus M; Pessin, Jeffrey E; Yang, Fajun

    2016-01-01

    The Mediator complex was originally discovered in yeast, but it is conserved in all eukaryotes. Its best-known function is to regulate RNA polymerase II-dependent gene transcription. Although the mechanisms by which the Mediator complex regulates transcription are often complicated by the context-dependent regulation, this transcription cofactor complex plays a pivotal role in numerous biological pathways. Biochemical, molecular, and physiological studies using cancer cell lines or model organisms have established the current paradigm of the Mediator functions. However, the physiological roles of the mammalian Mediator complex remain poorly defined, but have attracted a great interest in recent years. In this short review, we will summarize some of the reported functions of selective Mediator subunits in the regulation of metabolism. These intriguing findings suggest that the Mediator complex may be an important player in nutrient sensing and energy balance in mammals.

  5. CREBH Regulates Systemic Glucose and Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Yoshimi Nakagawa

    2018-05-01

    Full Text Available The cyclic adenosine monophosphate (cAMP-responsive element-binding protein H (CREBH, encoded by CREB3L3 is a membrane-bound transcriptional factor that primarily localizes in the liver and small intestine. CREBH governs triglyceride metabolism in the liver, which mediates the changes in gene expression governing fatty acid oxidation, ketogenesis, and apolipoproteins related to lipoprotein lipase (LPL activation. CREBH in the small intestine reduces cholesterol transporter gene Npc1l1 and suppresses cholesterol absorption from diet. A deficiency of CREBH in mice leads to severe hypertriglyceridemia, fatty liver, and atherosclerosis. CREBH, in synergy with peroxisome proliferator-activated receptor α (PPARα, has a crucial role in upregulating Fgf21 expression, which is implicated in metabolic homeostasis including glucose and lipid metabolism. CREBH binds to and functions as a co-activator for both PPARα and liver X receptor alpha (LXRα in regulating gene expression of lipid metabolism. Therefore, CREBH has a crucial role in glucose and lipid metabolism in the liver and small intestine.

  6. Development, regulation, metabolism and function of bone marrow adipose tissues.

    Science.gov (United States)

    Li, Ziru; Hardij, Julie; Bagchi, Devika P; Scheller, Erica L; MacDougald, Ormond A

    2018-05-01

    Most adipocytes exist in discrete depots throughout the body, notably in well-defined white and brown adipose tissues. However, adipocytes also reside within specialized niches, of which the most abundant is within bone marrow. Whereas bone marrow adipose tissue (BMAT) shares many properties in common with white adipose tissue, the distinct functions of BMAT are reflected by its development, regulation, protein secretion, and lipid composition. In addition to its potential role as a local energy reservoir, BMAT also secretes proteins, including adiponectin, RANK ligand, dipeptidyl peptidase-4, and stem cell factor, which contribute to local marrow niche functions and which may also influence global metabolism. The characteristics of BMAT are also distinct depending on whether marrow adipocytes are contained within yellow or red marrow, as these can be thought of as 'constitutive' and 'regulated', respectively. The rBMAT for instance can be expanded or depleted by myriad factors, including age, nutrition, endocrine status and pharmaceuticals. Herein we review the site specificity, age-related development, regulation and metabolic characteristics of BMAT under various metabolic conditions, including the functional interactions with bone and hematopoietic cells. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Metabolic signals in sleep regulation: recent insights

    Directory of Open Access Journals (Sweden)

    Shukla C

    2016-01-01

    Full Text Available Charu Shukla, Radhika Basheer Department of Psychiatry, VA Boston Healthcare System, Harvard Medical School, West Roxbury, MA, USA Abstract: Sleep and energy balance are essential for health. The two processes act in concert to regulate central and peripheral homeostasis. During sleep, energy is conserved due to suspended activity, movement, and sensory responses, and is redirected to restore and replenish proteins and their assemblies into cellular structures. During wakefulness, various energy-demanding activities lead to hunger. Thus, hunger promotes arousal, and subsequent feeding, followed by satiety that promotes sleep via changes in neuroendocrine or neuropeptide signals. These signals overlap with circuits of sleep-wakefulness, feeding, and energy expenditure. Here, we will briefly review the literature that describes the interplay between the circadian system, sleep-wake, and feeding-fasting cycles that are needed to maintain energy balance and a healthy metabolic profile. In doing so, we describe the neuroendocrine, hormonal/peptide signals that integrate sleep and feeding behavior with energy metabolism. Keywords: sleep, energy balance, hypothalamus, metabolism, homeostasis

  8. Nuclear magnetic resonance studies of metabolic regulation

    International Nuclear Information System (INIS)

    Sillerud, L.O.; Han, C.H.; Whaley, T.W.

    1983-01-01

    Nuclear magnetic resonance (NMR) techniques for the detection of the metabolic transformations of biological compounds labeled with stable isotopes, particularly carbon-13 have been explored. We have studied adipose tissue in the intact rat, the exteriorized epididymal fat pad, and the isolated adipocyte. Triacylglycerol metabolism in adipose tissue is regulated by lipogenic factors (insulin, corticosterone, thyroxine, and growth hormone) and lipolytic factors (glucagon and catecholamines). The synthesis of triglyceride from 5.5 mM glucose was stimulated by about 4-fold by 10 nM insulin. Triglyceride synthesis from glucose in the presence of insulin occurred at a rate of 330 nmol/hr/10 6 cells. Since the NMR signals from free and esterified fatty acids and glycerol are distinct, we could directly measure the rate of hormone-stimulated lipolysis. Epinephrine (10 μM) gave a lipolytic rate of 0.30 μmol/hr/10 6 cells as monitored by free-glycerol appearance in the medium. 13 C NMR provides a superior method for the measurement of triglyceride metabolism since it directly measures the changes in the substrates and products in situ

  9. Global approaches to regulating electronic cigarettes

    Science.gov (United States)

    Kennedy, Ryan David; Awopegba, Ayodeji; De León, Elaine; Cohen, Joanna E

    2017-01-01

    Objectives Classify and describe the policy approaches used by countries to regulate e-cigarettes. Methods National policies regulating e-cigarettes were identified by (1) conducting web searches on Ministry of Health websites, and (2) broad web searches. The mechanisms used to regulate e-cigarettes were classified as new/amended laws, or existing laws. The policy domains identified include restrictions or prohibitions on product: sale, manufacturing, importation, distribution, use, product design including e-liquid ingredients, advertising/promotion/sponsorship, trademarks, and regulation requiring: taxation, health warning labels and child-safety standards. The classification of the policy was reviewed by a country expert. Results The search identified 68 countries that regulate e-cigarettes: 22 countries regulate e-cigarettes using existing regulations; 25 countries enacted new policies to regulate e-cigarettes; 7 countries made amendments to existing legislation; 14 countries use a combination of new/amended and existing regulation. Common policies include a minimum-age-of-purchase, indoor-use (vape-free public places) bans and marketing restrictions. Few countries are applying a tax to e-cigarettes. Conclusions A range of regulatory approaches are being applied to e-cigarettes globally; many countries regulate e-cigarettes using legislation not written for e-cigarettes. PMID:27903958

  10. Interactions between host metabolism, immune regulation, and the gut microbiota in diet-associated obesity and metabolic dysfunction

    DEFF Research Database (Denmark)

    Andersen, Daniel

    The increase in the prevalence of obesity and obesity-associated complications such as the metabolic syndrome is becoming a global challenge. Dietary habits and nutrient consumption modulates host homeostasis, which manifests in various diet-induced complications marked by changes in host...... metabolism and immune regulation, which are intricately linked. In addition, diet effectively shapes the gut microbiota composition and activity, which in turn interacts with the host to modulate host metabolism and immune regulation. In the three studies included in this PhD thesis, we have explored...... the impact of specific dietary components on host metabolic function, immune regulation and gut microbiota composition and activity. In the first study, we have characterized the effect of a combined high-fat and gliadin-rich diet, since dietary gliadin has been reported to be associated with intestinal...

  11. [Regulation of terpene metabolism]. Progress report

    International Nuclear Information System (INIS)

    Croteau, R.

    1986-01-01

    Studies on the regulation of monoterpene metabolism in M. piperita were conducted. All of the steps from the acyclic precursor geranyl pyrophosphate to the various menthol isomers have been demonstrated. The first intermediate to accumulate in vivo is d-pulegone. The emphasis has been on the demonstration, partial purification and characterization of the relevant enzymes in the pathway. The studies on the isopiperitenol dehydrogenase and isopiperitenone isomerase have been completed. We are not studying the endocyclic double-bond reductase (NADPH-dependent) and, based on substrate specificity studies and the previously demonstrated isomerization of cis- isopulegone to pulegone, are now virtually convinced that the major pathway to menthol(s) in peppermint involves reduction of isopiperitenone to isopulegone and isomerication of isopulegone to pulegone. 16 refs., 1 fig

  12. Ras signaling in aging and metabolic regulation.

    Science.gov (United States)

    Slack, Cathy

    2017-12-07

    Aberrant signal transduction downstream of the Ras GTPase has a well-established role in tumorigenesis. Mutations that result in hyperactivation of Ras are responsible for a third of all human cancers. Hence, small molecule inhibitors of the Ras signal transduction cascade have been under intense focus as potential cancer treatments. In both invertebrate and mammalian models, emerging evidence has also implicated components of the Ras signaling pathway in aging and metabolic regulation. Here, I review the current evidence for Ras signaling in these newly discovered roles highlighting the interactions between the Ras pathway and other longevity assurance mechanisms. Defining the role of Ras signaling in maintaining age-related health may have important implications for the development of interventions that could not only increase lifespan but also delay the onset and/or progression of age-related functional decline.

  13. Global network reorganization during dynamic adaptations of Bacillus subtilis metabolism

    DEFF Research Database (Denmark)

    Buescher, Joerg Martin; Liebermeister, Wolfram; Jules, Matthieu

    2012-01-01

    Adaptation of cells to environmental changes requires dynamic interactions between metabolic and regulatory networks, but studies typically address only one or a few layers of regulation. For nutritional shifts between two preferred carbon sources of Bacillus subtilis, we combined statistical...

  14. Uncovering transcriptional regulation of metabolism by using metabolic network topology

    DEFF Research Database (Denmark)

    Patil, Kiran Raosaheb; Nielsen, Jens

    2005-01-01

    in the metabolic network that follow a common transcriptional response. Thus, the algorithm enables identification of so-called reporter metabolites (metabolites around which the most significant transcriptional changes occur) and a set of connected genes with significant and coordinated response to genetic......Cellular response to genetic and environmental perturbations is often reflected and/or mediated through changes in the metabolism, because the latter plays a key role in providing Gibbs free energy and precursors for biosynthesis. Such metabolic changes are often exerted through transcriptional...... therefore developed an algorithm that is based on hypothesis-driven data analysis to uncover the transcriptional regulatory architecture of metabolic networks. By using information on the metabolic network topology from genome-scale metabolic reconstruction, we show that it is possible to reveal patterns...

  15. Metabolic fuels: regulating fluxes to select mix.

    Science.gov (United States)

    Weber, Jean-Michel

    2011-01-15

    Animals must regulate the fluxes of multiple fuels to support changing metabolic rates that result from variation in physiological circumstances. The aim of fuel selection strategies is to exploit the advantages of individual substrates while minimizing the impact of disadvantages. All exercising mammals share a general pattern of fuel selection: at the same %V(O(2,max)) they oxidize the same ratio of lipids to carbohydrates. However, highly aerobic species rely more on intramuscular fuels because energy supply from the circulation is constrained by trans-sarcolemmal transfer. Fuel selection is performed by recruiting different muscles, different fibers within the same muscles or different pathways within the same fibers. Electromyographic analyses show that shivering humans can modulate carbohydrate oxidation either through the selective recruitment of type II fibers within the same muscles or by regulating pathway recruitment within type I fibers. The selection patterns of shivering and exercise are different: at the same %V(O(2,max)), a muscle producing only heat (shivering) or significant movement (exercise) strikes a different balance between lipid and carbohydrate oxidation. Long-distance migrants provide an excellent model to characterize how to increase maximal substrate fluxes. High lipid fluxes are achieved through the coordinated upregulation of mobilization, transport and oxidation by activating enzymes, lipid-solubilizing proteins and membrane transporters. These endurance athletes support record lipolytic rates in adipocytes, use lipoprotein shuttles to accelerate transport and show increased capacity for lipid oxidation in muscle mitochondria. Some migrant birds use dietary omega-3 fatty acids as performance-enhancing agents to boost their ability to process lipids. These dietary fatty acids become incorporated in membrane phospholipids and bind to peroxisome proliferator-activated receptors to activate membrane proteins and modify gene expression.

  16. Arbitrage and Competition in Global Financial Regulation

    DEFF Research Database (Denmark)

    Ringe, Wolf-Georg

    Regulatory arbitrage in financial markets refers to a number of strategies that market participants use to avoid the reach of regulation, in particular by virtue of shifting trading abroad or else relocating activities or operations of financial institutions to other jurisdictions. Where...... institutions’ excessive risk-taking. If such risk-taking would be judged by market discipline instead of posing a risk to global financial stability, the main downside of regulatory competition could be restrained. Within the boundaries of such a system, competition could then operate and contribute...... their standards solely to attract businesses and thereby impose externalities on the worldwide financial market by undermining financial stability as a global public good. Policymakers worldwide are experimenting with remedies to respond to the phenomenon. I introduce the importance of an effective special...

  17. Chokepoints global private regulation on the Internet

    CERN Document Server

    Tusikov, Natasha

    2016-01-01

    In January 2012, millions participated in the now-infamous "Internet blackout" against the Stop Online Piracy Act, protesting the power it would have given intellectual property holders over the Internet. However, while SOPA's withdrawal was heralded as a victory for an open Internet, a small group of corporations, tacitly backed by the US and other governments, have implemented much of SOPA via a series of secret, handshake agreements. Drawing on extensive interviews, Natasha Tusikov details the emergence of a global regime in which large Internet firms act as regulators for powerful intellec

  18. Deletion of the Mitochondrial Chaperone TRAP-1 Uncovers Global Reprogramming of Metabolic Networks

    Directory of Open Access Journals (Sweden)

    Sofia Lisanti

    2014-08-01

    Full Text Available Reprogramming of metabolic pathways contributes to human disease, especially cancer, but the regulators of this process are unknown. Here, we have generated a mouse knockout for the mitochondrial chaperone TRAP-1, a regulator of bioenergetics in tumors. TRAP-1−/− mice are viable and showed reduced incidence of age-associated pathologies, including obesity, inflammatory tissue degeneration, dysplasia, and spontaneous tumor formation. This was accompanied by global upregulation of oxidative phosphorylation and glycolysis transcriptomes, causing deregulated mitochondrial respiration, oxidative stress, impaired cell proliferation, and a switch to glycolytic metabolism in vivo. These data identify TRAP-1 as a central regulator of mitochondrial bioenergetics, and this pathway could contribute to metabolic rewiring in tumors.

  19. Metabolic-flux dependent regulation of microbial physiology.

    Science.gov (United States)

    Litsios, Athanasios; Ortega, Álvaro D; Wit, Ernst C; Heinemann, Matthias

    2018-04-01

    According to the most prevalent notion, changes in cellular physiology primarily occur in response to altered environmental conditions. Yet, recent studies have shown that changes in metabolic fluxes can also trigger phenotypic changes even when environmental conditions are unchanged. This suggests that cells have mechanisms in place to assess the magnitude of metabolic fluxes, that is, the rate of metabolic reactions, and use this information to regulate their physiology. In this review, we describe recent evidence for metabolic flux-sensing and flux-dependent regulation. Furthermore, we discuss how such sensing and regulation can be mechanistically achieved and present a set of new candidates for flux-signaling metabolites. Similar to metabolic-flux sensing, we argue that cells can also sense protein translation flux. Finally, we elaborate on the advantages that flux-based regulation can confer to cells. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Metabolic rate regulates L1 longevity in C. elegans.

    Directory of Open Access Journals (Sweden)

    Inhwan Lee

    Full Text Available Animals have to cope with starvation. The molecular mechanisms by which animals survive long-term starvation, however, are not clearly understood. When they hatch without food, C. elegans arrests development at the first larval stage (L1 and survives more than two weeks. Here we show that the survival span of arrested L1s, which we call L1 longevity, is a starvation response regulated by metabolic rate during starvation. A high rate of metabolism shortens the L1 survival span, whereas a low rate of metabolism lengthens it. The longer worms are starved, the slower they grow once they are fed, suggesting that L1 arrest has metabolic costs. Furthermore, mutants of genes that regulate metabolism show altered L1 longevity. Among them, we found that AMP-dependent protein kinase (AMPK, as a key energy sensor, regulates L1 longevity by regulating this metabolic arrest. Our results suggest that L1 longevity is determined by metabolic rate and that AMPK as a master regulator of metabolism controls this arrest so that the animals survive long-term starvation.

  1. Regulation of terpene metabolism. Progress report, 1983

    International Nuclear Information System (INIS)

    Croteau, R.

    1986-01-01

    Studies on the metabolism of terpenes by peppermint (Menta piperita) are described. The studies describe the characterization of enzymes involved in the biosynthesis and catabolism of terpenes and the ultrastructure of the oil glands. 10 refs. (DT)

  2. [Regulation of terpene metabolism]. [Mentha piperita, Mentha spicata

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1989-01-01

    Progress in understanding of the metabolism of monoterpenes by peppermint and spearmint is recorded including the actions of two key enzymes, geranyl pyrophosphate:limonene cyclase and a UDP-glucose dependent glucosyl transferase; concerning the ultrastructure of oil gland senescence; enzyme subcellular localization; regulation of metabolism; and tissue culture systems.

  3. Regulation of Specialized Metabolism by WRKY Transcription Factors

    Science.gov (United States)

    Schluttenhofer, Craig; Yuan, Ling

    2015-01-01

    WRKY transcription factors (TFs) are well known for regulating plant abiotic and biotic stress tolerance. However, much less is known about how WRKY TFs affect plant-specialized metabolism. Analysis of WRKY TFs regulating the production of specialized metabolites emphasizes the values of the family outside of traditionally accepted roles in stress tolerance. WRKYs with conserved roles across plant species seem to be essential in regulating specialized metabolism. Overall, the WRKY family plays an essential role in regulating the biosynthesis of important pharmaceutical, aromatherapy, biofuel, and industrial components, warranting considerable attention in the forthcoming years. PMID:25501946

  4. Integration of Genome Scale Metabolic Networks and Gene Regulation of Metabolic Enzymes With Physiologically Based Pharmacokinetics.

    Science.gov (United States)

    Maldonado, Elaina M; Leoncikas, Vytautas; Fisher, Ciarán P; Moore, J Bernadette; Plant, Nick J; Kierzek, Andrzej M

    2017-11-01

    The scope of physiologically based pharmacokinetic (PBPK) modeling can be expanded by assimilation of the mechanistic models of intracellular processes from systems biology field. The genome scale metabolic networks (GSMNs) represent a whole set of metabolic enzymes expressed in human tissues. Dynamic models of the gene regulation of key drug metabolism enzymes are available. Here, we introduce GSMNs and review ongoing work on integration of PBPK, GSMNs, and metabolic gene regulation. We demonstrate example models. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  5. Fat metabolism during exercise: mechanisms of regulation

    Directory of Open Access Journals (Sweden)

    Monique da Silva Gevaerd

    2006-12-01

    Full Text Available Fats are important energetic fuel to exercise. However, the regulation of fat uptake during exercise is unclear. The main objective of this review was to focus on physiological control mechanisms of mobilization, transport and fat uptake during exercise. The articles of fat metabolism were searched in Pubmed and Lilacs indexes. Classical and current papers were preferred. Evidence suggests that transport of fatty acids (FA from extracellular to intracellular spaces could be the main factor to limit fatty acid uptake. Future studies on fat uptake during exercise can focus on this mechanism. In intense exercise, the lower blood fl ow in the adipose tissue and higher fatty acid reesterifi cation rate impairs fat uptake during exercise. Supplementation of the FA has been used, however, the ideal quantities and forms to prevent gastrointestinal discomfort were not yet determined. In the biological point of view, intramuscular reserve of FA could be more effi cient, because is not necessary to FA to cross the cell membrane. RESUMO Os lipídios são considerados importantes fontes energéticas para a realização de exercícios físicos. Entretanto, os mecanismos de regulação do consumo desse substrato durante o exercício não estão totalmente esclarecidos. O objetivo principal da presente revisão foi abordar mecanismos fisiológicos de controle da mobilização, transporte e utilização de gordura durante o exercício. Os trabalhos indexados no banco de dados Pubmed e Lilacs sobre metabolismo de gordura, foram analisados e os clássicos e recentes foram preferencialmente utilizados. A partir dos dados recentes da literatura, especula-se que o transporte de ácidos graxos do meio extracelular para o meio intracelular pode constituir um dos principais mecanismos limitantes no consumo desse substrato. Estudos sobre o consumo de lipídios durante o exercício devem ser focados sobre esse mecanismo. Em exercício intenso, o menor fl uxo de sangue

  6. Temporal dynamics and regulation of lake metabolism

    DEFF Research Database (Denmark)

    Stæhr, Peter Anton; Jensen, Kaj Sand

    2007-01-01

    and minima from fall to spring after broad-scale changes in irradiance, temperature, mixing depth, and biomass and growth rate of the algal community and concentrations of inorganic nutrients. Lake metabolism was annually balanced (mean GPP :R 1.04 in 2003 and 1.01 in 2004), with net autotrophy occurring...

  7. The Lin28/let-7 Axis Regulates Glucose Metabolism

    NARCIS (Netherlands)

    Zhu, Hao; Shyh-Chang, Ng; Segre, Ayellet V.; Shinoda, Gen; Shah, Samar P.; Einhorn, William S.; Takeuchi, Ayumu; Engreitz, Jesse M.; Hagan, John P.; Kharas, Michael G.; Urbach, Achia; Thornton, James E.; Triboulet, Robinson; Gregory, Richard I.; Altshuler, David; Daley, George Q.

    2011-01-01

    The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating-metabolism. When overexpressed in mice, both

  8. Ornithine: the overlooked molecule in the regulation of polyamine metabolism

    Science.gov (United States)

    Rajtilak Majumdar; Lin Shao; Rakesh Minocha; Stephanie Long; Subhash C. Minocha

    2013-01-01

    We overexpressed a mouse ornithine decarboxylase gene under the control of a constitutive and an estradiol-inducible promoter in Arabidopsis thaliana to increase our understanding of the regulation of polyamine metabolism. Of particular interest was the role of the substrate ornithine not only in the regulation of polyamine biosynthesis, but also in...

  9. Cancer metabolism meets systems biology: Pyruvate kinase isoform PKM2 is a metabolic master regulator

    OpenAIRE

    Fabian V Filipp

    2013-01-01

    Pyruvate kinase activity is controlled by a tightly woven regulatory network. The oncofetal isoform of pyruvate kinase (PKM2) is a master regulator of cancer metabolism. PKM2 engages in parallel, feed-forward, positive and negative feedback control contributing to cancer progression. Besides its metabolic role, non-metabolic functions of PKM2 as protein kinase and transcriptional coactivator for c-MYC and hypoxia-inducible factor 1-alpha are essential for epidermal growth factor receptor acti...

  10. Metabolic Regulation of Methionine Restriction in Diabetes.

    Science.gov (United States)

    Yin, Jie; Ren, Wenkai; Chen, Shuai; Li, Yuying; Han, Hui; Gao, Jing; Liu, Gang; Wu, Xin; Li, Tiejun; Kim, Sung Woo; Yin, Yulong

    2018-03-30

    Although the effects of dietary methionine restriction have been investigated in the physiology of aging and diseases related to oxidative stress, the relationship between methionine restriction and the development of metabolic disorders has not been explored extensively. This review summarizes studies of the possible involvement of dietary methionine restriction in improving insulin resistance, glucose homeostasis, oxidative stress, lipid metabolism, the pentose phosphate pathway, and inflammation, with an emphasis on the fibroblast growth factor 21 and protein phosphatase 2A signals and autophagy in diabetes. Diets deficient in methionine may be a useful nutritional strategy in patients with diabetes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  11. Regulation of uric acid metabolism and excretion.

    Science.gov (United States)

    Maiuolo, Jessica; Oppedisano, Francesca; Gratteri, Santo; Muscoli, Carolina; Mollace, Vincenzo

    2016-06-15

    Purines perform many important functions in the cell, being the formation of the monomeric precursors of nucleic acids DNA and RNA the most relevant one. Purines which also contribute to modulate energy metabolism and signal transduction, are structural components of some coenzymes and have been shown to play important roles in the physiology of platelets, muscles and neurotransmission. All cells require a balanced quantity of purines for growth, proliferation and survival. Under physiological conditions the enzymes involved in the purine metabolism maintain in the cell a balanced ratio between their synthesis and degradation. In humans the final compound of purines catabolism is uric acid. All other mammals possess the enzyme uricase that converts uric acid to allantoin that is easily eliminated through urine. Overproduction of uric acid, generated from the metabolism of purines, has been proven to play emerging roles in human disease. In fact the increase of serum uric acid is inversely associated with disease severity and especially with cardiovascular disease states. This review describes the enzymatic pathways involved in the degradation of purines, getting into their structure and biochemistry until the uric acid formation. Copyright © 2015. Published by Elsevier Ireland Ltd.

  12. Regulation of flux through metabolic cycles

    International Nuclear Information System (INIS)

    Walsh, K.

    1984-01-01

    The branchpoint of the tricarboxylic acid and glyoxylate shunt was characterized in the intact organism by a multidimensional approach. Theory and methodology were developed to determine velocities for the net flow of carbon through the major steps of acetate metabolism in E. coli. Rates were assigned based on the 13 C-NMR spectrum of intracellular glutamate, measured rates of substrate incorporation into end products, the constituent composition of E. coli and a series of conservation equations which described the system at steady state. The in vivo fluxes through the branchpoint of the tricarboxylic acid and glyoxylate cycles were compared to rates calculated from the kinetic constants of the branchpoint enzymes and the intracellular concentrations of their substrates. These studies elucidated the role of isocitrate dehydrogenase phosphorylation in the Krebs cycle and led to the development of a generalized mathematical description of the sensitivity of branchpoints to regulatory control. This theoretical analysis was termed the branchpoint effect and it describes conditions which result in large changes in the flux through an enzyme even though that enzyme is not subject to direct regulatory control. The theoretical and experimental characterization of this system provided a framework to study the effects of enzyme overproduction and underproduction on metabolic processes in the cell. An in vivo method was developed to determine the extent to which an enzyme catalyzes a rate-controlling reaction. The enzyme chosen for this study was citrate synthase

  13. Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome

    DEFF Research Database (Denmark)

    Liaset, Bjørn; Hao, Qin; Jørgensen, Henry Johs. Høgh

    2011-01-01

    Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by e...... metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome.......Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated...... with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1a, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited...

  14. Overfeeding, autonomic regulation and metabolic consequences.

    NARCIS (Netherlands)

    Scheurink, A.J.W.; Balkan, B; Strubbe, J.H.; van Dijk, G.; Steffens, A.B

    The autonomic nervous system plays an important role in the regulation of body processes in health and disease. Overfeeding and obesity (a disproportional increase of the fat mass of the body) are often accompanied by alterations in both sympathetic and parasympathetic autonomic functions. The

  15. Central nervous system regulation of intestinal lipid and lipoprotein metabolism.

    Science.gov (United States)

    Farr, Sarah; Taher, Jennifer; Adeli, Khosrow

    2016-02-01

    In response to nutrient availability, the small intestine and brain closely communicate to modulate energy homeostasis and metabolism. The gut-brain axis involves complex nutrient sensing mechanisms and an integration of neuronal and hormonal signaling. This review summarizes recent evidence implicating the gut-brain axis in regulating lipoprotein metabolism, with potential implications for the dyslipidemia of insulin resistant states. The intestine and brain possess distinct mechanisms for sensing lipid availability, which triggers subsequent regulation of feeding, glucose homeostasis, and adipose tissue metabolism. More recently, central receptors, neuropeptides, and gut hormones that communicate with the brain have been shown to modulate hepatic and intestinal lipoprotein metabolism via parasympathetic and sympathetic signaling. Gut-derived glucagon-like peptides appear to be particularly important in modulating the intestinal secretion of chylomicron particles via a novel brain-gut axis. Dysregulation of these pathways may contribute to postprandial diabetic dyslipidemia. Emerging evidence implicates the central and enteric nervous systems in controlling many aspects of lipid and lipoprotein metabolism. Bidirectional communication between the gut and brain involving neuronal pathways and gut peptides is critical for regulating feeding and metabolism, and forms a neuroendocrine circuit to modulate dietary fat absorption and intestinal production of atherogenic chylomicron particles.

  16. Dissecting specific and global transcriptional regulation of bacterial gene expression

    NARCIS (Netherlands)

    Gerosa, Luca; Kochanowski, Karl; Heinemann, Matthias; Sauer, Uwe

    Gene expression is regulated by specific transcriptional circuits but also by the global expression machinery as a function of growth. Simultaneous specific and global regulation thus constitutes an additional-but often neglected-layer of complexity in gene expression. Here, we develop an

  17. Sirtuins as regulators of the yeast metabolic network

    Directory of Open Access Journals (Sweden)

    Markus eRalser

    2012-03-01

    Full Text Available There is growing evidence that the metabolic network is an integral regulator of cellularphysiology. Dynamic changes in metabolite concentrations, metabolic flux, or networktopology act as reporters of biological or environmental signals, and are required for the cellto trigger an appropriate biological reaction. Changes in the metabolic network are recognizedby specific sensory macromolecules and translated into a transcriptional or translationalresponse. The protein family of sirtuins, discovered more than 30 years ago as regulators ofsilent chromatin, seems to fulfill the role of a metabolic sensor during aging and conditions ofcaloric restriction. NAD+/NADH interconverting metabolic enzymes glyceraldehyde-3-phosphate dehydrogenase and alcohol dehydrogenase, as well as enzymes involved inNAD(H, synthesis provide or deprive NAD+ in close proximity to Sir2. This influence sirtuinactivity, and facilitates a dynamic response of the metabolic network to changes inmetabolism with effects on physiology and aging. The molecular network downstream Sir2,however, is complex. In just two orders, Sir2’s metabolism-related interactions span half ofthe yeast proteome, and are connected with virtually every physiological process. Thus,although it is fundamental to analyze single molecular mechanisms, it is at the same timecrucial to consider this genome-scale complexity when correlating single molecular eventswith phenotypes such as aging, cell growth, or stress resistance.

  18. [Regulation of terpene metabolism.] Progress report

    International Nuclear Information System (INIS)

    Croteau, R.

    1984-01-01

    This research program represents a very broad-based approach to understanding the biochemistry of the monoterpene and sesquiterpene constituents of the essential oils. This program includes basic research on the pathways, enzymes and mechanisms of terpene biosynthesis and catabolism, on the physiology of essential oil production, and on the morphology and development of oil glands, as well as practical approaches to manipulating essential oil composition and yield. As a natural extension of research on monoterpene biosynthesis and catabolism in sage and peppermint we have explored some aspects of possible regulatory mechanisms. Tentative evidence has been obtained for developmental regulation of the levels of biosynthetic and catabolic enzymes. 10 refs., 8 figs

  19. Redox regulation in metabolic programming and inflammation.

    Science.gov (United States)

    Griffiths, Helen R; Gao, Dan; Pararasa, Chathyan

    2017-08-01

    Energy metabolism and redox state are intrinsically linked. In order to mount an adequate immune response, cells must have an adequate and rapidly available energy resource to migrate to the inflammatory site, to generate reactive oxygen species using NADPH as a cofactor and to engulf bacteria or damaged tissue. The first responder cells of the innate immune response, neutrophils, are largely dependent on glycolysis. Neutrophils are relatively short-lived, dying via apoptosis in the process of bacterial killing through production of hypochlorous acid and release of extracellular NETs. Later on, the most prevalent recruited innate immune cells are monocytes. Their role is to complete a damage limitation exercise initiated by neutrophils and then, as re-programmed M2 macrophages, to resolve the inflammatory event. Almost twenty five years ago, it was noted that macrophages lose their glycolytic capacity and become anti-inflammatory after treatment with corticosteroids. In support of this we now understand that, in contrast to early responders, M2 macrophages are predominantly dependent on oxidative phosphorylation for energy. During early inflammation, polarisation towards M1 macrophages is dependent on NOX2 activation which, via protein tyrosine phosphatase oxidation and AKT activation, increases trafficking of glucose transporters to the membrane and consequently increases glucose uptake for glycolysis. In parallel, mitochondrial efficiency is likely to be compromised via nitrosylation of the electron transport chain. Resolution of inflammation is triggered by encounter with apoptotic membranes exposing oxidised phosphatidylserine that interact with the scavenger receptor, CD36. Downstream of CD36, activation of AMPK and PPARγ elicits mitochondrial biogenesis, arginase expression and a switch towards oxidative phosphorylation in the M2 macrophage. Proinflammatory cytokine production by M2 cells decreases, but anti-inflammatory and wound healing growth factor

  20. TXNIP regulates peripheral glucose metabolism in humans

    DEFF Research Database (Denmark)

    Parikh, Hemang; Carlsson, Emma; Chutkow, William A

    2007-01-01

    combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated...... expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. CONCLUSIONS: TXNIP regulates both insulin-dependent and insulin......-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic beta-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM....

  1. Global approaches to regulating electronic cigarettes

    OpenAIRE

    Kennedy, Ryan David; Awopegba, Ayodeji; De Le?n, Elaine; Cohen, Joanna E

    2016-01-01

    Objectives Classify and describe the policy approaches used by countries to regulate e-cigarettes. Methods National policies regulating e-cigarettes were identified by (1) conducting web searches on Ministry of Health websites, and (2) broad web searches. The mechanisms used to regulate e-cigarettes were classified as new/amended laws, or existing laws. The policy domains identified include restrictions or prohibitions on product: sale, manufacturing, importation, distribution, use, product d...

  2. Insulin Action in Brain Regulates Systemic Metabolism and Brain Function

    OpenAIRE

    Kleinridders, Andr?; Ferris, Heather A.; Cai, Weikang; Kahn, C. Ronald

    2014-01-01

    Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain. Insulin acts on these receptors to modulate peripheral metabolism, including regulation of appetite, reproductive function, body temperature, white fat mass, hepatic glucose output, and response to hypoglycemia. Insulin signaling also modulates neurotransmitter channel activity, brain cholesterol synthesis, and mitochondrial function. Disruption of insulin action in t...

  3. APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons

    Directory of Open Access Journals (Sweden)

    Steven Moore

    2015-05-01

    Full Text Available Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD. To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons.

  4. Prolyl hydroxylase domain enzymes: important regulators of cancer metabolism

    Directory of Open Access Journals (Sweden)

    Yang M

    2014-08-01

    Full Text Available Ming Yang,1 Huizhong Su,1 Tomoyoshi Soga,2 Kamil R Kranc,3 Patrick J Pollard1 1Cancer Biology and Metabolism Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; 2Institute for Advanced Biosciences, Keio University, Mizukami, Tsuruoka, Yamagata, Japan; 3MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK Abstract: The hypoxia-inducible factor (HIF prolyl hydroxylase domain enzymes (PHDs regulate the stability of HIF protein by post-translational hydroxylation of two conserved prolyl residues in its α subunit in an oxygen-dependent manner. Trans-4-prolyl hydroxylation of HIFα under normal oxygen (O2 availability enables its association with the von Hippel-Lindau (VHL tumor suppressor pVHL E3 ligase complex, leading to the degradation of HIFα via the ubiquitin-proteasome pathway. Due to the obligatory requirement of molecular O2 as a co-substrate, the activity of PHDs is inhibited under hypoxic conditions, resulting in stabilized HIFα, which dimerizes with HIFβ and, together with transcriptional co-activators CBP/p300, activates the transcription of its target genes. As a key molecular regulator of adaptive response to hypoxia, HIF plays important roles in multiple cellular processes and its overexpression has been detected in various cancers. The HIF1α isoform in particular has a strong impact on cellular metabolism, most notably by promoting anaerobic, whilst inhibiting O2-dependent, metabolism of glucose. The PHD enzymes also seem to have HIF-independent functions and are subject to regulation by factors other than O2, such as by metabolic status, oxidative stress, and abnormal levels of endogenous metabolites (oncometabolites that have been observed in some types of cancers. In this review, we aim to summarize current understandings of the function and regulation of PHDs in cancer with an emphasis on their roles in metabolism. Keywords: prolyl hydroxylase domain (PHD

  5. Citrus Flavonoids as Regulators of Lipoprotein Metabolism and Atherosclerosis.

    Science.gov (United States)

    Mulvihill, Erin E; Burke, Amy C; Huff, Murray W

    2016-07-17

    Citrus flavonoids are polyphenolic compounds with significant biological properties. This review summarizes recent advances in understanding the ability of citrus flavonoids to modulate lipid metabolism, other metabolic parameters related to the metabolic syndrome, and atherosclerosis. Citrus flavonoids, including naringenin, hesperitin, nobiletin, and tangeretin, have emerged as potential therapeutics for the treatment of metabolic dysregulation. Epidemiological studies reveal an association between the intake of citrus flavonoid-containing foods and a decreased incidence of cardiovascular disease. Studies in cell culture and animal models, as well as a limited number of clinical studies, reveal the lipid-lowering, insulin-sensitizing, antihypertensive, and anti-inflammatory properties of citrus flavonoids. In animal models, supplementation of rodent diets with citrus flavonoids prevents hepatic steatosis, dyslipidemia, and insulin resistance primarily through inhibition of hepatic fatty acid synthesis and increased fatty acid oxidation. Citrus flavonoids blunt the inflammatory response in metabolically important tissues including liver, adipose, kidney, and the aorta. The mechanisms underlying flavonoid-induced metabolic regulation have not been completely established, although several potential targets have been identified. In mouse models, citrus flavonoids show marked suppression of atherogenesis through improved metabolic parameters as well as through direct impact on the vessel wall. Recent studies support a role for citrus flavonoids in the treatment of dyslipidemia, insulin resistance, hepatic steatosis, obesity, and atherosclerosis. Larger human studies examining dose, bioavailability, efficacy, and safety are required to promote the development of these promising therapeutic agents.

  6. Identification of metabolic system parameters using global optimization methods

    Directory of Open Access Journals (Sweden)

    Gatzke Edward P

    2006-01-01

    Full Text Available Abstract Background The problem of estimating the parameters of dynamic models of complex biological systems from time series data is becoming increasingly important. Methods and results Particular consideration is given to metabolic systems that are formulated as Generalized Mass Action (GMA models. The estimation problem is posed as a global optimization task, for which novel techniques can be applied to determine the best set of parameter values given the measured responses of the biological system. The challenge is that this task is nonconvex. Nonetheless, deterministic optimization techniques can be used to find a global solution that best reconciles the model parameters and measurements. Specifically, the paper employs branch-and-bound principles to identify the best set of model parameters from observed time course data and illustrates this method with an existing model of the fermentation pathway in Saccharomyces cerevisiae. This is a relatively simple yet representative system with five dependent states and a total of 19 unknown parameters of which the values are to be determined. Conclusion The efficacy of the branch-and-reduce algorithm is illustrated by the S. cerevisiae example. The method described in this paper is likely to be widely applicable in the dynamic modeling of metabolic networks.

  7. Regulation of Ketone Body Metabolism and the Role of PPARα

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    Maja Grabacka

    2016-12-01

    Full Text Available Ketogenesis and ketolysis are central metabolic processes activated during the response to fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor α (PPARα is one of the key transcription factors taking part in this regulation. PPARα is an important element in the metabolic network, where it participates in signaling driven by the main nutrient sensors, such as AMP-activated protein kinase (AMPK, PPARγ coactivator 1α (PGC-1α, and mammalian (mechanistic target of rapamycin (mTOR and induces hormonal mediators, such as fibroblast growth factor 21 (FGF21. This work describes the regulation of ketogenesis and ketolysis in normal and malignant cells and briefly summarizes the positive effects of ketone bodies in various neuropathologic conditions.

  8. Volatile profiling reveals intracellular metabolic changes in Aspergillus parasiticus: veA regulates branched chain amino acid and ethanol metabolism

    Directory of Open Access Journals (Sweden)

    Roze Ludmila V

    2010-08-01

    Full Text Available Abstract Background Filamentous fungi in the genus Aspergillus produce a variety of natural products, including aflatoxin, the most potent naturally occurring carcinogen known. Aflatoxin biosynthesis, one of the most highly characterized secondary metabolic pathways, offers a model system to study secondary metabolism in eukaryotes. To control or customize biosynthesis of natural products we must understand how secondary metabolism integrates into the overall cellular metabolic network. By applying a metabolomics approach we analyzed volatile compounds synthesized by Aspergillus parasiticus in an attempt to define the association of secondary metabolism with other metabolic and cellular processes. Results Volatile compounds were examined using solid phase microextraction - gas chromatography/mass spectrometry. In the wild type strain Aspergillus parasiticus SU-1, the largest group of volatiles included compounds derived from catabolism of branched chain amino acids (leucine, isoleucine, and valine; we also identified alcohols, esters, aldehydes, and lipid-derived volatiles. The number and quantity of the volatiles produced depended on media composition, time of incubation, and light-dark status. A block in aflatoxin biosynthesis or disruption of the global regulator veA affected the volatile profile. In addition to its multiple functions in secondary metabolism and development, VeA negatively regulated catabolism of branched chain amino acids and synthesis of ethanol at the transcriptional level thus playing a role in controlling carbon flow within the cell. Finally, we demonstrated that volatiles generated by a veA disruption mutant are part of the complex regulatory machinery that mediates the effects of VeA on asexual conidiation and sclerotia formation. Conclusions 1 Volatile profiling provides a rapid, effective, and powerful approach to identify changes in intracellular metabolic networks in filamentous fungi. 2 VeA coordinates the

  9. Obestatin as a regulator of adipocyte metabolism and adipogenesis

    Science.gov (United States)

    Gurriarán-Rodríguez, Uxía; Al-Massadi, Omar; Roca-Rivada, Arturo; Crujeiras, Ana Belén; Gallego, Rosalía; Pardo, Maria; Seoane, Luisa Maria; Pazos, Yolanda; Casanueva, Felipe F; Camiña, Jesús P

    2011-01-01

    Abstract The role of obestatin, a 23-amino-acid peptide encoded by the ghrelin gene, on the control of the metabolism of pre-adipocyte and adipocytes as well as on adipogenesis was determined. For in vitro assays, pre-adipocyte and adipocyte 3T3-L1 cells were used to assess the obestatin effect on cell metabolism and adipogenesis based on the regulation of the key enzymatic nodes, Akt and AMPK and their downstream targets. For in vivo assays, white adipose tissue (WAT) was obtained from male rats under continuous subcutaneous infusion of obestatin. Obestatin activated Akt and its downstream targets, GSK3α/β, mTOR and S6K1, in 3T3-L1 adipocyte cells. Simultaneously, obestatin inactivated AMPK in this cell model. In keeping with this, ACC phosphorylation was also decreased. This fact was confirmed in vivo in white adipose tissue (omental, subcutaneous and gonadal) obtained from male rats under continuous sc infusion of obestatin (24 and 72 hrs). The relevance of obestatin as regulator of adipocyte metabolism was supported by AS160 phosphorylation, GLUT4 translocation and augment of glucose uptake in 3T3-L1 adipocyte cells. In contrast, obestatin failed to modify translocation of fatty acid transporters, FATP1, FATP4 and FAT/CD36, to plasma membrane. Obestatin treatment in combination with IBMX and DEX showed to regulate the expression of C/EBPα, C/EBPβ, C/EBPδ and PPARγ promoting adipogenesis. Remarkable, preproghrelin expression, and thus obestatin expression, increased during adipogenesis being sustained throughout terminal differentiation. Neutralization of endogenous obestatin secreted by 3T3-L1 cells by anti-obestatin antibody decreased adipocyte differentiation. Furthermore, knockdown experiments by preproghrelin siRNA supported that obestatin contributes to adipogenesis. In summary, obestatin promotes adipogenesis in an autocrine/paracrine manner, being a regulator of adipocyte metabolism. These data point to a putative role in the pathogenesis of

  10. 75 FR 75904 - Global Terrorism Sanctions Regulations; Terrorism Sanctions Regulations; Foreign Terrorist...

    Science.gov (United States)

    2010-12-07

    ... Terrorism Sanctions Regulations; Terrorism Sanctions Regulations; Foreign Terrorist Organizations Sanctions... Foreign Assets Control (``OFAC'') of the U.S. Department of the Treasury is amending the Global Terrorism Sanctions Regulations (``GTSR'') and the Terrorism Sanctions Regulations (``TSR'') to expand the scope of...

  11. The Factor Inhibiting HIF Asparaginyl Hydroxylase Regulates Oxidative Metabolism and Accelerates Metabolic Adaptation to Hypoxia.

    Science.gov (United States)

    Sim, Jingwei; Cowburn, Andrew S; Palazon, Asis; Madhu, Basetti; Tyrakis, Petros A; Macías, David; Bargiela, David M; Pietsch, Sandra; Gralla, Michael; Evans, Colin E; Kittipassorn, Thaksaon; Chey, Yu C J; Branco, Cristina M; Rundqvist, Helene; Peet, Daniel J; Johnson, Randall S

    2018-04-03

    Animals require an immediate response to oxygen availability to allow rapid shifts between oxidative and glycolytic metabolism. These metabolic shifts are highly regulated by the HIF transcription factor. The factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that controls HIF transcriptional activity in an oxygen-dependent manner. We show here that FIH loss increases oxidative metabolism, while also increasing glycolytic capacity, and that this gives rise to an increase in oxygen consumption. We further show that the loss of FIH acts to accelerate the cellular metabolic response to hypoxia. Skeletal muscle expresses 50-fold higher levels of FIH than other tissues: we analyzed skeletal muscle FIH mutants and found a decreased metabolic efficiency, correlated with an increased oxidative rate and an increased rate of hypoxic response. We find that FIH, through its regulation of oxidation, acts in concert with the PHD/vHL pathway to accelerate HIF-mediated metabolic responses to hypoxia. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  12. Regulation of terpene metabolism. Final technical report, March 15, 1988--March 14, 1996

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1996-12-31

    This research focuses on the following topics: the biosynthesis and catabolism of monoterpenes; the organization of monoterpene metabolism; the developmental regulation of monoterpene metabolism; the flux control of precursor supply; and the integration of monoterpene and higher terpenoid metabolism.

  13. Integrated co-regulation of bacterial arsenic and phosphorus metabolisms.

    Science.gov (United States)

    Kang, Yoon-Suk; Heinemann, Joshua; Bothner, Brian; Rensing, Christopher; McDermott, Timothy R

    2012-12-01

    Arsenic ranks first on the US Environmental Protection Agency Superfund List of Hazardous Substances. Its mobility and toxicity depend upon chemical speciation, which is significantly driven by microbial redox transformations. Genome sequence-enabled surveys reveal that in many microorganisms genes essential to arsenite (AsIII) oxidation are located immediately adjacent to genes coding for functions associated with phosphorus (Pi) acquisition, implying some type of functional importance to the metabolism of As, Pi or both. We extensively document how expression of genes key to AsIII oxidation and the Pi stress response are intricately co-regulated in the soil bacterium Agrobacterium tumefaciens. These observations significantly expand our understanding of how environmental factors influence microbial AsIII metabolism and contribute to the current discussion of As and P metabolism in the microbial cell. © 2012 Society for Applied Microbiology and Blackwell Publishing Ltd.

  14. The role of gut microbiota in metabolic regulation

    Directory of Open Access Journals (Sweden)

    Ekaterina N. Kravchuk

    2016-09-01

    Full Text Available Obesity and metabolic syndrome are among the major problems of modern society. The increase in obesity is associated with a corresponding increase in type 2 diabetes, cardiovascular disease and cancer. A huge amount of scientific research has been devoted to the development of methods to reduce obesity and its complications. In recent years, attention has shifted towards studying the intestinal microbiota not only as a possible component of the pathological process but also as a target of therapeutic intervention. Recent evidence, primarily from investigations in animal models, suggests that the intestinal microbiota affects nutrient acquisition and energy regulation. This review will discuss the role of the intestinal microbiota in metabolic processes as well as the latest developments on the improvement of disturbances specific to obesity and metabolic syndrome.

  15. Global metabolic profiling procedures for urine using UPLC-MS.

    Science.gov (United States)

    Want, Elizabeth J; Wilson, Ian D; Gika, Helen; Theodoridis, Georgios; Plumb, Robert S; Shockcor, John; Holmes, Elaine; Nicholson, Jeremy K

    2010-06-01

    The production of 'global' metabolite profiles involves measuring low molecular-weight metabolites (sample preparation, stability/storage and the selection of chromatographic conditions that balance metabolome coverage, chromatographic resolution and throughput. We discuss quality control and metabolite identification, as well as provide details of multivariate data analysis approaches for analyzing such MS data. Using this protocol, the analysis of a sample set in 96-well plate format, would take ca. 30 h, including 1 h for system setup, 1-2 h for sample preparation, 24 h for UPLC-MS analysis and 1-2 h for initial data processing. The use of UPLC-MS for metabolic profiling in this way is not faster than the conventional HPLC-based methods but, because of improved chromatographic performance, provides superior metabolome coverage.

  16. Metabolic regulation of neuronal plasticity by the energy sensor AMPK.

    Directory of Open Access Journals (Sweden)

    Wyatt B Potter

    Full Text Available Long Term Potentiation (LTP is a leading candidate mechanism for learning and memory and is also thought to play a role in the progression of seizures to intractable epilepsy. Maintenance of LTP requires RNA transcription, protein translation and signaling through the mammalian Target of Rapamycin (mTOR pathway. In peripheral tissue, the energy sensor AMP-activated Protein Kinase (AMPK negatively regulates the mTOR cascade upon glycolytic inhibition and cellular energy stress. We recently demonstrated that the glycolytic inhibitor 2-deoxy-D-glucose (2DG alters plasticity to retard epileptogenesis in the kindling model of epilepsy. Reduced kindling progression was associated with increased recruitment of the nuclear metabolic sensor CtBP to NRSF at the BDNF promoter. Given that energy metabolism controls mTOR through AMPK in peripheral tissue and the role of mTOR in LTP in neurons, we asked whether energy metabolism and AMPK control LTP. Using a combination of biochemical approaches and field-recordings in mouse hippocampal slices, we show that the master regulator of energy homeostasis, AMPK couples energy metabolism to LTP expression. Administration of the glycolytic inhibitor 2-deoxy-D-glucose (2DG or the mitochondrial toxin and anti-Type II Diabetes drug, metformin, or AMP mimetic AICAR results in activation of AMPK, repression of the mTOR pathway and prevents maintenance of Late-Phase LTP (L-LTP. Inhibition of AMPK by either compound-C or the ATP mimetic ara-A rescues the suppression of L-LTP by energy stress. We also show that enhanced LTP via AMPK inhibition requires mTOR signaling. These results directly link energy metabolism to plasticity in the mammalian brain and demonstrate that AMPK is a modulator of LTP. Our work opens up the possibility of using modulators of energy metabolism to control neuronal plasticity in diseases and conditions of aberrant plasticity such as epilepsy.

  17. Regulation of Lipid and Glucose Metabolism by Phosphatidylcholine Transfer Protein

    Science.gov (United States)

    Kang, Hye Won; Wei, Jie; Cohen, David E.

    2010-01-01

    Phosphatidylcholine transfer protein (PC-TP, a.k.a. StARD2) binds phosphatidylcholines and catalyzes their intermembrane transfer and exchange in vitro. The structure of PC-TP comprises a hydrophobic pocket and a well-defined head-group binding site, and its gene expression is regulated by peroxisome proliferator activated receptor α. Recent studies have revealed key regulatory roles for PC-TP in lipid and glucose metabolism. Notably, Pctp−/− mice are sensitized to insulin action and exhibit more efficient brown fat-mediated thermogenesis. PC-TP appears to limit access of fatty acids to mitochondria by stimulating the activity of thioesterase superfamily member 2, a newly characterized long-chain fatty acyl-CoA thioesterase. Because PC-TP discriminates among phosphatidylcholines within lipid bilayers, it may function as a sensor that links metabolic regulation to membrane composition. PMID:20338778

  18. The dynamic regulation of NAD metabolism in mitochondria

    Science.gov (United States)

    Stein, Liana Roberts; Imai, Shin-ichiro

    2012-01-01

    Mitochondria are intracellular powerhouses that produce ATP and carry out diverse functions for cellular energy metabolism. While the maintenance of an optimal NAD/NADH ratio is essential for mitochondrial function, it has recently become apparent that the maintenance of the mitochondrial NAD pool also has critical importance. The biosynthesis, transport, and catabolism of NAD and its key intermediates play an important role in the regulation of NAD-consuming mediators, such as sirtuins, poly-ADP-ribose polymerases, and CD38/157 ectoenzymes, in intra- and extracellular compartments. Mitochondrial NAD biosynthesis is also modulated in response to nutritional and environmental stimuli. In this article, we discuss this dynamic regulation of NAD metabolism in mitochondria to shed light on the intimate connection between NAD and mitochondrial function. PMID:22819213

  19. Shaping the landscape: Metabolic regulation of S1P gradients

    Science.gov (United States)

    Olivera, Ana; Allende, Maria Laura; Proia, Richard L.

    2012-01-01

    Sphingosine-1-phosphate (S1P) is a lipid that functions as a metabolic intermediate and a cellular signaling molecule. These roles are integrated when compartments with differing extracellular S1P concentrations are formed that serve to regulate functions within the immune and vascular systems, as well as during pathologic conditions. Gradients of S1P concentration are achieved by the organization of cells with specialized expression of S1P metabolic pathways within tissues. S1P concentration gradients underpin the ability of S1P signaling to regulate in vivo physiology. This review will discuss the mechanisms that are necessary for the formation and maintenance of S1P gradients, with the aim of understanding how a simple lipid controls complex physiology. PMID:22735358

  20. Sox17 regulates liver lipid metabolism and adaptation to fasting.

    Directory of Open Access Journals (Sweden)

    Samuel Rommelaere

    Full Text Available Liver is a major regulator of lipid metabolism and adaptation to fasting, a process involving PPARalpha activation. We recently showed that the Vnn1 gene is a PPARalpha target gene in liver and that release of the Vanin-1 pantetheinase in serum is a biomarker of PPARalpha activation. Here we set up a screen to identify new regulators of adaptation to fasting using the serum Vanin-1 as a marker of PPARalpha activation. Mutagenized mice were screened for low serum Vanin-1 expression. Functional interactions with PPARalpha were investigated by combining transcriptomic, biochemical and metabolic approaches. We characterized a new mutant mouse in which hepatic and serum expression of Vanin-1 is depressed. This mouse carries a mutation in the HMG domain of the Sox17 transcription factor. Mutant mice display a metabolic phenotype featuring lipid abnormalities and inefficient adaptation to fasting. Upon fasting, a fraction of the PPARα-driven transcriptional program is no longer induced and associated with impaired fatty acid oxidation. The transcriptional phenotype is partially observed in heterozygous Sox17+/- mice. In mutant mice, the fasting phenotype but not all transcriptomic signature is rescued by the administration of the PPARalpha agonist fenofibrate. These results identify a novel role for Sox17 in adult liver as a modulator of the metabolic adaptation to fasting.

  1. Basic mechanisms of iron metabolism regulation and their clinical significance

    Directory of Open Access Journals (Sweden)

    L. M. Meshсheryakova

    2014-01-01

    Full Text Available This article is а composition of literature and experimental data of iron metabolism. There were studied the level of DMT-1, ferroportin, hepcidin at different stages of anemia and hemochromatosis. It is clear that the level of DMT-1 regulates by the hepcidin. Increaseing of the hepcidin concentration and decreasing DMT-1 level in patients with hemochromatosis explained good results of treatment.

  2. Basic mechanisms of iron metabolism regulation and their clinical significance

    Directory of Open Access Journals (Sweden)

    L. M. Meshсheryakova

    2015-01-01

    Full Text Available This article is а composition of literature and experimental data of iron metabolism. There were studied the level of DMT-1, ferroportin, hepcidin at different stages of anemia and hemochromatosis. It is clear that the level of DMT-1 regulates by the hepcidin. Increaseing of the hepcidin concentration and decreasing DMT-1 level in patients with hemochromatosis explained good results of treatment.

  3. The liberal battlefields of global business regulation

    Directory of Open Access Journals (Sweden)

    Kate Macdonald

    2010-11-01

    Full Text Available The global justice movement has often been associated with opposition to the broad programme of ‘neoliberalism’ and associated patterns of ‘corporate globalisation’, creating a widespread impression that this movement is opposed to liberalism more broadly conceived. Our goal in this article is to challenge this widespread view. By engaging in critical interpretive analysis of the contemporary ‘corporate accountability’ movement, we argue that the corporate accountability agenda is not opposed to the core values of a liberal project. Rather, it is seeking to reconfigure the design of liberal institutions of individual rights-protection, adjusting these for new material conditions associated with economic globalisation, under which powerful corporations alongside states now pose direct and significant threats to individual rights. This activist agenda is, therefore, much less radical in its challenge to the prevailing liberal global order than it may initially appear, since it functions to buttress rather than corrode many core normative commitments underpinning the liberal political project.

  4. translin Is Required for Metabolic Regulation of Sleep.

    Science.gov (United States)

    Murakami, Kazuma; Yurgel, Maria E; Stahl, Bethany A; Masek, Pavel; Mehta, Aradhana; Heidker, Rebecca; Bollinger, Wesley; Gingras, Robert M; Kim, Young-Joon; Ja, William W; Suter, Beat; DiAngelo, Justin R; Keene, Alex C

    2016-04-04

    Dysregulation of sleep or feeding has enormous health consequences. In humans, acute sleep loss is associated with increased appetite and insulin insensitivity, while chronically sleep-deprived individuals are more likely to develop obesity, metabolic syndrome, type II diabetes, and cardiovascular disease. Conversely, metabolic state potently modulates sleep and circadian behavior; yet, the molecular basis for sleep-metabolism interactions remains poorly understood. Here, we describe the identification of translin (trsn), a highly conserved RNA/DNA binding protein, as essential for starvation-induced sleep suppression. Strikingly, trsn does not appear to regulate energy stores, free glucose levels, or feeding behavior suggesting the sleep phenotype of trsn mutant flies is not a consequence of general metabolic dysfunction or blunted response to starvation. While broadly expressed in all neurons, trsn is transcriptionally upregulated in the heads of flies in response to starvation. Spatially restricted rescue or targeted knockdown localizes trsn function to neurons that produce the tachykinin family neuropeptide Leucokinin. Manipulation of neural activity in Leucokinin neurons revealed these neurons to be required for starvation-induced sleep suppression. Taken together, these findings establish trsn as an essential integrator of sleep and metabolic state, with implications for understanding the neural mechanism underlying sleep disruption in response to environmental perturbation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Glucose metabolism regulates T cell activation, differentiation and functions

    Directory of Open Access Journals (Sweden)

    Clovis Steve Palmer

    2015-01-01

    Full Text Available The adaptive immune system is equipped to eliminate both tumors and pathogenic microorganisms. It requires a series of complex and coordinated signals to drive the activation, proliferation and differentiation of appropriate T cell subsets. It is now established that changes in cellular activation are coupled to profound changes in cellular metabolism. In addition, emerging evidence now suggest that specific metabolic alterations associated with distinct T cell subsets may be ancillary to their differentiation and influential in their immune functions. The Warburg effect originally used to describe a phenomenon in which most cancer cells relied on aerobic glycolysis for their growth is a key process that sustain T cell activation and differentiation. Here we review how different aspects of metabolism in T cells influence their functions, focusing on the emerging role of key regulators of glucose metabolism such as HIF-1α. A thorough understanding of the role of metabolism in T cell function could provide insights into mechanisms involved in inflammatory-mediated conditions, with the potential for developing novel therapeutic approaches to treat these diseases.

  6. Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility.

    Science.gov (United States)

    Navarro, Victor M; Tena-Sempere, Manuel

    2011-09-13

    The neurohormonal control of reproduction involves a hierarchical network of central and peripheral signals in the hypothalamic-pituitary-gonadal (HPG) axis. Development and function of this neuroendocrine system is the result of a lifelong delicate balance between endogenous regulators and environmental cues, including nutritional and metabolic factors. Kisspeptins are the peptide products of KISS1, which operate via the G-protein-coupled receptor GPR54 (also known as Kiss1R). These peptides have emerged as essential upstream regulators of neurons secreting gonadotropin-releasing hormone (GnRH), the major hypothalamic node for the stimulatory control of the HPG axis. They are potent elicitors of gonadotropin secretion in various species and physiological settings. Moreover, Kiss1 neurons in the hypothalamus participate in crucial features of reproductive maturation and function, such as brain-level sex differentiation, puberty onset and the neuroendocrine regulation of gonadotropin secretion and ovulation. Cotransmitters of Kiss1 neurons, such as neurokinin B, with roles in controlling the HPG axis have been identified by genetic, neuroanatomical and physiological studies. In addition, a putative role has been proposed for Kiss1 neurons in transmitting metabolic information to GnRH neurons, although the precise mechanisms are as yet unclear. In this Review, we present the major reproductive features of kisspeptins, especially their interplay with neurokinin B and potential roles in the metabolic control of puberty and fertility, and suggest new avenues for research.

  7. Global niche of marine anaerobic metabolisms expanded by particle microenvironments

    Science.gov (United States)

    Bianchi, Daniele; Weber, Thomas S.; Kiko, Rainer; Deutsch, Curtis

    2018-04-01

    In ocean waters, anaerobic microbial respiration should be confined to the anoxic waters found in coastal regions and tropical oxygen minimum zones, where it is energetically favourable. However, recent molecular and geochemical evidence has pointed to a much broader distribution of denitrifying and sulfate-reducing microbes. Anaerobic metabolisms are thought to thrive in microenvironments that develop inside sinking organic aggregates, but the global distribution and geochemical significance of these microenvironments is poorly understood. Here, we develop a new size-resolved particle model to predict anaerobic respiration from aggregate properties and seawater chemistry. Constrained by observations of the size spectrum of sinking particles, the model predicts that denitrification and sulfate reduction can be sustained throughout vast, hypoxic expanses of the ocean, and could explain the trace metal enrichment observed in particles due to sulfide precipitation. Globally, the expansion of the anaerobic niche due to particle microenvironments doubles the rate of water column denitrification compared with estimates based on anoxic zones alone, and changes the sensitivity of the marine nitrogen cycle to deoxygenation in a warming climate.

  8. Efficient protein production by yeast requires global tuning of metabolism

    DEFF Research Database (Denmark)

    Huang, Mingtao; Bao, Jichen; Hallstrom, Bjorn M.

    2017-01-01

    The biotech industry relies on cell factories for production of pharmaceutical proteins, of which several are among the top-selling medicines. There is, therefore, considerable interest in improving the efficiency of protein production by cell factories. Protein secretion involves numerous...... intracellular processes with many underlying mechanisms still remaining unclear. Here, we use RNA-seq to study the genome-wide transcriptional response to protein secretion in mutant yeast strains. We find that many cellular processes have to be attuned to support efficient protein secretion. In particular...... that by tuning metabolism cells are able to efficiently secrete recombinant proteins. Our findings provide increased understanding of which cellular regulations and pathways are associated with efficient protein secretion....

  9. Regulation of alcohol marketing: a global view.

    Science.gov (United States)

    Casswell, Sally; Maxwell, Anna

    2005-09-01

    The marketing of alcohol produces a new challenge for policy development internationally, in part because of the increase in the use of new, unmeasured technologies. Many of these new developments are, as yet, relatively invisible in the policy arena. New approaches in branding, the utilization of marketing opportunities via branded events and new products provide additional complexity to attempts to monitor and to restrict the impact of marketing on young people and other vulnerable groups. Current attempts to restrict marketing globally, which rely primarily on voluntary codes and focus on traditional media, are inadequate to these challenges. A new statutory framework is required to enable the monitoring and control of the full marketing mix in ways which match the sophistication of the marketing efforts themselves.

  10. Metabolic regulation of carotenoid-enriched Golden rice line

    Directory of Open Access Journals (Sweden)

    Dipak Gayen

    2016-10-01

    Full Text Available Vitamin A deficiency (VAD is the leading cause of blindness among children and is associated with high risk of maternal mortality. In order to enhance the bioavailability of vitamin A, high carotenoid transgenic golden rice has been developed by manipulating enzymes, such as phytoene synthase (psy and phytoene desaturase (crtI. In this study, proteome and metabolite analyses were carried out to comprehend metabolic regulation and adaptation of transgenic golden rice after the manipulation of endosperm specific carotenoid pathways. The main alteration was observed in carbohydrate metabolism pathways of the transgenic seeds. The 2D based proteomic studies demonstrated that carbohydrate metabolism-related enzymes, such as pullulanase, UDP-glucose pyrophosphorylase and glucose-1-phosphate adenylyl transferase, were primarily up-regulated in transgenic rice seeds. In addition, the enzyme PPDK was also elevated in transgenic seeds thus enhancing pyruvate biosynthesis, which is the precursor in the carotenoids biosynthetic pathway. GC-MS based metabolite profiling demonstrated an increase in the levels of glyceric acid, fructo-furanose, and galactose, while decrease in galactonic acid and gentiobiose in the transgenic rice compared to WT. It is noteworthy to mention that the carotenoid content, especially β-carotene level in transgenic rice (4.3 µg/g was significantly enhanced. The present study highlights the metabolic adaptation process of a transgenic golden rice line (homozygous T4 progeny of SKBR-244 after enhancing carotenoid biosynthesis. The presented information would be helpful in the development of crops enriched in carotenoids by expressing metabolic flux of pyruvate biosynthesis.

  11. Metabolism and Regulation of Glycerolipids in the Yeast Saccharomyces cerevisiae

    Science.gov (United States)

    Henry, Susan A.; Kohlwein, Sepp D.; Carman, George M.

    2012-01-01

    Due to its genetic tractability and increasing wealth of accessible data, the yeast Saccharomyces cerevisiae is a model system of choice for the study of the genetics, biochemistry, and cell biology of eukaryotic lipid metabolism. Glycerolipids (e.g., phospholipids and triacylglycerol) and their precursors are synthesized and metabolized by enzymes associated with the cytosol and membranous organelles, including endoplasmic reticulum, mitochondria, and lipid droplets. Genetic and biochemical analyses have revealed that glycerolipids play important roles in cell signaling, membrane trafficking, and anchoring of membrane proteins in addition to membrane structure. The expression of glycerolipid enzymes is controlled by a variety of conditions including growth stage and nutrient availability. Much of this regulation occurs at the transcriptional level and involves the Ino2–Ino4 activation complex and the Opi1 repressor, which interacts with Ino2 to attenuate transcriptional activation of UASINO-containing glycerolipid biosynthetic genes. Cellular levels of phosphatidic acid, precursor to all membrane phospholipids and the storage lipid triacylglycerol, regulates transcription of UASINO-containing genes by tethering Opi1 to the nuclear/endoplasmic reticulum membrane and controlling its translocation into the nucleus, a mechanism largely controlled by inositol availability. The transcriptional activator Zap1 controls the expression of some phospholipid synthesis genes in response to zinc availability. Regulatory mechanisms also include control of catalytic activity of glycerolipid enzymes by water-soluble precursors, products and lipids, and covalent modification of phosphorylation, while in vivo function of some enzymes is governed by their subcellular location. Genome-wide genetic analysis indicates coordinate regulation between glycerolipid metabolism and a broad spectrum of metabolic pathways. PMID:22345606

  12. Regulation of brown adipocyte metabolism by myostatin/follistatin signaling

    Directory of Open Access Journals (Sweden)

    Rajan eSingh

    2014-10-01

    Full Text Available Obesity develops from perturbations of cellular bioenergetics, when energy uptake exceeds energy expenditure, and represents a major risk factor for the development of type 2 diabetes, dyslipidemia, cardiovascular disease, cancer, and other conditions. Brown adipose tissue (BAT has long been known to dissipate energy as heat and contribute to energy expenditure, but its presence and physiological role in adult human physiology has been questioned for years. Recent demonstrations of metabolically active brown fat depots in adult humans have revolutionized current therapeutic approaches for obesity-related diseases. The balance between white adipose tissue (WAT and BAT affects the systemic energy balance and is widely believed to be the key determinant in the development of obesity and related metabolic diseases. Members of the transforming growth factor-beta (TGF-β superfamily play an important role in regulating overall energy homeostasis by modulation of brown adipocyte characteristics. Inactivation of TGF-β/Smad3/myostatin (Mst signaling promotes browning of white adipocytes, increases mitochondrial biogenesis and protects mice from diet-induced obesity, suggesting the need for development of a novel class of TGF-β/Mst antagonists for the treatment of obesity and related metabolic diseases. We recently described an important role of follistatin (Fst, a soluble glycoprotein that is known to bind and antagonize Mst actions, during brown fat differentiation and the regulation of cellular metabolism. Here we highlight various investigations performed using different in vitro and in vivo models to support the contention that targeting TGF-β/Mst signaling enhances brown adipocyte functions and regulates energy balance, reducing insulin resistance and curbing the development of obesity and diabetes.

  13. USA IN THE EMERGING SYSTEM OF GLOBAL FINANCIAL REGULATION

    Directory of Open Access Journals (Sweden)

    V. K. Kulakova

    2016-01-01

    Full Text Available In the globalizing world of fi nancial and economic interdependence, a polycentric, multi-level, and hierarchical system of global financial regulation is emerging. The article highlights two vectors of recent development in international fi nancial regulation: the rise of cooperation through the mechanisms of the Group of Twenty (G-20 on the one hand, and the efforts to maintain the US leading role in global fi nance, on the other hand. In the circumstances of the global fi nancial crisis of 2008, the G-20 countries initiated an international reform of fi nancial regulation. According to G-20 decisions, international standardsetting organizations developed transnational regulatory regimes in the fi elds of banking, derivatives and bankruptcy resolution, and the states now implement these regimes in their jurisdictions. The so-called “soft law system”, which is not legally binding, allows the states to sustain national sovereignty in their fi nancial policy. The United States play a leading role in the international fi nancial reform, as well as in the shaping of the global fi nancial regulation system. The American regulators push for extraterritorial application of the US norms and take other unilateral actions on the international arena. The article also touches upon legitimacy problems of the emerging system of global fi nancial regulation. The most important constrains are the excessive infl uence of the fi nancial industry (“regulatory capture”, the weakness of civil society participation, and also the fact that for the rest of the world the American norms lack legitimacy, as they are adopted by regulators assigned by offi cials elected by population of a foreign territory.

  14. Regulation of intestinal protein metabolism by amino acids.

    Science.gov (United States)

    Bertrand, Julien; Goichon, Alexis; Déchelotte, Pierre; Coëffier, Moïse

    2013-09-01

    Gut homeostasis plays a major role in health and may be regulated by quantitative and qualitative food intake. In the intestinal mucosa, an intense renewal of proteins occurs, at approximately 50% per day in humans. In some pathophysiological conditions, protein turnover is altered and may contribute to intestinal or systemic diseases. Amino acids are key effectors of gut protein turnover, both as constituents of proteins and as regulatory molecules limiting intestinal injury and maintaining intestinal functions. Many studies have focused on two amino acids: glutamine, known as the preferential substrate of rapidly dividing cells, and arginine, another conditionally essential amino acid. The effects of glutamine and arginine on protein synthesis appear to be model and condition dependent, as are the involved signaling pathways. The regulation of gut protein degradation by amino acids has been minimally documented until now. This review will examine recent data, helping to better understand how amino acids regulate intestinal protein metabolism, and will explore perspectives for future studies.

  15. Central regulation of metabolism by protein tyrosine phosphatases

    Directory of Open Access Journals (Sweden)

    Ryan eTsou

    2013-01-01

    Full Text Available Protein tyrosine phosphatases (PTPs are important regulators of intracellular signaling pathways via the dephosphorylation of phosphotyrosyl residues on various receptor and non-receptor substrates. The phosphorylation state of central nervous system (CNS signaling components underlies the molecular mechanisms of a variety of physiological functions including the control of energy balance and glucose homeostasis. In this review, we summarize the current evidence implicating PTPs as central regulators of metabolism, specifically highlighting their interactions with the neuronal leptin and insulin signaling pathways. We discuss the role of a number of PTPs (PTP1B, SHP2, TCPTP, RPTPe, and PTEN, reviewing the findings from genetic mouse models and in vitro studies which highlight these phosphatases as key central regulators of energy homeostasis.

  16. AMPK regulates metabolism and survival in response to ionizing radiation

    International Nuclear Information System (INIS)

    Zannella, Vanessa E.; Cojocari, Dan; Hilgendorf, Susan; Vellanki, Ravi N.; Chung, Stephen; Wouters, Bradly G.; Koritzinsky, Marianne

    2011-01-01

    Background and purpose: AMPK is a metabolic sensor and an upstream inhibitor of mTOR activity. AMPK is phosphorylated by ionizing radiation (IR) in an ATM dependent manner, but the cellular consequences of this phosphorylation event have remained unclear. The objective of this study was to assess whether AMPK plays a functional role in regulating cellular responses to IR. Methods: The importance of AMPK expression for radiation responses was investigated using both MEFs (mouse embryo fibroblasts) double knockout for AMPK α1/α2 subunits and human colorectal carcinoma cells (HCT 116) with AMPK α1/α2 shRNA mediated knockdown. Results: We demonstrate here that IR results in phosphorylation of both AMPK and its substrate, ACC. IR moderately stimulated mTOR activity, and this was substantially exacerbated in the absence of AMPK. AMPK was required for IR induced expression of the mTOR inhibitor REDD1, indicating that AMPK restrains mTOR activity through multiple mechanisms. Likewise, cellular metabolism was deregulated following irradiation in the absence of AMPK, as evidenced by a substantial increase in oxygen consumption rates and lactate production. AMPK deficient cells showed impairment of the G1/S cell cycle checkpoint, and were unable to support long-term proliferation during starvation following radiation. Lastly, we show that AMPK proficiency is important for clonogenic survival after radiation during starvation. Conclusions: These data reveal novel functional roles for AMPK in regulating mTOR signaling, cell cycle, survival and metabolic responses to IR.

  17. APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

    Science.gov (United States)

    Moore, Steven; Evans, Lewis D B; Andersson, Therese; Portelius, Erik; Smith, James; Dias, Tatyana B; Saurat, Nathalie; McGlade, Amelia; Kirwan, Peter; Blennow, Kaj; Hardy, John; Zetterberg, Henrik; Livesey, Frederick J

    2015-05-05

    Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Intrinsic limits to gene regulation by global crosstalk

    Science.gov (United States)

    Friedlander, Tamar; Prizak, Roshan; Guet, Călin C.; Barton, Nicholas H.; Tkačik, Gašper

    2016-01-01

    Gene regulation relies on the specificity of transcription factor (TF)–DNA interactions. Limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF–DNA interactions or remains erroneously inactive. As each TF can have numerous interactions with noncognate cis-regulatory elements, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyse the effects of global crosstalk on gene regulation. We find that crosstalk presents a significant challenge for organisms with low-specificity TFs, such as metazoans. Crosstalk is not easily mitigated by known regulatory schemes acting at equilibrium, including variants of cooperativity and combinatorial regulation. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements. PMID:27489144

  19. Classical NF-κB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2

    Directory of Open Access Journals (Sweden)

    Priya Londhe

    2018-04-01

    Full Text Available BackgroundMetabolic reprogramming has emerged as a cancer hallmark, and one of the well-known cancer-associated metabolic alterations is the increase in the rate of glycolysis. Recent reports have shown that both the classical and alternative signaling pathways of nuclear factor κB (NF-κB play important roles in controlling the metabolic profiles of normal cells and cancer cells. However, how these signaling pathways affect the metabolism of sarcomas, specifically rhabdomyosarcoma (RMS and osteosarcoma (OS, has not been characterized.MethodsClassical NF-κB activity was inhibited through overexpression of the IκBα super repressor of NF-κB in RMS and OS cells. Global gene expression analysis was performed using Affymetrix GeneChip Human Transcriptome Array 2.0, and data were interpreted using gene set enrichment analysis. Seahorse Bioscience XFe24 was used to analyze oxygen consumption rate as a measure of aerobic respiration.ResultsInhibition of classical NF-κB activity in sarcoma cell lines restored alternative signaling as well as an increased oxidative respiratory metabolic phenotype in vitro. In addition, microarray analysis indicated that inhibition of NF-κB in sarcoma cells reduced glycolysis. We showed that a glycolytic gene, hexokinase (HK 2, is a direct NF-κB transcriptional target. Knockdown of HK2 shifted the metabolic profile in sarcoma cells away from aerobic glycolysis, and re-expression of HK2 rescued the metabolic shift induced by inhibition of NF-κB activity in OS cells.ConclusionThese findings suggest that classical signaling of NF-κB plays a crucial role in the metabolic profile of pediatric sarcomas potentially through the regulation of HK2.

  20. Insulin action in brain regulates systemic metabolism and brain function.

    Science.gov (United States)

    Kleinridders, André; Ferris, Heather A; Cai, Weikang; Kahn, C Ronald

    2014-07-01

    Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain. Insulin acts on these receptors to modulate peripheral metabolism, including regulation of appetite, reproductive function, body temperature, white fat mass, hepatic glucose output, and response to hypoglycemia. Insulin signaling also modulates neurotransmitter channel activity, brain cholesterol synthesis, and mitochondrial function. Disruption of insulin action in the brain leads to impairment of neuronal function and synaptogenesis. In addition, insulin signaling modulates phosphorylation of tau protein, an early component in the development of Alzheimer disease. Thus, alterations in insulin action in the brain can contribute to metabolic syndrome, and the development of mood disorders and neurodegenerative diseases. © 2014 by the American Diabetes Association.

  1. Study of collagen metabolism and regulation after β radiation injury

    International Nuclear Information System (INIS)

    Zhou Yinghui; Xu Lan; Wu Shiliang; Qiu Hao; Jiang Zhi; Tu Youbin; Zhang Xueguang

    2001-01-01

    The animal model of β radiation injury was established by the β radiation produced by the linear accelerator; and irradiated NIH 3T3 cells were studied. In the experiment the contents of total collagen, collagen type I and type III were measured. The activity of MMPs-1 were tested. The contents of TGF-β 1 , IL-6 were also detected. The results showed that after exposure to β radiation, little change was found in the content of total collagen, but the content of collagen I decreased and the content of collagen III, MMPs-1 activity increased; the expression of TGF-β 1 , IL-6 increased. The results suggest that changes in the metabolism of collagen play an important role in the irradiated injury of the skin; TGF-β 1 , IL-6 may be essential in the regulation of the collagen metabolism

  2. Study of collagen metabolism and regulation after {beta} radiation injury

    Energy Technology Data Exchange (ETDEWEB)

    Yinghui, Zhou; Lan, Xu; Shiliang, Wu; Hao, Qiu; Zhi, Jiang; Youbin, Tu; Xueguang, Zhang [Suzhou Medical College (China)

    2001-04-01

    The animal model of {beta} radiation injury was established by the {beta} radiation produced by the linear accelerator; and irradiated NIH 3T3 cells were studied. In the experiment the contents of total collagen, collagen type I and type III were measured. The activity of MMPs-1 were tested. The contents of TGF-{beta}{sub 1}, IL-6 were also detected. The results showed that after exposure to {beta} radiation, little change was found in the content of total collagen, but the content of collagen I decreased and the content of collagen III, MMPs-1 activity increased; the expression of TGF-{beta}{sub 1}, IL-6 increased. The results suggest that changes in the metabolism of collagen play an important role in the irradiated injury of the skin; TGF-{beta}{sub 1}, IL-6 may be essential in the regulation of the collagen metabolism.

  3. Glycogen metabolism and the homeostatic regulation of sleep

    KAUST Repository

    Petit, Jean-Marie

    2014-11-16

    In 1995 Benington and Heller formulated an energy hypothesis of sleep centered on a key role of glycogen. It was postulated that a major function of sleep is to replenish glycogen stores in the brain that have been depleted during wakefulness which is associated to an increased energy demand. Astrocytic glycogen depletion participates to an increase of extracellular adenosine release which influences sleep homeostasis. Here, we will review some evidence obtained by studies addressing the question of a key role played by glycogen metabolism in sleep regulation as proposed by this hypothesis or by an alternative hypothesis named “glycogenetic” hypothesis as well as the importance of the confounding effect of glucocorticoïds. Even though actual collected data argue in favor of a role of sleep in brain energy balance-homeostasis, they do not support a critical and direct involvement of glycogen metabolism on sleep regulation. For instance, glycogen levels during the sleep-wake cycle are driven by different physiological signals and therefore appear more as a marker-integrator of brain energy status than a direct regulator of sleep homeostasis. In support of this we provide evidence that blockade of glycogen mobilization does not induce more sleep episodes during the active period while locomotor activity is reduced. These observations do not invalidate the energy hypothesis of sleep but indicate that underlying cellular mechanisms are more complex than postulated by Benington and Heller.

  4. Brassinosteroid regulates cell elongation by modulating gibberellin metabolism in rice.

    Science.gov (United States)

    Tong, Hongning; Xiao, Yunhua; Liu, Dapu; Gao, Shaopei; Liu, Linchuan; Yin, Yanhai; Jin, Yun; Qian, Qian; Chu, Chengcai

    2014-11-01

    Brassinosteroid (BR) and gibberellin (GA) are two predominant hormones regulating plant cell elongation. A defect in either of these leads to reduced plant growth and dwarfism. However, their relationship remains unknown in rice (Oryza sativa). Here, we demonstrated that BR regulates cell elongation by modulating GA metabolism in rice. Under physiological conditions, BR promotes GA accumulation by regulating the expression of GA metabolic genes to stimulate cell elongation. BR greatly induces the expression of D18/GA3ox-2, one of the GA biosynthetic genes, leading to increased GA1 levels, the bioactive GA in rice seedlings. Consequently, both d18 and loss-of-function GA-signaling mutants have decreased BR sensitivity. When excessive active BR is applied, the hormone mostly induces GA inactivation through upregulation of the GA inactivation gene GA2ox-3 and also represses BR biosynthesis, resulting in decreased hormone levels and growth inhibition. As a feedback mechanism, GA extensively inhibits BR biosynthesis and the BR response. GA treatment decreases the enlarged leaf angles in plants with enhanced BR biosynthesis or signaling. Our results revealed a previously unknown mechanism underlying BR and GA crosstalk depending on tissues and hormone levels, which greatly advances our understanding of hormone actions in crop plants and appears much different from that in Arabidopsis thaliana. © 2014 American Society of Plant Biologists. All rights reserved.

  5. The Lin28/let-7 axis regulates glucose metabolism

    Science.gov (United States)

    Zhu, Hao; Shyh-Chang, Ng; Segrè, Ayellet V.; Shinoda, Gen; Shah, Samar P.; Einhorn, William S.; Takeuchi, Ayumu; Engreitz, Jesse M.; Hagan, John P.; Kharas, Michael G; Urbach, Achia; Thornton, James E.; Triboulet, Robinson; Gregory, Richard I.; Altshuler, David; Daley, George Q.

    2012-01-01

    SUMMARY The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by blocking let-7 biogenesis. In studies of the Lin28/let-7 pathway, we discovered unexpected roles in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promoted an insulin-sensitized state that resisted high fat diet-induced diabetes, whereas muscle-specific loss of Lin28a and overexpression of let-7 resulted in insulin resistance and impaired glucose tolerance. These phenomena occurred in part through let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. The mTOR inhibitor rapamycin abrogated the enhanced glucose uptake and insulin-sensitivity conferred by Lin28a in vitro and in vivo. In addition, we found that let-7 targets were enriched for genes that contain SNPs associated with type 2 diabetes and fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism. PMID:21962509

  6. Global loss of bmal1 expression alters adipose tissue hormones, gene expression and glucose metabolism.

    Directory of Open Access Journals (Sweden)

    David John Kennaway

    Full Text Available The close relationship between circadian rhythm disruption and poor metabolic status is becoming increasingly evident, but role of adipokines is poorly understood. Here we investigated adipocyte function and the metabolic status of mice with a global loss of the core clock gene Bmal1 fed either a normal or a high fat diet (22% by weight. Bmal1 null mice aged 2 months were killed across 24 hours and plasma adiponectin and leptin, and adipose tissue expression of Adipoq, Lep, Retn and Nampt mRNA measured. Glucose, insulin and pyruvate tolerance tests were conducted and the expression of liver glycolytic and gluconeogenic enzyme mRNA determined. Bmal1 null mice displayed a pattern of increased plasma adiponectin and plasma leptin concentrations on both control and high fat diets. Bmal1 null male and female mice displayed increased adiposity (1.8 fold and 2.3 fold respectively on the normal diet, but the high fat diet did not exaggerate these differences. Despite normal glucose and insulin tolerance, Bmal1 null mice had increased production of glucose from pyruvate, implying increased liver gluconeogenesis. The Bmal1 null mice had arrhythmic clock gene expression in epigonadal fat and liver, and loss of rhythmic transcription of a range of metabolic genes. Furthermore, the expression of epigonadal fat Adipoq, Retn, Nampt, AdipoR1 and AdipoR2 and liver Pfkfb3 mRNA were down-regulated. These results show for the first time that global loss of Bmal1, and the consequent arrhythmicity, results in compensatory changes in adipokines involved in the cellular control of glucose metabolism.

  7. [Research advance in nitrogen metabolism of plant and its environmental regulation].

    Science.gov (United States)

    Xu, Zhenzhu; Zhou, Guangsheng

    2004-03-01

    Nitrogen metabolism is not only one of the basic processes of plant physiology, but also one of the important parts of global chemical cycle. Plant nitrogen assimilation directly takes part in the synthesis and conversion of amino acid through the reduction of nitrate. During this stage, some key enzymes, e.g., nitrate reductase (NR), glutamine synthetase (GS), glutamate dehydrogenase (GDH), glutamine synthase (GOGAT), aspargine synthetase (AS), and asparate aminotransferase (AspAT) participate these processes. The protein is assimilated in plant cell through amino acid, and becomes a part of plant organism through modifying, classifying, transporting and storing processes, etc. The nitrogen metabolism is associated with carbonic metabolism through key enzyme regulations and the conversion of products, which consists of basic life process. Among these amino acids in plant cell, glutamic acid (Glu), glutamine (Gln), aspartic acid (Asp) and asparagines (Asn), etc., play a key role, which regulates their conversion each other and their contents in the plant cell through regulating formation and activity of those key enzymes. Environmental factors also affect the conversion and recycle of the key amino acids through regulating gene expression of the key enzymes and their activities. Nitrate and light intensity positively regulate the gene transcription of NR, but ammonium ions and Glu, Gln do the negative way. Water deficit is a very serious constraint on N2 fixation rate and soybean (Glycine max Merr.) grain yield, in which, ureide accumulation and degradation under water deficit appear to be the key issues of feedback mechanism on nitrogen fixation. Water stress decreases NR activity, but increases proteinase activity, and thus, they regulate plant nitrogen metabolism, although there are some different effects among species and cultivars. Water stress also decreases plant tissue protein content, ratio of protein and amino acid, and reduces the absorption of amino

  8. Homocysteine regulates fatty acid and lipid metabolism in yeast.

    Science.gov (United States)

    Visram, Myriam; Radulovic, Maja; Steiner, Sabine; Malanovic, Nermina; Eichmann, Thomas O; Wolinski, Heimo; Rechberger, Gerald N; Tehlivets, Oksana

    2018-04-13

    S -Adenosyl-l-homocysteine hydrolase (AdoHcy hydrolase; Sah1 in yeast/AHCY in mammals) degrades AdoHcy, a by-product and strong product inhibitor of S -adenosyl-l-methionine (AdoMet)-dependent methylation reactions, to adenosine and homocysteine (Hcy). This reaction is reversible, so any elevation of Hcy levels, such as in hyperhomocysteinemia (HHcy), drives the formation of AdoHcy, with detrimental consequences for cellular methylation reactions. HHcy, a pathological condition linked to cardiovascular and neurological disorders, as well as fatty liver among others, is associated with a deregulation of lipid metabolism. Here, we developed a yeast model of HHcy to identify mechanisms that dysregulate lipid metabolism. Hcy supplementation to wildtype cells up-regulated cellular fatty acid and triacylglycerol content and induced a shift in fatty acid composition, similar to changes observed in mutants lacking Sah1. Expression of the irreversible bacterial pathway for AdoHcy degradation in yeast allowed us to dissect the impact of AdoHcy accumulation on lipid metabolism from the impact of elevated Hcy. Expression of this pathway fully suppressed the growth deficit of sah1 mutants as well as the deregulation of lipid metabolism in both the sah1 mutant and Hcy-exposed wildtype, showing that AdoHcy accumulation mediates the deregulation of lipid metabolism in response to elevated Hcy in yeast. Furthermore, Hcy supplementation in yeast led to increased resistance to cerulenin, an inhibitor of fatty acid synthase, as well as to a concomitant decline of condensing enzymes involved in very long-chain fatty acid synthesis, in line with the observed shift in fatty acid content and composition. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator

    DEFF Research Database (Denmark)

    Usaite, Renata; Jewett, Michael Christopher; Soberano de Oliveira, Ana Paula

    2009-01-01

    Highly conserved among eukaryotic cells, the AMP-activated kinase (AMPK) is a central regulator of carbon metabolism. To map the complete network of interactions around AMPK in yeast (Snf1) and to evaluate the role of its regulatory subunit Snf4, we measured global mRNA, protein and metabolite...

  10. Hepcidin: A Critical Regulator of Iron Metabolism during Hypoxia

    Directory of Open Access Journals (Sweden)

    Korry J. Hintze

    2011-01-01

    Full Text Available Iron status affects cognitive and physical performance in humans. Recent evidence indicates that iron balance is a tightly regulated process affected by a series of factors other than diet, to include hypoxia. Hypoxia has profound effects on iron absorption and results in increased iron acquisition and erythropoiesis when humans move from sea level to altitude. The effects of hypoxia on iron balance have been attributed to hepcidin, a central regulator of iron homeostasis. This paper will focus on the molecular mechanisms by which hypoxia affects hepcidin expression, to include a review of the hypoxia inducible factor (HIF/hypoxia response element (HRE system, as well as recent evidence indicating that localized adipose hypoxia due to obesity may affect hepcidin signaling and organismal iron metabolism.

  11. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology.

    Science.gov (United States)

    Shimano, Hitoshi; Sato, Ryuichiro

    2017-12-01

    Cellular lipid metabolism and homeostasis are controlled by sterol regulatory-element binding proteins (SREBPs). In addition to performing canonical functions in the transcriptional regulation of genes involved in the biosynthesis and uptake of lipids, genome-wide system analyses have revealed that these versatile transcription factors act as important nodes of convergence and divergence within biological signalling networks. Thus, they are involved in myriad physiological and pathophysiological processes, highlighting the importance of lipid metabolism in biology. Changes in cell metabolism and growth are reciprocally linked through SREBPs. Anabolic and growth signalling pathways branch off and connect to multiple steps of SREBP activation and form complex regulatory networks. In addition, SREBPs are implicated in numerous pathogenic processes such as endoplasmic reticulum stress, inflammation, autophagy and apoptosis, and in this way, they contribute to obesity, dyslipidaemia, diabetes mellitus, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, neurodegenerative diseases and cancers. This Review aims to provide a comprehensive understanding of the role of SREBPs in physiology and pathophysiology at the cell, organ and organism levels.

  12. Metabolic regulation of mycobacterial growth and antibiotic sensitivity.

    Directory of Open Access Journals (Sweden)

    Seung-Hun Baek

    2011-05-01

    Full Text Available Treatment of chronic bacterial infections, such as tuberculosis (TB, requires a remarkably long course of therapy, despite the availability of drugs that are rapidly bacteriocidal in vitro. This observation has long been attributed to the presence of bacterial populations in the host that are "drug-tolerant" because of their slow replication and low rate of metabolism. However, both the physiologic state of these hypothetical drug-tolerant populations and the bacterial pathways that regulate growth and metabolism in vivo remain obscure. Here we demonstrate that diverse growth-limiting stresses trigger a common signal transduction pathway in Mycobacterium tuberculosis that leads to the induction of triglyceride synthesis. This pathway plays a causal role in reducing growth and antibiotic efficacy by redirecting cellular carbon fluxes away from the tricarboxylic acid cycle. Mutants in which this metabolic switch is disrupted are unable to arrest their growth in response to stress and remain sensitive to antibiotics during infection. Thus, this regulatory pathway contributes to antibiotic tolerance in vivo, and its modulation may represent a novel strategy for accelerating TB treatment.

  13. The Importance of the Circadian Clock in Regulating Plant Metabolism

    Directory of Open Access Journals (Sweden)

    Jin A Kim

    2017-12-01

    Full Text Available Carbohydrates are the primary energy source for plant development. Plants synthesize sucrose in source organs and transport them to sink organs during plant growth. This metabolism is sensitive to environmental changes in light quantity, quality, and photoperiod. In the daytime, the synthesis of sucrose and starch accumulates, and starch is degraded at nighttime. The circadian clock genes provide plants with information on the daily environmental changes and directly control many developmental processes, which are related to the path of primary metabolites throughout the life cycle. The circadian clock mechanism and processes of metabolism controlled by the circadian rhythm were studied in the model plant Arabidopsis and in the crops potato and rice. However, the translation of molecular mechanisms obtained from studies of model plants to crop plants is still difficult. Crop plants have specific organs such as edible seed and tuber that increase the size or accumulate valuable metabolites by harvestable metabolic components. Human consumers are interested in the regulation and promotion of these agriculturally significant crops. Circadian clock manipulation may suggest various strategies for the increased productivity of food crops through using environmental signal or overcoming environmental stress.

  14. NeuCode Proteomics Reveals Bap1 Regulation of Metabolism

    Directory of Open Access Journals (Sweden)

    Joshua M. Baughman

    2016-07-01

    Full Text Available We introduce neutron-encoded (NeuCode amino acid labeling of mice as a strategy for multiplexed proteomic analysis in vivo. Using NeuCode, we characterize an inducible knockout mouse model of Bap1, a tumor suppressor and deubiquitinase whose in vivo roles outside of cancer are not well established. NeuCode proteomics revealed altered metabolic pathways following Bap1 deletion, including profound elevation of cholesterol biosynthetic machinery coincident with reduced expression of gluconeogenic and lipid homeostasis proteins in liver. Bap1 loss increased pancreatitis biomarkers and reduced expression of mitochondrial proteins. These alterations accompany a metabolic remodeling with hypoglycemia, hypercholesterolemia, hepatic lipid loss, and acinar cell degeneration. Liver-specific Bap1 null mice present with fully penetrant perinatal lethality, severe hypoglycemia, and hepatic lipid deficiency. This work reveals Bap1 as a metabolic regulator in liver and pancreas, and it establishes NeuCode as a reliable proteomic method for deciphering in vivo biology.

  15. Fair Trade: Social Regulation in Global Food Markets

    Science.gov (United States)

    Raynolds, Laura T.

    2012-01-01

    This article analyzes the theoretical and empirical parameters of social regulation in contemporary global food markets, focusing on the rapidly expanding Fair Trade initiative. Fair Trade seeks to transform North/South relations by fostering ethical consumption, producer empowerment, and certified commodity sales. This initiative joins an array…

  16. Hydroxylamine derivatives for regulation of spermine and spermidine metabolism.

    Science.gov (United States)

    Khomutov, M A; Weisell, J; Hyvönen, M; Keinänen, T A; Vepsäläinen, J; Alhonen, L; Khomutov, A R; Kochetkov, S N

    2013-12-01

    The biogenic polyamines spermine, spermidine, and their precursor putrescine are present in micro-to-millimolar concentrations in all cell types and are vitally important for their normal growth. High intracellular content of spermine and spermidine determines the multiplicity of the cellular functions of the polyamines. Many of these functions are not well characterized at the molecular level, ensuring the ongoing development of this field of biochemistry. Tumor cells have elevated polyamine level if compared with normal cells, and this greatly stimulates the search for new opportunities to deplete the intracellular pool of spermine and spermidine resulting in decrease in cell growth and even cell death. O-Substituted hydroxylamines occupy their own place among chemical regulators of the activity of the enzymes of polyamine metabolism. Varying the structure of the alkyl substituent made it possible to obtain within one class of chemical compounds highly effective inhibitors and regulators of the activity of all the enzymes of putrescine, spermine and spermidine metabolism (with the exception of FAD-dependent spermine oxidase and acetylpolyamine oxidase), effectors of the polyamine transport system, and even actively transported in cells "proinhibitor" of ornithine decarboxylase. Some principles for the design of specific inhibitors of these enzymes as well as the peculiarities of cellular effects of corresponding O-substituted hydroxylamines are discussed.

  17. Carotenoids in staple cereals: Metabolism, regulation, and genetic manipulation

    Directory of Open Access Journals (Sweden)

    shengnan zhai

    2016-08-01

    Full Text Available Carotenoids play a critical role in animal and human health. Animals and humans are unable to synthesize carotenoids de novo, and therefore rely upon diet as sources of these compounds. However, major staple cereals often contain only small amounts of carotenoids in their grain. Consequently, there is considerable interest in genetic manipulation of carotenoid content in cereal grain. In this review, we focus on carotenoid metabolism and regulation in non-green plant tissues, as well as genetic manipulation in staple cereals such as rice, maize, and wheat. Significant progress has been made in three aspects: (1 seven carotenogenes play vital roles in carotenoid regulation in non-green plant tissues, including DXS (1-deoxyxylulose-5-phosphate synthase influencing isoprenoid precursor supply, PSY (phytoene synthase, LCYB (β-cyclase and LCYE (ε-cyclase controlling biosynthesis, HYDB (1-hydroxy-2-methyl-2-(E-butenyl 4-diphosphate reductase and CCDs (carotenoid cleavage dioxygenases responsible for degradation, and OR (orange conditioning sequestration sink; (2 pro-vitamin A-biofortified crops, such as rice and maize, were developed by either metabolic engineering or marker-assisted breeding; (3 QTLs for carotenoid content on chromosomes 3B, 7A, and 7B were consistently identified, eight carotenogenes including 23 loci were detected, and ten gene-specific markers for carotenoid accumulation were developed and applied in wheat improvement. A comprehensive and deeper understanding of the regulatory mechanisms of carotenoid metabolism in crops will be benefitical in improving our precision in improving carotenoid contents. Genomic selection and gene editing are emerging as transformative technologies for vitamin A biofortification.

  18. The bacterial response regulator ArcA uses a diverse binding site architecture to regulate carbon oxidation globally.

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    Dan M Park

    Full Text Available Despite the importance of maintaining redox homeostasis for cellular viability, how cells control redox balance globally is poorly understood. Here we provide new mechanistic insight into how the balance between reduced and oxidized electron carriers is regulated at the level of gene expression by mapping the regulon of the response regulator ArcA from Escherichia coli, which responds to the quinone/quinol redox couple via its membrane-bound sensor kinase, ArcB. Our genome-wide analysis reveals that ArcA reprograms metabolism under anaerobic conditions such that carbon oxidation pathways that recycle redox carriers via respiration are transcriptionally repressed by ArcA. We propose that this strategy favors use of catabolic pathways that recycle redox carriers via fermentation akin to lactate production in mammalian cells. Unexpectedly, bioinformatic analysis of the sequences bound by ArcA in ChIP-seq revealed that most ArcA binding sites contain additional direct repeat elements beyond the two required for binding an ArcA dimer. DNase I footprinting assays suggest that non-canonical arrangements of cis-regulatory modules dictate both the length and concentration-sensitive occupancy of DNA sites. We propose that this plasticity in ArcA binding site architecture provides both an efficient means of encoding binding sites for ArcA, σ(70-RNAP and perhaps other transcription factors within the same narrow sequence space and an effective mechanism for global control of carbon metabolism to maintain redox homeostasis.

  19. Practical approach for the study of metabolic regulation

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    D.V. Macedo

    2004-05-01

    Full Text Available First year students in Physical Education must understand metabolic regulation to comprehend thewhole integration of biochemical pathways in attempt to establish the relation with exercise. Thiswhole view is not easy to learn and the task becomes even harder with the lack of time at theend of course, when normally the students think about metabolic integration. Trying to get thestudents attention to this important issue, we developed practical works beginning in the middle ofthe course, in parallel with theory classes. Blood and urine were collected for metabolite analysis ineach practice. The students were divided in groups (10 students and they created the protocols in formthat they only have been guided and directed by the teacher and monitors. The practical activitiesand biochemical analysis were: six 30m sprints with dierent recovery times (blood lactate and meanvelocities, lactate removal from muscle to blood after high intensity exercise (blood lactate, anaerobicthreshold (blood lactate and heart rate, the eect of glycogen depletion after high and moderateintensity exercises (plasma glucose and urea concentrations and low carbohydrate diet vs. normaldiet (plasma glucose and urine ketone bodies. After data collection, discussion and interpretation, thestudents presented orally each work in the same order above. Each presentation had the focus on themetabolic pathways involved in each practice. Group 1: phosphocreatine utilization and resynthesis.Group 2: anaerobic glycolysis, lactate production and removal. Group 3: transition between anaerobicglycolysis and oxidative metabolism. In attempt to promote the integration between muscle and liver-Group 4: protein catabolism after high intensity exercise with low muscular glycogen concentration(transamination, Cori Cycle and gluconeogenesis. Group 5: liver ketogenesis in low carbohydratediet. This sequence was intended to promote the comprehension of integrated metabolism. As a nalactivity, the

  20. GlnR-mediated regulation of nitrogen metabolism in the actinomycete Saccharopolyspora erythraea.

    Science.gov (United States)

    Yao, Li-Li; Liao, Cheng-Heng; Huang, Gang; Zhou, Ying; Rigali, Sebastien; Zhang, Buchang; Ye, Bang-Ce

    2014-09-01

    Nitrogen source sensing, uptake, and assimilation are central for growth and development of microorganisms which requires the participation of a global control of nitrogen metabolism-associated genes at the transcriptional level. In soil-dwelling antibiotic-producing actinomycetes, this role is played by GlnR, an OmpR family regulator. In this work, we demonstrate that SACE_7101 is the ortholog of actinomycetes' GlnR global regulators in the erythromycin producer Saccharopolyspora erythraea. Indeed, the chromosomal deletion of SACE_7101 severely affects the viability of S. erythraea when inoculated in minimal media supplemented with NaNO3, NaNO2, NH4Cl, glutamine, or glutamate as sole nitrogen source. Combination of in silico prediction of cis-acting elements, subsequent in vitro (through gel shift assays) and in vivo (real-time reverse transcription polymerase chain reaction) validations of the predicted target genes revealed a very large GlnR regulon aimed at adapting the nitrogen metabolism of S. erythraea. Indeed, enzymes/proteins involved in (i) uptake and assimilation of ammonium, (ii) transport and utilization of urea, (iii) nitrite/nitrate, (iv) glutamate/glutamine, (v) arginine metabolism, (vi) nitric oxide biosynthesis, and (vii) signal transduction associated with the nitrogen source supplied have at least one paralog gene which expression is controlled by GlnR. Our work highlights a GlnR-binding site consensus sequence (t/gna/cAC-n6-GaAAc) which is similar although not identical to the consensus sequences proposed for other actinomycetes. Finally, we discuss the distinct and common features of the GlnR-mediated transcriptional control of nitrogen metabolism between S. erythraea and the model organism Streptomyces coelicolor.

  1. Global pharmaceutical regulation: the challenge of integration for developing states.

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    Pezzola, Anthony; Sweet, Cassandra M

    2016-12-20

    This paper has set out to map the state of pharmaceutical regulation in the developing world through the construction of cross-national indices drawing from World Health Organization data. The last two decades have been characterized by deep changes for the pharmaceutical sector, including the complete transformation of intellectual property systems at the behest of the World Trade Organization and the consolidation of global active ingredient suppliers in China and India. Although the rules for ownership of medicine have been set and globally implemented, we know surprisingly little about how the standards for market entrance and regulation of pharmaceutical products have changed at the national level. How standardized are national pharmaceutical market systems? Do we find homogeneity or variation across the developing world? Are their patterns for understanding why some countries have moved closer to one global norm for pharmaceutical regulation and others have developed hybrid models for oversight of this sector? Access to medicine is a core tool in public health. This paper gauges the levels of standards in public and private generics markets for developing countries building on national-level pharmaceutical market surveys for 78 countries to offer three indicators of market oversight: State Regulatory Infrastructure, Monitoring the Private Market and Public Quality Control. Identifying the different variables that affect a state's institutional capacity and current standard level offers new insights to the state of pharmaceuticals in the developing world. It is notable that there are very few (none at the time of this paper) studies that map out the new global terrain for pharmaceutical regulation in the post-TRIPS context. This paper uses item response theory to develop original indicators of pharmaceutical regulation. We find remarkable resistance to the implementation of global pharmaceutical norms for quality standards in developing states and in

  2. [THE INCONSISTENCIES OF REGULATION OF METABOLISM IN PHYLOGENESIS AT THREE LEVELS OF "RELATIVE BIOLOGICAL PERFECTION": ETIOLOGY OF METABOLIC PANDEMICS].

    Science.gov (United States)

    Titov, V N

    2015-11-01

    The regulation of metabolism in vivo can be comprehended by considering stages of becoming inphylogenesis of humoral, hormonal, vegetative regulators separately: at the level of cells; in paracrin-regulated cenosises of cells; organs and systems under open blood circulation and closed system of blood flow. The levels of regulations formed at different stages of phylogenesis. Their completion occurred at achievement of "relative biological perfection". Only this way need of cells in functional, structural interaction and forming of multicellular developed. The development of organs and systems of organs also completed at the level of "relative biological perfection". From the same level the third stage of becoming of regulation of metabolism at the level of organism started. When three conditions of "relative biological perfection" achieved consequently at level in vivo are considered in species Homo sapiens using system approach it is detected that "relative biological perfection" in vivo is accompanied by different inconsistencies of regulation of metabolism. They are etiologic factors of "metabolic pandemics ". The inconsistencies (etiological factors) are consider as exemplified by local (at the level of paracrin-regulated cenosises of cells) and system (at the level of organism) regulation of biological reaction metabolism-microcirculation that results in dysfunction of target organs and development of pathogenesis of essential metabolic arterial hypertension. The article describes phylogenetic difference between visceral fatty cells and adpocytes, regulation of metabolism by phylogenetically late insulin, reaction of albumin at increasing of content of unesterified fatty acids in blood plasma, difference of function of resident macrophage and monocytes-macrophages in pathogenesis of atherosclerosis, metabolic syndrome, insulin resistance, obesity, under diabetes mellitus and essential metabolic arterial hypertension.

  3. Inferring transcriptional gene regulation network of starch metabolism in Arabidopsis thaliana leaves using graphical Gaussian model

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    Ingkasuwan Papapit

    2012-08-01

    Full Text Available Abstract Background Starch serves as a temporal storage of carbohydrates in plant leaves during day/night cycles. To study transcriptional regulatory modules of this dynamic metabolic process, we conducted gene regulation network analysis based on small-sample inference of graphical Gaussian model (GGM. Results Time-series significant analysis was applied for Arabidopsis leaf transcriptome data to obtain a set of genes that are highly regulated under a diurnal cycle. A total of 1,480 diurnally regulated genes included 21 starch metabolic enzymes, 6 clock-associated genes, and 106 transcription factors (TF. A starch-clock-TF gene regulation network comprising 117 nodes and 266 edges was constructed by GGM from these 133 significant genes that are potentially related to the diurnal control of starch metabolism. From this network, we found that β-amylase 3 (b-amy3: At4g17090, which participates in starch degradation in chloroplast, is the most frequently connected gene (a hub gene. The robustness of gene-to-gene regulatory network was further analyzed by TF binding site prediction and by evaluating global co-expression of TFs and target starch metabolic enzymes. As a result, two TFs, indeterminate domain 5 (AtIDD5: At2g02070 and constans-like (COL: At2g21320, were identified as positive regulators of starch synthase 4 (SS4: At4g18240. The inference model of AtIDD5-dependent positive regulation of SS4 gene expression was experimentally supported by decreased SS4 mRNA accumulation in Atidd5 mutant plants during the light period of both short and long day conditions. COL was also shown to positively control SS4 mRNA accumulation. Furthermore, the knockout of AtIDD5 and COL led to deformation of chloroplast and its contained starch granules. This deformity also affected the number of starch granules per chloroplast, which increased significantly in both knockout mutant lines. Conclusions In this study, we utilized a systematic approach of microarray

  4. TIMP3 interplays with apelin to regulate cardiovascular metabolism in hypercholesterolemic mice

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    Robert Stöhr

    2015-10-01

    Conclusion: TIMP3 regulates lipid metabolism as well as oxidative stress response via apelin. These findings therefore suggest that TIMP3 maintains metabolic flexibility in the heart, particularly during episodes of increased cardiac stress.

  5. Nucleotide synthesis is regulated by cytoophidium formation during neurodevelopment and adaptive metabolism

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    Gabriel N. Aughey

    2014-10-01

    Full Text Available The essential metabolic enzyme CTP synthase (CTPsyn can be compartmentalised to form an evolutionarily-conserved intracellular structure termed the cytoophidium. Recently, it has been demonstrated that the enzymatic activity of CTPsyn is attenuated by incorporation into cytoophidia in bacteria and yeast cells. Here we demonstrate that CTPsyn is regulated in a similar manner in Drosophila tissues in vivo. We show that cytoophidium formation occurs during nutrient deprivation in cultured cells, as well as in quiescent and starved neuroblasts of the Drosophila larval central nervous system. We also show that cytoophidia formation is reversible during neurogenesis, indicating that filament formation regulates pyrimidine synthesis in a normal developmental context. Furthermore, our global metabolic profiling demonstrates that CTPsyn overexpression does not significantly alter CTPsyn-related enzymatic activity, suggesting that cytoophidium formation facilitates metabolic stabilisation. In addition, we show that overexpression of CTPsyn only results in moderate increase of CTP pool in human stable cell lines. Together, our study provides experimental evidence, and a mathematical model, for the hypothesis that inactive CTPsyn is incorporated into cytoophidia.

  6. The logics of metabolic regulation in bacteria challenges biosensor-based metabolic engineering

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    Matthieu Jules

    2017-12-01

    Full Text Available Synthetic Biology (SB aims at the rational design and engineering of novel biological functions and systems. By facilitating the engineering of living organisms, SB promises to facilitate the development of many new applications for health, biomanufacturing, and the environment. Over the last decade, SB promoted the construction of libraries of components enabling the fine-tuning of genetic circuits expression and the development of novel genome engineering methodologies for many organisms of interest. SB thus opened new perspectives in the field of metabolic engineering, which was until then mainly limited to (overproducing naturally synthesized metabolic compounds. To engineer efficient cell factories, it is key to precisely reroute cellular resources from the central carbon metabolism (CCM to the synthetic circuitry. This task is however difficult as there is still significant lack of knowledge regarding both the function of several metabolic components and the regulation of the CCM fluxes for many industrially important bacteria. Pyruvate is a pivotal metabolite at the heart of the CCM and a key precursor for the synthesis of several commodity compounds and fine chemicals. Numerous bacterial species can also use it as a carbon source when present in the environment but bacterial, pyruvate-specific uptake systems were to be discovered. This is an issue for metabolic engineering as one can imagine to make use of pyruvate transport systems to replenish synthetic metabolic pathways towards the synthesis of chemicals of interest. Here we describe a recent study (MBio 8(5: e00976-17, which identified and characterized a pyruvate transport system in the Gram-positive (G+ve bacterium Bacillus subtilis, a well-established biotechnological workhorse for the production of enzymes, fine chemicals and antibiotics. This study also revealed that the activity of the two-component system (TCS responsible for its induction is retro-inhibited by the level of

  7. miRNA regulation of LDL-cholesterol metabolism.

    Science.gov (United States)

    Goedeke, Leigh; Wagschal, Alexandre; Fernández-Hernando, Carlos; Näär, Anders M

    2016-12-01

    In the past decade, microRNAs (miRNAs) have emerged as key regulators of circulating levels of lipoproteins. Specifically, recent work has uncovered the role of miRNAs in controlling the levels of atherogenic low-density lipoprotein LDL (LDL)-cholesterol by post-transcriptionally regulating genes involved in very low-density lipoprotein (VLDL) secretion, cholesterol biosynthesis, and hepatic LDL receptor (LDLR) expression. Interestingly, several of these miRNAs are located in genomic loci associated with abnormal levels of circulating lipids in humans. These findings reinforce the interest of targeting this subset of non-coding RNAs as potential therapeutic avenues for regulating plasma cholesterol and triglyceride (TAG) levels. In this review, we will discuss how these new miRNAs represent potential pre-disposition factors for cardiovascular disease (CVD), and putative therapeutic targets in patients with cardiometabolic disorders. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Regulation of glycolysis and level of the Crassulacean acid metabolism.

    Science.gov (United States)

    Pierre, J N; Queiroz, O

    1979-01-01

    Glycolysis shows different patterns of operation and different control steps, depending on whether the level of Crassulacean acid metabolism (CAM) is low or high in the leaves of Kalanchoe blossfeldiana v.Poelln., when subjected to appropriate photoperiodic treatments: at a low level of CAM operation all the enzymes of glycolysis and phosphoenol pyruvate (PEP) carboxylase present a 12 h rhythm of capacity, resulting from the superposition of two 24h rhythms out of phase; phosphofructokinase appears to be the main regulation step; attainment of high CAM level involves (1) an increase in the peak of capacity occurring during the night of all the glycolytic enzymes, thus achieving an over-all 24h rhythm, in strict allometric coherence with the increase in PEP carboxylase capacity, (2) the establishment of different phase relationships between the rhythms of enzyme capacity, and (3) the control of three enzymic steps (phosphofructokinase, the group 3-P-glyceraldehyde dehydrogenase - 3-P-glycerate kinase, and PEP carboxylase). Results show that the hypothesis of allosteric regulation of phosphofructokinase (by PEP) and PEP carboxylase (by malate and glucose-6-P) cannot provide a complete explanation for the temporal organization of glycolysis and that changes in the phase relationships between the rhythms of enzyme capacity along the pathway and a strict correlation between the level of PEP carboxylase capacity and the levels of capacity of the glycolytic enzymes are important components of the regulation of glycolysis in relation to CAM.

  9. Metabolic regulation during sport events: factual interpretations and inadequate allegations

    Directory of Open Access Journals (Sweden)

    Jacques Remy Poortmans

    2013-09-01

    Full Text Available Different fuels are available to generate ATP for muscle activities during sport events. Glycogen from striated muscles and liver stores may be converted to lactic acid or almost completely oxidized to carbon dioxide (CO2, triacylglycerol within the muscle itself and fatty acids from adipose tissue could be converted to CO2 in acting muscles, some free amino acids can be released within the muscle itself and from intestinal stores to sustain the amount of ATP generation indispensable for muscle contraction. All single biochemical reactions, but one, need one or several enzymes to activate the conversion of a substrate into a product. The energy transformation in biochemical reactions is led by application of so-called free energy. Reversible and non-reversible reactions within a metabolic pathway are dependent on specific enzymes near or far from equilibrium. Allosteric enzymes are regulatory enzymes that provide the direction in the pathway. A regulatory enzyme is either activated or inhibited by small regulators (ligands. A reversible substrate cycle between A and B is catalyzed by two enzymes with different fluxes. The need of ATP production for muscle contraction is under the leadership of regulatory enzymes and available substrate stores. The improvement of adapted metabolic reactions under sport training depends on the appropriate increase of regulatory enzymes within the glycolytic and oxidative pathways. The amount of some specific enzymes is increased by training in order to improve the maximum activity of the metabolic pathway. Unfortunately, several publications do not precisely implicate the appropriate enzyme(s to explain or reject the adaptation induced by the training schedule. A few examples will illustrate the factual interpretation and the inadequate allegation.

  10. Hepcidin: an important iron metabolism regulator in chronic kidney disease

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    Sandra Azevedo Antunes

    Full Text Available Abstract Anemia is a common complication and its impact on morbimortality in patients with chronic kidney disease (CKD is well known. The discovery of hepcidin and its functions has contributed to a better understanding of iron metabolism disorders in CKD anemia. Hepcidin is a peptide mainly produced by hepatocytes and, through a connection with ferroportin, it regulates iron absorption in the duodenum and its release of stock cells. High hepcidin concentrations described in patients with CKD, especially in more advanced stages are attributed to decreased renal excretion and increased production. The elevation of hepcidin has been associated with infection, inflammation, atherosclerosis, insulin resistance and oxidative stress. Some strategies were tested to reduce the effects of hepcidin in patients with CKD, however more studies are necessary to assess the impact of its modulation in the management of anemia in this population.

  11. Ghrelin in the regulation of body weight and metabolism.

    Science.gov (United States)

    Castañeda, T R; Tong, J; Datta, R; Culler, M; Tschöp, M H

    2010-01-01

    Ghrelin, a peptide hormone predominantly produced by the stomach, was isolated as the endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is a potent stimulator of growth hormone (GH) secretion and is the only circulatory hormone known to potently enhance feeding and weight gain and to regulate energy homeostasis following central and systemic administration. Therapeutic intervention with ghrelin in catabolic situations may induce a combination of enhanced food intake, increased gastric emptying and nutrient storage, coupled with an increase in GH thereby linking nutrient partitioning with growth and repair processes. These qualities have fostered the idea that ghrelin-based compounds may have therapeutic utility in treating malnutrition and wasting induced by various sub-acute and chronic disorders. Conversely, compounds that inhibit ghrelin action may be useful for the prevention or treatment of metabolic syndrome components such as obesity, impaired lipid metabolism or insulin resistance. In recent years, the effects of ghrelin on glucose homeostasis, memory function and gastrointestinal motility have attracted considerable amount of attention and revealed novel therapeutic targets in treating a wide range of pathologic conditions. Furthermore, discovery of ghrelin O-acyltransferase has also opened new research opportunities that could lead to major understanding of ghrelin physiology. This review summarizes the current knowledge on ghrelin synthesis, secretion, mechanism of action and biological functions with an additional focus on potential for ghrelin-based pharmacotherapies. 2009 Elsevier Inc. All rights reserved.

  12. Endocrine regulation of carbohydrate metabolism in hypometabolic animals

    Science.gov (United States)

    Musacchia, X. J.

    1988-01-01

    Experimental hypothermia and natural hibernation are two forms of hypometabolism with recognized physiological changes, including depression of endocrine and metabolic functions. To better understand functional changes, helox (i.e., helium and oxygen (80:20) mixtures) and low ambient temperatures have been used to induce hypothermia in hamsters and rats. Both clinical and biological survival, i.e., survival without recovery and survival with recovery from hypothermia, respectively, are related to depth and length of hypothermia. In the rat, body temperatures of 15 degrees C for periods greater than 6-10 h greatly restrict biological survival. The role of glucocorticoids in enhancing thermogenic capacity of rats was assessed using triamcinolone [correction of triamcinalone] acetonide. In the hamster, treatment with cortisone acetate prolonged both clinical and biological survival. Hypothermic hamsters continue utilizing circulating glucose until they become hypoglycemic and die. Hypothermic rats do not utilize glucose and respond with a significant hypoinsulinema. The role of endocrines in the regulation of carbohydrate homeostasis and metabolism differs in hibernation and hypothermia. Glucocorticoids influence the hypothermic response in both species, specifically by prolonging induction of hypothermia in rats and by prolonging survival in hypothermic hamsters.

  13. [Thiamine and its derivatives in the regulation of cell metabolism].

    Science.gov (United States)

    Tylicki, Adam; Siemieniuk, Magdalena

    2011-07-06

    For over 70 years thiamine (vitamin B1) has aroused the interest of biologists, biochemists and medical doctors because of its multilateral participation in key biochemical and physiological processes. The thiamine molecule is composed of pyrimidine and thiazole rings which are linked by a methylene bridge. It is synthesized by microorganisms, fungi and plants, whereas animals and humans have to obtain it from food. There are several known forms of vitamin B1 inside cells: free thiamine, three phosphate esters (mono-, di-, and triphosphate), and the recently found adenosine thiamine triphosphate. Thiamine has a dual, coenzymatic and non-coenzymatic role. First of all, it is a precursor of thiamin diphosphate, which is a coenzyme for over 20 characterized enzymes which are involved in cell bioenergetic processes leading to the synthesis of ATP. Moreover, these enzymes take part in the biosynthesis of pentose (required for the synthesis of nucleotides), amino acids and other organic compounds of cell metabolism. On the other hand, recent discoveries show the non-coenzymatic role of thiamine derivatives in the process of regulation of gene expression (riboswitches in microorganisms and plants), the stress response, and perhaps so far unknown signal transduction pathways associated with adverse environmental conditions, or transduction of nerve signals with participation of thiamine triphosphate and adenosine thiamine triphosphate. From the clinical point of view thiamine deficiency is related to beri-beri, Parkinson disease, Alzheimer disease, Wernicke-Korsakoff syndrome and other pathologies of the nervous system, and it is successfully applied in medical practice. On the other hand, identifying new synthetic analogues of thiamine which could be used as cytostatics, herbicides or agents preventing deficiency of vitamin B1 is currently the major goal of the research. In this paper we present the current state of knowledge of thiamine and its derivatives, indicating

  14. Plate tectonic regulation of global marine animal diversity

    Science.gov (United States)

    Zaffos, Andrew; Finnegan, Seth; Peters, Shanan E.

    2017-05-01

    Valentine and Moores [Valentine JW, Moores EM (1970) Nature 228:657-659] hypothesized that plate tectonics regulates global biodiversity by changing the geographic arrangement of continental crust, but the data required to fully test the hypothesis were not available. Here, we use a global database of marine animal fossil occurrences and a paleogeographic reconstruction model to test the hypothesis that temporal patterns of continental fragmentation have impacted global Phanerozoic biodiversity. We find a positive correlation between global marine invertebrate genus richness and an independently derived quantitative index describing the fragmentation of continental crust during supercontinental coalescence-breakup cycles. The observed positive correlation between global biodiversity and continental fragmentation is not readily attributable to commonly cited vagaries of the fossil record, including changing quantities of marine rock or time-variable sampling effort. Because many different environmental and biotic factors may covary with changes in the geographic arrangement of continental crust, it is difficult to identify a specific causal mechanism. However, cross-correlation indicates that the state of continental fragmentation at a given time is positively correlated with the state of global biodiversity for tens of millions of years afterward. There is also evidence to suggest that continental fragmentation promotes increasing marine richness, but that coalescence alone has only a small negative or stabilizing effect. Together, these results suggest that continental fragmentation, particularly during the Mesozoic breakup of the supercontinent Pangaea, has exerted a first-order control on the long-term trajectory of Phanerozoic marine animal diversity.

  15. Global health security and the International Health Regulations

    Directory of Open Access Journals (Sweden)

    Oliva Otavio

    2010-12-01

    Full Text Available Abstract Global nuclear proliferation, bioterrorism, and emerging infections have challenged national capacities to achieve and maintain global security. Over the last century, emerging infectious disease threats resulted in the development of the preliminary versions of the International Health Regulations (IHR of the World Health Organization (WHO. The current HR(2005 contain major differences compared to earlier versions, including: substantial shifts from containment at the border to containment at the source of the event; shifts from a rather small disease list (smallpox, plague, cholera, and yellow fever required to be reported, to all public health threats; and shifts from preset measures to tailored responses with more flexibility to deal with the local situations on the ground. The new IHR(2005 call for accountability. They also call for strengthened national capacity for surveillance and control; prevention, alert, and response to international public health emergencies beyond the traditional short list of required reporting; global partnership and collaboration; and human rights, obligations, accountability, and procedures of monitoring. Under these evolved regulations, as well as other measures, such as the Revolving Fund for vaccine procurement of the Pan American Health Organization (PAHO, global health security could be maintained in the response to urban yellow fever in Paraguay in 2008 and the influenza (H1N1 pandemic of 2009-2010.

  16. Local and global responses in complex gene regulation networks

    Science.gov (United States)

    Tsuchiya, Masa; Selvarajoo, Kumar; Piras, Vincent; Tomita, Masaru; Giuliani, Alessandro

    2009-04-01

    An exacerbated sensitivity to apparently minor stimuli and a general resilience of the entire system stay together side-by-side in biological systems. This apparent paradox can be explained by the consideration of biological systems as very strongly interconnected network systems. Some nodes of these networks, thanks to their peculiar location in the network architecture, are responsible for the sensitivity aspects, while the large degree of interconnection is at the basis of the resilience properties of the system. One relevant feature of the high degree of connectivity of gene regulation networks is the emergence of collective ordered phenomena influencing the entire genome and not only a specific portion of transcripts. The great majority of existing gene regulation models give the impression of purely local ‘hard-wired’ mechanisms disregarding the emergence of global ordered behavior encompassing thousands of genes while the general, genome wide, aspects are less known. Here we address, on a data analysis perspective, the discrimination between local and global scale regulations, this goal was achieved by means of the examination of two biological systems: innate immune response in macrophages and oscillating growth dynamics in yeast. Our aim was to reconcile the ‘hard-wired’ local view of gene regulation with a global continuous and scalable one borrowed from statistical physics. This reconciliation is based on the network paradigm in which the local ‘hard-wired’ activities correspond to the activation of specific crucial nodes in the regulation network, while the scalable continuous responses can be equated to the collective oscillations of the network after a perturbation.

  17. Hegemonic transitions and global shifts in social metabolism: Implications for resource-rich countries. Introduction to the special section

    NARCIS (Netherlands)

    Muradian Sarache, R.P.; Walter, M.; Martinez-Alier, J.

    2012-01-01

    This introductory paper to the special section of Global Environmental Change entitled "Global transformations, social metabolism and the dynamics of socio-environmental conflicts" argues that the emergence of new global economic centers is inducing a major expansion in the global social metabolism

  18. Stearoyl-CoA desaturase – the lipid metabolism regulator

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    Mirosław Kucharski

    2014-03-01

    Full Text Available Stearoyl-CoA desaturase is an enzyme from the class of oxidoreductase, which catalyzes the formation of a fatty acid double bond between C9 and C10. It plays a key role in composition of the fatty acid profile in adipose tissue and animal products such as meat and milk. Additionally, it is an important regulator of metabolic processes in the body, and it determines the maintenance of energy homeostasis. This enzyme is encoded by an SCD gene, which, depending on the species, may exist as different isoforms. mRNA expression of stearoyl-CoA desaturase is dependent on many factors, including diet, hormones, and the activity of other genes. In previous studies, several mutations were characterized within the sequence of Δ9-desaturase, which may affect the activity of the protein in the tissues, as well as the value of breeding animals. Effects of particular mutations of the gene encoding the enzyme appears to be particularly important for diseases associated with obesity, diabetes, hypertension, heart diseases or cancer in humans. Also, it seems that using sheep as a potential animal model could be helpful in uncovering and understanding the mechanisms regulated by stearoyl-CoA desaturase.

  19. BONE METABOLISM AND ITS REGULATION IN PATIENTS WITH ANKYLOSING SPONDYLITIS

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    O. V. Bugrova

    2016-01-01

    Full Text Available Osteoporosis in ankylosing spondylitis (AS may exacerbate pain and functional disorders and increases the risk of fractures. The mechanisms  of its development in AS have not been adequately studied.Objective: to study bone mineral density (BMD  and its regulation in patients with AS.Subjects and methods. 70 patients (mean age, 43.2±9.2 years with a documented diagnosis of AS (mean disease duration, 17.1±7.8 years and a control group of 30 healthy individuals were examined. All the patients underwent estimation of BMD and the serum concentrations of osteocalcin,  CrossLaps, and key regulators of osteoclastogenesis, such as osteoprotegerin (OPG  and a receptor activator of nuclear factor kappa-B ligand (RANKL by an enzyme immunoassay. Results and discussion. In patients with AS, bone metabolism was characterized  by a decrease in bone formation and by some increase in bone tissue degradation especially in high AS activity. These patients showed the elevated levels of the major blocker of osteoclastogenesis OPG and the OPG/RANKL ratio, which can cause the process of ossification characteristic  of AS.

  20. A Quantitative Study of Oxygen as a Metabolic Regulator

    Science.gov (United States)

    Radhakrishnan, Krishnan; LaManna, Joseph C.; Cabrera, Marco E.

    1999-01-01

    An acute reduction in oxygen (O2) delivery to a tissue is generally associated with a decrease in phosphocreatine, increases in ADP, NADH/NAD, and inorganic phosphate, increased rates of glycolysis and lactate production, and reduced rates of pyruvate and fatty acid oxidation. However, given the complexity of the human bioenergetic system and its components, it is difficult to determine quantitatively how cellular metabolic processes interact to maintain ATP homeostasis during stress (e.g., hypoxia, ischemia, and exercise). Of special interest is the determination of mechanisms relating tissue oxygenation to observed metabolic responses at the tissue, organ, and whole body levels and the quantification of how changes in tissue O2 availability affect the pathways of ATP synthesis and the metabolites that control these pathways. In this study, we extend a previously developed mathematical model of human bioenergetics to provide a physicochemical framework that permits quantitative understanding of O2 as a metabolic regulator. Specifically, the enhancement permits studying the effects of variations in tissue oxygenation and in parameters controlling the rate of cellular respiration on glycolysis, lactate production, and pyruvate oxidation. The whole body is described as a bioenergetic system consisting of metabolically distinct tissue/organ subsystems that exchange materials with the blood. In order to study the dynamic response of each subsystem to stimuli, we solve the ordinary differential equations describing the temporal evolution of metabolite levels, given the initial concentrations. The solver used in the present study is the packaged code LSODE, as implemented in the NASA Lewis kinetics and sensitivity analysis code, LSENS. A major advantage of LSENS is the efficient procedures supporting systematic sensitivity analysis, which provides the basic methods for studying parameter sensitivities (i.e., changes in model behavior due to parameter variation

  1. Global identification of bursicon-regulated genes in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Beerntsen Brenda

    2008-09-01

    Full Text Available Abstract Background Bursicon is a heterodimer neuropeptide responsible for regulating cuticle sclerotization and wing expansion in several insect species. Recent studies indicate that the action of bursicon is mediated by a specific G protein-coupled receptor DLGR2 and the cAMP/PKA signaling pathway. However, little is known regarding the genes that are regulated by bursicon. The identification of bursicon-regulated genes is the focus of this investigation. Results We used DNA microarray analysis to identify bursicon-regulated genes in neck-ligated flies (Drosophila melanogaster that received recombinant bursicon (r-bursicon. Fifty four genes were found to be regulated by bursicon 1 h post r-bursicon injection, 52 being up-regulated and 2 down-regulated while 33 genes were influenced by r-bursicon 3 h post-injection (24 up-regulated and 9 down-regulated genes. Analysis of these genes by inference from the fly database http://flybase.bio.indiana.edu revealed that these genes encode proteins with diverse functions, including cell signaling, gene transcription, DNA/RNA binding, ion trafficking, proteolysis-peptidolysis, metabolism, cytoskeleton formation, immune response and cell-adhesion. Twenty eight genes randomly selected from the microarray-identified list were verified by real time PCR (qPCR which supported the microarray data. Temporal response studies of 13 identified and verified genes by qPCR revealed that the temporal expression patterns of these genes are consistent with the microarray data. Conclusion Using r-bursicon, we identified 87 genes that are regulated by bursicon, 30 of which have no previously known function. Most importantly, all genes randomly selected from the microarray-identified list were verified by real time PCR. Temporal analysis of 13 verified genes revealed that the expression of these genes was indeed induced by bursicon and correlated well with the cuticle sclerotization process. The composite data suggest that

  2. Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk.

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    Cathy Slack

    2010-03-01

    Full Text Available Drosophila Lnk is the single ancestral orthologue of a highly conserved family of structurally-related intracellular adaptor proteins, the SH2B proteins. As adaptors, they lack catalytic activity but contain several protein-protein interaction domains, thus playing a critical role in signal transduction from receptor tyrosine kinases to form protein networks. Physiological studies of SH2B function in mammals have produced conflicting data. However, a recent study in Drosophila has shown that Lnk is an important regulator of the insulin/insulin-like growth factor (IGF-1 signaling (IIS pathway during growth, functioning in parallel to the insulin receptor substrate, Chico. As this pathway also has an evolutionary conserved role in the determination of organism lifespan, we investigated whether Lnk is required for normal lifespan in Drosophila. Phenotypic analysis of mutants for Lnk revealed that loss of Lnk function results in increased lifespan and improved survival under conditions of oxidative stress and starvation. Starvation resistance was found to be associated with increased metabolic stores of carbohydrates and lipids indicative of impaired metabolism. Biochemical and genetic data suggest that Lnk functions in both the IIS and Ras/Mitogen activated protein Kinase (MapK signaling pathways. Microarray studies support this model, showing transcriptional feedback onto genes in both pathways as well as indicating global changes in both lipid and carbohydrate metabolism. Finally, our data also suggest that Lnk itself may be a direct target of the IIS responsive transcription factor, dFoxo, and that dFoxo may repress Lnk expression. We therefore describe novel functions for a member of the SH2B protein family and provide the first evidence for potential mechanisms of SH2B regulation. Our findings suggest that IIS signaling in Drosophila may require the activity of a second intracellular adaptor, thereby yielding fundamental new insights into the

  3. Global Metabolic Reconstruction and Metabolic Gene Evolution in the Cattle Genome

    Science.gov (United States)

    Kim, Woonsu; Park, Hyesun; Seo, Seongwon

    2016-01-01

    The sequence of cattle genome provided a valuable opportunity to systematically link genetic and metabolic traits of cattle. The objectives of this study were 1) to reconstruct genome-scale cattle-specific metabolic pathways based on the most recent and updated cattle genome build and 2) to identify duplicated metabolic genes in the cattle genome for better understanding of metabolic adaptations in cattle. A bioinformatic pipeline of an organism for amalgamating genomic annotations from multiple sources was updated. Using this, an amalgamated cattle genome database based on UMD_3.1, was created. The amalgamated cattle genome database is composed of a total of 33,292 genes: 19,123 consensus genes between NCBI and Ensembl databases, 8,410 and 5,493 genes only found in NCBI or Ensembl, respectively, and 266 genes from NCBI scaffolds. A metabolic reconstruction of the cattle genome and cattle pathway genome database (PGDB) was also developed using Pathway Tools, followed by an intensive manual curation. The manual curation filled or revised 68 pathway holes, deleted 36 metabolic pathways, and added 23 metabolic pathways. Consequently, the curated cattle PGDB contains 304 metabolic pathways, 2,460 reactions including 2,371 enzymatic reactions, and 4,012 enzymes. Furthermore, this study identified eight duplicated genes in 12 metabolic pathways in the cattle genome compared to human and mouse. Some of these duplicated genes are related with specific hormone biosynthesis and detoxifications. The updated genome-scale metabolic reconstruction is a useful tool for understanding biology and metabolic characteristics in cattle. There has been significant improvements in the quality of cattle genome annotations and the MetaCyc database. The duplicated metabolic genes in the cattle genome compared to human and mouse implies evolutionary changes in the cattle genome and provides a useful information for further research on understanding metabolic adaptations of cattle. PMID

  4. Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator

    Science.gov (United States)

    Usaite, Renata; Jewett, Michael C; Oliveira, Ana Paula; Yates, John R; Olsson, Lisbeth; Nielsen, Jens

    2009-01-01

    Highly conserved among eukaryotic cells, the AMP-activated kinase (AMPK) is a central regulator of carbon metabolism. To map the complete network of interactions around AMPK in yeast (Snf1) and to evaluate the role of its regulatory subunit Snf4, we measured global mRNA, protein and metabolite levels in wild type, Δsnf1, Δsnf4, and Δsnf1Δsnf4 knockout strains. Using four newly developed computational tools, including novel DOGMA sub-network analysis, we showed the benefits of three-level ome-data integration to uncover the global Snf1 kinase role in yeast. We for the first time identified Snf1's global regulation on gene and protein expression levels, and showed that yeast Snf1 has a far more extensive function in controlling energy metabolism than reported earlier. Additionally, we identified complementary roles of Snf1 and Snf4. Similar to the function of AMPK in humans, our findings showed that Snf1 is a low-energy checkpoint and that yeast can be used more extensively as a model system for studying the molecular mechanisms underlying the global regulation of AMPK in mammals, failure of which leads to metabolic diseases. PMID:19888214

  5. Intrinsic limits to gene regulation by global crosstalk

    Science.gov (United States)

    Friedlander, Tamar; Prizak, Roshan; Guet, Calin; Barton, Nicholas H.; Tkacik, Gasper

    Gene activity is mediated by the specificity of binding interactions between special proteins, called transcription factors, and short regulatory sequences on the DNA, where different protein species preferentially bind different DNA targets. Limited interaction specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to spurious interactions or remains erroneously inactive. Since each protein can potentially interact with numerous DNA targets, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyze the effects of global crosstalk on gene regulation, using statistical mechanics. We find that crosstalk in regulatory interactions puts fundamental limits on the reliability of gene regulation that are not easily mitigated by tuning proteins concentrations or by complex regulatory schemes proposed in the literature. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA Grant agreement Nr. 291734 (T.F.) and ERC Grant Nr. 250152 (N.B.).

  6. Metabolic regulation of trisporic acid on Blakeslea trispora revealed by a GC-MS-based metabolomic approach.

    Directory of Open Access Journals (Sweden)

    Jie Sun

    Full Text Available The zygomycete Blakeslea trispora is used commercially as natural source of â-carotene. Trisporic acid (TA is secreted from the mycelium of B. trispora during mating between heterothallic strains and is considered as a mediator of the regulation of mating processes and an enhancer of carotene biosynthesis. Gas chromatography-mass spectrometry and multivariate analysis were employed to investigate TA-associated intracellular biochemical changes in B. trispora. By principal component analysis, the differential metabolites discriminating the control groups from the TA-treated groups were found, which were also confirmed by the subsequent hierarchical cluster analysis. The results indicate that TA is a global regulator and its main effects at the metabolic level are reflected on the content changes in several fatty acids, carbohydrates, and amino acids. The carbon metabolism and fatty acids synthesis are sensitive to TA addition. Glycerol, glutamine, and ã-aminobutyrate might play important roles in the regulation of TA. Complemented by two-dimensional electrophoresis, the results indicate that the actions of TA at the metabolic level involve multiple metabolic processes, such as glycolysis and the bypass of the classical tricarboxylic acid cycle. These results reveal that the metabolomics strategy is a powerful tool to gain insight into the mechanism of a microorganism's cellular response to signal inducers at the metabolic level.

  7. Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging

    NARCIS (Netherlands)

    Sapir, Amir; Tsur, Assaf; Koorman, Thijs; Ching, Kaitlin; Mishra, Prashant; Bardenheier, Annabelle; Podolsky, Lisa; Bening-Abu-Shach, Ulrike; Boxem, Mike; Chou, Tsui-Fen; Broday, Limor; Sternberg, Paul W

    2014-01-01

    Many metabolic pathways are critically regulated during development and aging but little is known about the molecular mechanisms underlying this regulation. One key metabolic cascade in eukaryotes is the mevalonate pathway. It catalyzes the synthesis of sterol and nonsterol isoprenoids, such as

  8. Future development of global regulations of Chinese herbal products.

    Science.gov (United States)

    Fan, Tai-Ping; Deal, Greer; Koo, Hoi-Lun; Rees, Daryl; Sun, He; Chen, Shaw; Dou, Jin-Hui; Makarov, Valery G; Pozharitskaya, Olga N; Shikov, Alexander N; Kim, Yeong Shik; Huang, Yi-Tsau; Chang, Yuan Shiun; Jia, William; Dias, Alberto; Wong, Vivian Chi-Woon; Chan, Kelvin

    2012-04-10

    GP-TCM is the first EU-funded Coordination Action consortium dedicated to traditional Chinese medicine (TCM) research. One of the key deliverables of the Work Package 7 in GP-TCM was to investigate information of the existing requirements for registration of TCM products listed by global regulatory bodies. The paper aims to collate data and draw comparison of these regulations. Case studies are also presented to illustrate the problems involved in registering TCM products in different regions worldwide. A collaborative network task force was established during the early stage of the GP-TCM project and operated through exchanges, teleconferences and focused discussions at annual meetings. The task force involved coordinators, academics who are actively involved with R&D of Chinese herbal medicines, experts on monographic standards of Chinese materia medica, representatives from regulatory agencies, experts from industries in marketing Chinese medicines/herbal medicines and natural products. The co-ordinators took turns to chair teleconferences, led discussions on specific issues at AGM discussion sessions, at joint workshops with other work-packages such as WP1 (quality issues), WP3 (toxicology issues) and WP6 (clinical trial issues). Collectively the authors were responsible for collating discussion outcomes and updating written information. A global overview of regulations on herbal registration has been compiled during the three years of the consortium. The regulatory requirements for registration of herbal products in the EU and China were compared, and this is extended to other regions/countries: Africa, Australia, Brazil, Canada, Japan, Russia, South Korea, Taiwan, and the United States. A wide variation of the regulations for the categories of herbal products exists: food (functional food, novel foods, dietary food for special medical purpose, foods for particular nutritional use, food supplement); cosmetic, traditional herbal medicine products; herbal

  9. p73 regulates basal and starvation-induced liver metabolism in vivo

    OpenAIRE

    He, Zhaoyue; Agostini, Massimiliano; Liu, He; Melino, Gerry; Simon, Hans-Uwe

    2015-01-01

    As a member of the p53 gene family, p73 regulates cell cycle arrest, apoptosis, neurogenesis, immunity and inflammation. Recently, p73 has been shown to transcriptionally regulate selective metabolic enzymes, such as cytochrome c oxidase subunit IV isoform 1, glucose 6-phosphate dehydrogenase and glutaminase-2, resulting in significant effects on metabolism, including hepatocellular lipid metabolism, glutathione homeostasis and the pentose phosphate pathway. In order to further investigate th...

  10. BAD-Dependent Regulation of Fuel Metabolism and KATP Channel Activity Confers Resistance to Epileptic Seizures

    OpenAIRE

    Giménez-Cassina, Alfredo; Martínez-François, Juan Ramón; Fisher, Jill K.; Szlyk, Benjamin; Polak, Klaudia; Wiwczar, Jessica; Tanner, Geoffrey R.; Lutas, Andrew; Yellen, Gary; Danial, Nika N.

    2012-01-01

    Neuronal excitation can be substantially modulated by alterations in metabolism, as evident from the anticonvulsant effect of diets that reduce glucose utilization and promote ketone body metabolism. We provide genetic evidence that BAD, a protein with dual functions in apoptosis and glucose metabolism, imparts reciprocal effects on metabolism of glucose and ketone bodies in brain cells. These effects involve phospho-regulation of BAD and are independent of its apoptotic function. BAD modific...

  11. Regulation of Mammalian Metabolism by Facilitated Transport Across the Inner Mitochondrial Membrane

    OpenAIRE

    Vacanti, Nathaniel Martin

    2015-01-01

    The enzymes and reactions of the metabolic network provide cells with a means to utilize the energy stored in substrate chemical bonds and to rearrange those bonds to form biosynthetic building blocks. The chapters of this dissertation are all independent bodies of work exploring how the metabolic network influences and regulates cellular function or dysfunction. Chapter 1, titled "Exploring Metabolic Pathways that Contribute to the Stem Cell Phenotype", is a case study on how the metabolic n...

  12. Thyroid hormone’s role in regulating brain glucose metabolism and potentially modulating hippocampal cognitive processes

    Science.gov (United States)

    Jahagirdar, V; McNay, EC

    2012-01-01

    Cognitive performance is dependent on adequate glucose supply to the brain. Insulin, which regulates systemic glucose metabolism, has been recently shown both to regulate hippocampal metabolism and to be a mandatory component of hippocampally-mediated cognitive performance. Thyroid hormones (TH) regulate systemic glucose metabolism and may also be involved in regulation of brain glucose metabolism. Here we review potential mechanisms for such regulation. Importantly, TH imbalance is often encountered in combination with metabolic disorders, such as diabetes, and may cause additional metabolic dysregulation and hence worsening of disease states. TH’s potential as a regulator of brain glucose metabolism is heightened by interactions with insulin signaling, but there have been relatively few studies on this topic or on the actions of TH in a mature brain. This review discusses evidence for mechanistic links between TH, insulin, cognitive function, and brain glucose metabolism, and suggests that TH is a good candidate to be a modulator of memory processes, likely at least in part by modulation of central insulin signaling and glucose metabolism. PMID:22437199

  13. Signaling Pathways Regulating Redox Balance in Cancer Metabolism.

    Science.gov (United States)

    De Santis, Maria Chiara; Porporato, Paolo Ettore; Martini, Miriam; Morandi, Andrea

    2018-01-01

    The interplay between rewiring tumor metabolism and oncogenic driver mutations is only beginning to be appreciated. Metabolic deregulation has been described for decades as a bystander effect of genomic aberrations. However, for the biology of malignant cells, metabolic reprogramming is essential to tackle a harsh environment, including nutrient deprivation, reactive oxygen species production, and oxygen withdrawal. Besides the well-investigated glycolytic metabolism, it is emerging that several other metabolic fluxes are relevant for tumorigenesis in supporting redox balance, most notably pentose phosphate pathway, folate, and mitochondrial metabolism. The relationship between metabolic rewiring and mutant genes is still unclear and, therefore, we will discuss how metabolic needs and oncogene mutations influence each other to satisfy cancer cells' demands. Mutations in oncogenes, i.e., PI3K/AKT/mTOR, RAS pathway, and MYC, and tumor suppressors, i.e., p53 and liver kinase B1, result in metabolic flexibility and may influence response to therapy. Since metabolic rewiring is shaped by oncogenic driver mutations, understanding how specific alterations in signaling pathways affect different metabolic fluxes will be instrumental for the development of novel targeted therapies. In the era of personalized medicine, the combination of driver mutations, metabolite levels, and tissue of origins will pave the way to innovative therapeutic interventions.

  14. Global patterns in lake ecosystem responses to warming based on the temperature dependence of metabolism.

    Science.gov (United States)

    Kraemer, Benjamin M; Chandra, Sudeep; Dell, Anthony I; Dix, Margaret; Kuusisto, Esko; Livingstone, David M; Schladow, S Geoffrey; Silow, Eugene; Sitoki, Lewis M; Tamatamah, Rashid; McIntyre, Peter B

    2017-05-01

    Climate warming is expected to have large effects on ecosystems in part due to the temperature dependence of metabolism. The responses of metabolic rates to climate warming may be greatest in the tropics and at low elevations because mean temperatures are warmer there and metabolic rates respond exponentially to temperature (with exponents >1). However, if warming rates are sufficiently fast in higher latitude/elevation lakes, metabolic rate responses to warming may still be greater there even though metabolic rates respond exponentially to temperature. Thus, a wide range of global patterns in the magnitude of metabolic rate responses to warming could emerge depending on global patterns of temperature and warming rates. Here we use the Boltzmann-Arrhenius equation, published estimates of activation energy, and time series of temperature from 271 lakes to estimate long-term (1970-2010) changes in 64 metabolic processes in lakes. The estimated responses of metabolic processes to warming were usually greatest in tropical/low-elevation lakes even though surface temperatures in higher latitude/elevation lakes are warming faster. However, when the thermal sensitivity of a metabolic process is especially weak, higher latitude/elevation lakes had larger responses to warming in parallel with warming rates. Our results show that the sensitivity of a given response to temperature (as described by its activation energy) provides a simple heuristic for predicting whether tropical/low-elevation lakes will have larger or smaller metabolic responses to warming than higher latitude/elevation lakes. Overall, we conclude that the direct metabolic consequences of lake warming are likely to be felt most strongly at low latitudes and low elevations where metabolism-linked ecosystem services may be most affected. © 2016 John Wiley & Sons Ltd.

  15. Cell shape regulates global histone acetylation in human mammaryepithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Le Beyec, Johanne; Xu, Ren; Lee, Sun-Young; Nelson, Celeste M.; Rizki, Aylin; Alcaraz, Jordi; Bissell, Mina J.

    2007-02-28

    Extracellular matrix (ECM) regulates cell morphology and gene expression in vivo; these relationships are maintained in three-dimensional (3D) cultures of mammary epithelial cells. In the presence of laminin-rich ECM (lrECM), mammary epithelial cells round up and undergo global histone deacetylation, a process critical for their functional differentiation. However, it remains unclear whether lrECM-dependent cell rounding and global histone deacetylation are indeed part of a common physical-biochemical pathway. Using 3D cultures as well as nonadhesive and micropatterned substrata, here we showed that the cell 'rounding' caused by lrECM was sufficient to induce deacetylation of histones H3 and H4 in the absence of biochemical cues. Microarray and confocal analysis demonstrated that this deacetylation in 3D culture is associated with a global increase in chromatin condensation and a reduction in gene expression. Whereas cells cultured on plastic substrata formed prominent stress fibers, cells grown in 3D lrECM or on micropatterns lacked these structures. Disruption of the actin cytoskeleton with cytochalasin D phenocopied the lrECM-induced cell rounding and histone deacetylation. These results reveal a novel link between ECM-controlled cell shape and chromatin structure, and suggest that this link is mediated by changes in the actin cytoskeleton.

  16. translin is required for metabolic regulation of sleep

    OpenAIRE

    Murakami, Kazuma; Yurgel, Maria E.; Stahl, Bethany A.; Masek, Pavel; Mehta, Aradhana; Heidker, Rebecca; Bollinger, Wesley; Gingras, Robert M.; Kim, Young-Joon; Ja, William W.; Suter, Beat; DiAngelo, Justin R.; Keene, Alex C.

    2016-01-01

    Dysregulation of sleep or feeding has enormous health consequences. In humans, acute sleep loss is associated with increased appetite and insulin insensitivity, while chronically sleep-deprived individuals are more likely to develop obesity, metabolic syndrome, type II diabetes, and cardiovascular disease. Conversely, metabolic state potently modulates sleep and circadian behavior; yet, the molecular basis for sleep-metabolism interactions remains poorly understood. Here, we describe the iden...

  17. PamR, a new MarR-like regulator affecting prophages and metabolic genes expression in Bacillus subtilis.

    Directory of Open Access Journals (Sweden)

    Alba De San Eustaquio-Campillo

    Full Text Available B. subtilis adapts to changing environments by reprogramming its genetic expression through a variety of transcriptional regulators from the global transition state regulators that allow a complete resetting of the cell genetic expression, to stress specific regulators controlling only a limited number of key genes required for optimal adaptation. Among them, MarR-type transcriptional regulators are known to respond to a variety of stresses including antibiotics or oxidative stress, and to control catabolic or virulence gene expression. Here we report the characterization of the ydcFGH operon of B. subtilis, containing a putative MarR-type transcriptional regulator. Using a combination of molecular genetics and high-throughput approaches, we show that this regulator, renamed PamR, controls directly its own expression and influence the expression of large sets of prophage-related and metabolic genes. The extent of the regulon impacted by PamR suggests that this regulator reprograms the metabolic landscape of B. subtilis in response to a yet unknown signal.

  18. The Central Metabolism Regulator EIIAGlc Switches Salmonella from Growth Arrest to Acute Virulence through Activation of Virulence Factor Secretion

    Directory of Open Access Journals (Sweden)

    Alain Mazé

    2014-06-01

    Full Text Available The ability of Salmonella to cause disease depends on metabolic activities and virulence factors. Here, we show that a key metabolic protein, EIIAGlc, is absolutely essential for acute infection, but not for Salmonella survival, in a mouse typhoid fever model. Surprisingly, phosphorylation-dependent EIIAGlc functions, including carbohydrate transport and activation of adenylate cyclase for global regulation, do not explain this virulence phenotype. Instead, biochemical studies, in vitro secretion and translocation assays, and in vivo genetic epistasis experiments suggest that EIIAGlc binds to the type three secretion system 2 (TTSS-2 involved in systemic virulence, stabilizes its cytoplasmic part including the crucial TTSS-2 ATPase, and activates virulence factor secretion. This unexpected role of EIIAGlc reveals a striking direct link between central Salmonella metabolism and a crucial virulence mechanism.

  19. Histaminergic regulation of seasonal metabolic rhythms in Siberian hamsters.

    Science.gov (United States)

    I'anson, Helen; Jethwa, Preeti H; Warner, Amy; Ebling, Francis J P

    2011-06-01

    We investigated whether histaminergic tone contributes to the seasonal catabolic state in Siberian hamsters by determining the effect of ablation of histaminergic neurons on food intake, metabolic rate and body weight. A ribosomal toxin (saporin) conjugated to orexin-B was infused into the ventral tuberomammillary region of the hypothalamus, since most histaminergic neurons express orexin receptors. This caused not only 75-80% loss of histaminergic neurons in the posterior hypothalamus, but also some loss of other orexin-receptor expressing cells e.g. MCH neurons. In the long-day anabolic state, lesions produced a transient post-surgical decrease in body weight, but the hamsters recovered and maintained constant body weight, whereas weight gradually increased in sham-lesioned hamsters. VO(2) in the dark phase was significantly higher in the lesioned hamsters compared to shams, and locomotor activity also tended to be higher. In a second study in short days, sham-treated hamsters showed the expected seasonal decrease in body weight, but weight remained constant in the lesioned hamsters, as in the long-day study. Lesioned hamsters consumed more during the early dark phase and less during the light phase due to an increase in the frequency of meals during the dark and decreased meal size during the light, and their cumulative food intake in their home cages was greater than in the control hamsters. In summary, ablation of orexin-responsive cells in the posterior hypothalamus blocks the short-day induced decline in body weight by preventing seasonal hypophagia, evidence consistent with the hypothesis that central histaminergic mechanisms contribute to long-term regulation of body weight. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Globalization of environmental regulations for offshore E & P operations

    Energy Technology Data Exchange (ETDEWEB)

    Shannon, B.E.

    1995-12-31

    One of the enduring legacies of the Rio Environmental Summit of 1992 (United Nations Conference on Environment and Development, UNCED) is Agenda 21 (Chapter 17 - Protection of the Oceans), which among other things called for the assessment of the need for a global authority to regulate offshore Exploration & Production (E&P) discharges, emissions and safety. Despite advice to the contrary from the International Maritime Organization (IMO), interest is building within the European community for the standardization of regulations for offshore E&P activities. Several international of regulations for offshore E&P activities. Several international frameworks or forums have been mentioned as possible candidates. These include the United Nations Convention on the Law of the Sea, 1982 (UNCLOS); London Convention 1972 (LC 1972) and the International Convention for the Prevention of Pollution from Ships, 1973, as modified by the Protocol of 1978 (MARPOL) 73/78. International offshore oil and gas operators operate within requirements of regional conventions under the United Nations Environmental Program`s (UNEP) - Regional Seas Program. Domestic offshore operations are undertaken under the auspices of the U.S. Environmental Protection Agency and Minerals Management Service.

  1. The Hunger Games: p53 regulates metabolism upon serine starvation.

    Science.gov (United States)

    Tavana, Omid; Gu, Wei

    2013-02-05

    Cancer cells reprogram their metabolism to support a high proliferative rate. A new study shows that, upon serine starvation, the tumor suppressor p53 activates p21 to shift metabolic flux from purine biosynthesis to glutathione production, which enhances cellular proliferation and viability by combating ROS (Maddocks et al., 2013). Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Activating transcription factor 3 regulates immune and metabolic homeostasis.

    Science.gov (United States)

    Rynes, Jan; Donohoe, Colin D; Frommolt, Peter; Brodesser, Susanne; Jindra, Marek; Uhlirova, Mirka

    2012-10-01

    Integration of metabolic and immune responses during animal development ensures energy balance, permitting both growth and defense. Disturbed homeostasis causes organ failure, growth retardation, and metabolic disorders. Here, we show that the Drosophila melanogaster activating transcription factor 3 (Atf3) safeguards metabolic and immune system homeostasis. Loss of Atf3 results in chronic inflammation and starvation responses mounted primarily by the larval gut epithelium, while the fat body suffers lipid overload, causing energy imbalance and death. Hyperactive proinflammatory and stress signaling through NF-κB/Relish, Jun N-terminal kinase, and FOXO in atf3 mutants deregulates genes important for immune defense, digestion, and lipid metabolism. Reducing the dose of either FOXO or Relish normalizes both lipid metabolism and gene expression in atf3 mutants. The function of Atf3 is conserved, as human ATF3 averts some of the Drosophila mutant phenotypes, improving their survival. The single Drosophila Atf3 may incorporate the diversified roles of two related mammalian proteins.

  3. Regulation of sucrose metabolism in higher plants: localization and regulation of activity of key enzymes

    Science.gov (United States)

    Winter, H.; Huber, S. C.; Brown, C. S. (Principal Investigator)

    2000-01-01

    Sucrose (Suc) plays a central role in plant growth and development. It is a major end product of photosynthesis and functions as a primary transport sugar and in some cases as a direct or indirect regulator of gene expression. Research during the last 2 decades has identified the pathways involved and which enzymes contribute to the control of flux. Availability of metabolites for Suc synthesis and 'demand' for products of sucrose degradation are important factors, but this review specifically focuses on the biosynthetic enzyme sucrose-phosphate synthase (SPS), and the degradative enzymes, sucrose synthase (SuSy), and the invertases. Recent progress has included the cloning of genes encoding these enzymes and the elucidation of posttranslational regulatory mechanisms. Protein phosphorylation is emerging as an important mechanism controlling SPS activity in response to various environmental and endogenous signals. In terms of Suc degradation, invertase-catalyzed hydrolysis generally has been associated with cell expansion, whereas SuSy-catalyzed metabolism has been linked with biosynthetic processes (e.g., cell wall or storage products). Recent results indicate that SuSy may be localized in multiple cellular compartments: (1) as a soluble enzyme in the cytosol (as traditionally assumed); (2) associated with the plasma membrane; and (3) associated with the actin cytoskeleton. Phosphorylation of SuSy has been shown to occur and may be one of the factors controlling localization of the enzyme. The purpose of this review is to summarize some of the recent developments relating to regulation of activity and localization of key enzymes involved in sucrose metabolism in plants.

  4. Global parameter estimation for thermodynamic models of transcriptional regulation.

    Science.gov (United States)

    Suleimenov, Yerzhan; Ay, Ahmet; Samee, Md Abul Hassan; Dresch, Jacqueline M; Sinha, Saurabh; Arnosti, David N

    2013-07-15

    Deciphering the mechanisms involved in gene regulation holds the key to understanding the control of central biological processes, including human disease, population variation, and the evolution of morphological innovations. New experimental techniques including whole genome sequencing and transcriptome analysis have enabled comprehensive modeling approaches to study gene regulation. In many cases, it is useful to be able to assign biological significance to the inferred model parameters, but such interpretation should take into account features that affect these parameters, including model construction and sensitivity, the type of fitness calculation, and the effectiveness of parameter estimation. This last point is often neglected, as estimation methods are often selected for historical reasons or for computational ease. Here, we compare the performance of two parameter estimation techniques broadly representative of local and global approaches, namely, a quasi-Newton/Nelder-Mead simplex (QN/NMS) method and a covariance matrix adaptation-evolutionary strategy (CMA-ES) method. The estimation methods were applied to a set of thermodynamic models of gene transcription applied to regulatory elements active in the Drosophila embryo. Measuring overall fit, the global CMA-ES method performed significantly better than the local QN/NMS method on high quality data sets, but this difference was negligible on lower quality data sets with increased noise or on data sets simplified by stringent thresholding. Our results suggest that the choice of parameter estimation technique for evaluation of gene expression models depends both on quality of data, the nature of the models [again, remains to be established] and the aims of the modeling effort. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. FGF21 as an Endocrine Regulator in Lipid Metabolism: From Molecular Evolution to Physiology and Pathophysiology

    Directory of Open Access Journals (Sweden)

    Yusuke Murata

    2011-01-01

    Full Text Available The FGF family comprises twenty-two structurally related proteins with functions in development and metabolism. The Fgf21 gene was generated early in vertebrate evolution. FGF21 acts as an endocrine regulator in lipid metabolism. Hepatic Fgf21 expression is markedly induced in mice by fasting or a ketogenic diet. Experiments with Fgf21 transgenic mice and cultured cells indicate that FGF21 exerts pharmacological effects on glucose and lipid metabolism in hepatocytes and adipocytes via cell surface FGF receptors. However, experiments with Fgf21 knockout mice indicate that FGF21 inhibits lipolysis in adipocytes during fasting and attenuates torpor induced by a ketogenic diet but maybe not a physiological regulator for these hepatic functions. These findings suggest the pharmacological effects to be distinct from the physiological roles. Serum FGF21 levels are increased in patients with metabolic diseases having insulin resistance, indicating that FGF21 is a metabolic regulator and a biomarker for these diseases.

  6. Hepcidin: an important iron metabolism regulator in chronic kidney disease.

    Science.gov (United States)

    Antunes, Sandra Azevedo; Canziani, Maria Eugênia Fernandes

    2016-01-01

    Anemia is a common complication and its impact on morbimortality in patients with chronic kidney disease (CKD) is well known. The discovery of hepcidin and its functions has contributed to a better understanding of iron metabolism disorders in CKD anemia. Hepcidin is a peptide mainly produced by hepatocytes and, through a connection with ferroportin, it regulates iron absorption in the duodenum and its release of stock cells. High hepcidin concentrations described in patients with CKD, especially in more advanced stages are attributed to decreased renal excretion and increased production. The elevation of hepcidin has been associated with infection, inflammation, atherosclerosis, insulin resistance and oxidative stress. Some strategies were tested to reduce the effects of hepcidin in patients with CKD, however more studies are necessary to assess the impact of its modulation in the management of anemia in this population. Resumo Anemia é uma complicação frequente e seu impacto na morbimortalidade é bem conhecido em pacientes com doença renal crônica (DRC). A descoberta da hepcidina e de suas funções contribuíram para melhor compreensão dos distúrbios do metabolismo de ferro na anemia da DRC. Hepcidina é um peptídeo produzido principalmente pelos hepatócitos, e através de sua ligação com a ferroportina, regula a absorção de ferro no duodeno e sua liberação das células de estoque. Altas concentrações de hepcidina descritas em pacientes com DRC, principalmente em estádios mais avançados, são atribuídas à diminuição da excreção renal e ao aumento de sua produção. Elevação de hepcidina tem sido associada à ocorrência de infecção, inflamação, aterosclerose, resistência à insulina e estresse oxidativo. Algumas estratégias foram testadas para diminuir os efeitos da hepcidina em pacientes com DRC, entretanto, serão necessários mais estudos para avaliar o impacto de sua modulação no manejo da anemia nessa população.

  7. Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism.

    Science.gov (United States)

    Roh, Eun; Song, Do Kyeong; Kim, Min-Seon

    2016-03-11

    Accumulated evidence from genetic animal models suggests that the brain, particularly the hypothalamus, has a key role in the homeostatic regulation of energy and glucose metabolism. The brain integrates multiple metabolic inputs from the periphery through nutrients, gut-derived satiety signals and adiposity-related hormones. The brain modulates various aspects of metabolism, such as food intake, energy expenditure, insulin secretion, hepatic glucose production and glucose/fatty acid metabolism in adipose tissue and skeletal muscle. Highly coordinated interactions between the brain and peripheral metabolic organs are critical for the maintenance of energy and glucose homeostasis. Defective crosstalk between the brain and peripheral organs contributes to the development of obesity and type 2 diabetes. Here we comprehensively review the above topics, discussing the main findings related to the role of the brain in the homeostatic regulation of energy and glucose metabolism.

  8. Global regulation of gene expression by the MafR protein of Enterococcus faecalis

    Directory of Open Access Journals (Sweden)

    Sofía eRuiz-Cruz

    2016-01-01

    Full Text Available Enterococcus faecalis is a natural inhabitant of the human gastrointestinal tract. However, as an opportunistic pathogen, it is able to colonize other host niches and cause life-threatening infections. Its adaptation to new environments involves global changes in gene expression. The EF3013 gene (here named mafR of E. faecalis strain V583 encodes a protein (MafR, 482 residues that has sequence similarity to global response regulators of the Mga/AtxA family. The enterococcal OG1RF genome also encodes the MafR protein (gene OG1RF_12293. In this work, we have identified the promoter of the mafR gene using several in vivo approaches. Moreover, we show that MafR influences positively the transcription of many genes on a genome-wide scale. The most significant target genes encode components of PTS-type membrane transporters, components of ABC-type membrane transporters, and proteins involved in the metabolism of carbon sources. Some of these genes were previously reported to be up-regulated during the growth of E. faecalis in blood and/or in human urine. Furthermore, we show that a mafR deletion mutant strain induces a significant lower degree of inflammation in the peritoneal cavity of mice, suggesting that enterococcal cells deficient in MafR are less virulent. Our work indicates that MafR is a global transcriptional regulator. It might facilitate the adaptation of E. faecalis to particular host niches and, therefore, contribute to its potential virulence.

  9. Review: Efficacy of alginate supplementation in relation to appetite regulation and metabolic risk factors

    DEFF Research Database (Denmark)

    Jensen, Morten Georg; Pedersen, C; Kristensen, Mette Bredal

    2013-01-01

    This review provides a critical update on human and animal studies investigating the effect of alginate supplementation on appetite regulation, glycaemic and insulinemic responses, and lipid metabolism with discussion of the evidence on potential mechanisms, efficacy and tolerability. Dependent...

  10. Coordinated Regulation of the EIIMan and fruRKI Operons of Streptococcus mutans by Global and Fructose-Specific Pathways.

    Science.gov (United States)

    Zeng, Lin; Chakraborty, Brinta; Farivar, Tanaz; Burne, Robert A

    2017-11-01

    The glucose/mannose-phosphotransferase system (PTS) permease EII Man encoded by manLMN in the dental caries pathogen Streptococcus mutans has a dominant influence on sugar-specific, CcpA-independent catabolite repression (CR). Mutations in manL affect energy metabolism and virulence-associated traits, including biofilm formation, acid tolerance, and competence. Using promoter::reporter fusions, expression of the manLMN and the fruRKI operons, encoding a transcriptional regulator, a fructose-1-phosphate kinase and a fructose-PTS permease EII Fru , respectively, was monitored in response to carbohydrate source and in mutants lacking CcpA, FruR, and components of EII Man Expression of genes for EII Man and EII Fru was directly regulated by CcpA and CR, as evinced by in vivo and in vitro methods. Unexpectedly, not only was the fruRKI operon negatively regulated by FruR, but also so was manLMN Carbohydrate transport by EII Man had a negative influence on expression of manLMN but not fruRKI In agreement with the proposed role of FruR in regulating these PTS operons, loss of fruR or fruK substantially altered growth on a number of carbohydrates, including fructose. RNA deep sequencing revealed profound changes in gene regulation caused by deletion of fruK or fruR Collectively, these findings demonstrate intimate interconnection of the regulation of two major PTS permeases in S. mutans and reveal novel and important contributions of fructose metabolism to global regulation of gene expression. IMPORTANCE The ability of Streptococcus mutans and other streptococcal pathogens to survive and cause human diseases is directly dependent upon their capacity to metabolize a variety of carbohydrates, including glucose and fructose. Our research reveals that metabolism of fructose has broad influences on the regulation of utilization of glucose and other sugars, and mutants with changes in certain genes involved in fructose metabolism display profoundly different abilities to grow and

  11. Metabolic regulation and behavior: how hunger produces arousal - an insect study.

    Science.gov (United States)

    Wicher, Dieter

    2007-12-01

    The metabolic state affects the level of general activity of an organism. Satiety is related to relaxation while hunger is coupled to elevated activity which supports the chance to balance the energy deficiency. The unrestricted food availability in modern industrial nations along with no required locomotor activity are risk factors to develop disorders such as obesity. One of the strategies to find new targets for future treatment of metabolic disorders in men is to gain detailed knowledge of molecular and cellular mechanisms involved in the regulation of metabolic homeostasis in less complex, i.e. invertebrate systems. This review reports recent molecular studies in insects about how hunger signals may be linked to global activation. Adipokinetic peptide hormones (AKHs) are the insect counterpart to the mammalian glucagon. They are released upon lack of energy and mobilize internal fuel reserves. In addition, AKHs stimulate the locomotor activity which involves their activity within the central nervous system. In the cockroach Periplaneta americana various neurons express the AKH receptor. Some of these, the dorsal unpaired median (DUM) neurons belonging to a general arousal system, release the biogenic amine octopamine, the insect counterpart to mammalian adrenergic hormones. The two Periplaneta AKHs activate Gs proteins, and AKH I also potently activates Gq proteins. AKH I and - less effectively - AKH II accelerate spiking of DUM neurons via an increase of a pacemaking Ca2+ current. Systemically injected AKH I stimulates locomotion in contrast to AKH II. This behavioral difference corresponds to the different effectiveness of the AKHs on the level of G-proteins.

  12. Comprehensive analysis of PPARα-dependent regulation of hepatic lipid metabolism by expression profiling - 5

    NARCIS (Netherlands)

    Rakhshandehroo, Maryam; Sanderson-Kjellberg, L.M.; Matilainen, Merja; Stienstra, Rinke; Carlberg, Carsten; Groot, de Philip; Muller, Michael; Kersten, Sander

    2007-01-01

    PPARα is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARα in hepatic lipid metabolism, many PPARα-dependent pathways and genes have yet to be discovered. In order to obtain an

  13. Comprehensive analysis of PPARa-dependent regulation of hepatic lipid metabolism by expression profiling

    NARCIS (Netherlands)

    Rakhshandehroo, Maryam; Sanderson-Kjellberg, L.M.; Matilainen, Merja; Stienstra, Rinke; Carlberg, Carsten; Groot, de Philip; Muller, Michael; Kersten, Sander

    2007-01-01

    PPARalpha is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARalpha in hepatic lipid metabolism, many PPARalpha-dependent pathways and genes have yet to be discovered. In order to

  14. Natural compounds regulate energy metabolism by the modulating the activity of lipid-sensing nuclear receptors.

    Science.gov (United States)

    Goto, Tsuyoshi; Kim, Young-Il; Takahashi, Nobuyuki; Kawada, Teruo

    2013-01-01

    Obesity causes excess fat accumulation in various tissues, most notoriously in the adipose tissue, along with other insulin-responsive organs such as skeletal muscle and the liver, which predisposes an individual to the development of metabolic abnormalities. The molecular mechanisms underlying obesity-induced metabolic abnormalities have not been completely elucidated; however, in recent years, the search for therapies to prevent the development of obesity and obesity-associated metabolic disorders has increased. It is known that several nuclear receptors, when activated by specific ligands, regulate carbohydrate and lipid metabolism at the transcriptional level. The expression of lipid metabolism-related enzymes is directly regulated by the activity of various nuclear receptors via their interaction with specific response elements in promoters of those genes. Many natural compounds act as ligands of nuclear receptors and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors. In this review, we describe our current knowledge of obesity, the role of lipid-sensing nuclear receptors in energy metabolism, and several examples of food factors that act as agonists or antagonists of nuclear receptors, which may be useful for the management of obesity and the accompanying energy metabolism abnormalities. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. [Regulation of terpene metabolism]. Annual progress report, March 15, 1988--March 14, 1989

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1989-12-31

    Progress in understanding of the metabolism of monoterpenes by peppermint and spearmint is recorded including the actions of two key enzymes, geranyl pyrophosphate:limonene cyclase and a UDP-glucose dependent glucosyl transferase; concerning the ultrastructure of oil gland senescence; enzyme subcellular localization; regulation of metabolism; and tissue culture systems.

  16. Neoliberalism and the regulation of global labor mobility

    NARCIS (Netherlands)

    Overbeek, H.W.

    2002-01-01

    Globalization involves the international expansion of market relations and the global pursuit of economic liberalism. The essential factor in this process is commodification, including the commodification of human labor. Globalization integrates an increasing proportion of the world population

  17. Computational Modelling of the Metabolic States Regulated by the Kinase Akt

    Directory of Open Access Journals (Sweden)

    Ettore eMosca

    2012-11-01

    Full Text Available Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB, also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism.

  18. SVD identifies transcript length distribution functions from DNA microarray data and reveals evolutionary forces globally affecting GBM metabolism.

    Directory of Open Access Journals (Sweden)

    Nicolas M Bertagnolli

    Full Text Available To search for evolutionary forces that might act upon transcript length, we use the singular value decomposition (SVD to identify the length distribution functions of sets and subsets of human and yeast transcripts from profiles of mRNA abundance levels across gel electrophoresis migration distances that were previously measured by DNA microarrays. We show that the SVD identifies the transcript length distribution functions as "asymmetric generalized coherent states" from the DNA microarray data and with no a-priori assumptions. Comparing subsets of human and yeast transcripts of the same gene ontology annotations, we find that in both disparate eukaryotes, transcripts involved in protein synthesis or mitochondrial metabolism are significantly shorter than typical, and in particular, significantly shorter than those involved in glucose metabolism. Comparing the subsets of human transcripts that are overexpressed in glioblastoma multiforme (GBM or normal brain tissue samples from The Cancer Genome Atlas, we find that GBM maintains normal brain overexpression of significantly short transcripts, enriched in transcripts that are involved in protein synthesis or mitochondrial metabolism, but suppresses normal overexpression of significantly longer transcripts, enriched in transcripts that are involved in glucose metabolism and brain activity. These global relations among transcript length, cellular metabolism and tumor development suggest a previously unrecognized physical mode for tumor and normal cells to differentially regulate metabolism in a transcript length-dependent manner. The identified distribution functions support a previous hypothesis from mathematical modeling of evolutionary forces that act upon transcript length in the manner of the restoring force of the harmonic oscillator.

  19. A global evolutionary and metabolic analysis of human obesity gene risk variants.

    Science.gov (United States)

    Castillo, Joseph J; Hazlett, Zachary S; Orlando, Robert A; Garver, William S

    2017-09-05

    It is generally accepted that the selection of gene variants during human evolution optimized energy metabolism that now interacts with our obesogenic environment to increase the prevalence of obesity. The purpose of this study was to perform a global evolutionary and metabolic analysis of human obesity gene risk variants (110 human obesity genes with 127 nearest gene risk variants) identified using genome-wide association studies (GWAS) to enhance our knowledge of early and late genotypes. As a result of determining the mean frequency of these obesity gene risk variants in 13 available populations from around the world our results provide evidence for the early selection of ancestral risk variants (defined as selection before migration from Africa) and late selection of derived risk variants (defined as selection after migration from Africa). Our results also provide novel information for association of these obesity genes or encoded proteins with diverse metabolic pathways and other human diseases. The overall results indicate a significant differential evolutionary pattern for the selection of obesity gene ancestral and derived risk variants proposed to optimize energy metabolism in varying global environments and complex association with metabolic pathways and other human diseases. These results are consistent with obesity genes that encode proteins possessing a fundamental role in maintaining energy metabolism and survival during the course of human evolution. Copyright © 2017. Published by Elsevier B.V.

  20. Current knowledge of microRNA-mediated regulation of drug metabolism in humans.

    Science.gov (United States)

    Nakano, Masataka; Nakajima, Miki

    2018-05-01

    Understanding the factors causing inter- and intra-individual differences in drug metabolism potencies is required for the practice of personalized or precision medicine, as well as for the promotion of efficient drug development. The expression of drug-metabolizing enzymes is controlled by transcriptional regulation by nuclear receptors and transcriptional factors, epigenetic regulation, such as DNA methylation and histone acetylation, and post-translational modification. In addition to such regulation mechanisms, recent studies revealed that microRNAs (miRNAs), endogenous ~22-nucleotide non-coding RNAs that regulate gene expression through the translational repression and degradation of mRNAs, significantly contribute to post-transcriptional regulation of drug-metabolizing enzymes. Areas covered: This review summarizes the current knowledge regarding miRNAs-dependent regulation of drug-metabolizing enzymes and transcriptional factors and its physiological and clinical significance. We also describe recent advances in miRNA-dependent regulation research, showing that the presence of pseudogenes, single-nucleotide polymorphisms, and RNA editing affects miRNA targeting. Expert opinion: It is unwavering fact that miRNAs are critical factors causing inter- and intra-individual differences in the expression of drug-metabolizing enzymes. Consideration of miRNA-dependent regulation would be a helpful tool for optimizing personalized and precision medicine.

  1. Leucine metabolism in regulation of insulin secretion from pancreatic beta cells

    OpenAIRE

    Yang, Jichun; Chi, Yujing; Burkhardt, Brant R.; Guan, Youfei; Wolf, Bryan A

    2010-01-01

    Leucine, a the branched-chain amino acids that must be supplied in daily diet, plays an important role in controlling protein synthesis and regulating cell metabolism in various cell types. In pancreatic β cells, leucine acutely stimulates insulin secretion by serving as both metabolic fuel and allosteric activator of glutamate dehydrogenase to enhance glutaminolysis. Leucine has also been shown to regulate gene transcription and protein synthesis in pancreatic islet β cells via both mTOR-dep...

  2. Scaffold Attachment Factor B1: A Novel Chromatin Regulator of Prostate Cancer Metabolism

    Science.gov (United States)

    2016-10-01

    AWARD NUMBER: W81XWH-14-1-0152 TITLE: Scaffold Attachment Factor B1: A Novel Chromatin Regulator of Prostate Cancer Metabolism PRINCIPAL...TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-14-1-0152 Scaffold Attachment Factor B1: A Novel Chromatin Regulator of Prostate Cancer Metabolism... chromatin immunoprecipitation-next generation DNA sequencing (ChIP-seq) and integrative network modeling to identify the SAFB1 cistrome and the extent of

  3. Acyl coenzyme A thioesterase 7 regulates neuronal fatty acid metabolism to prevent neurotoxicity.

    Science.gov (United States)

    Ellis, Jessica M; Wong, G William; Wolfgang, Michael J

    2013-05-01

    Numerous neurological diseases are associated with dysregulated lipid metabolism; however, the basic metabolic control of fatty acid metabolism in neurons remains enigmatic. Here we have shown that neurons have abundant expression and activity of the long-chain cytoplasmic acyl coenzyme A (acyl-CoA) thioesterase 7 (ACOT7) to regulate lipid retention and metabolism. Unbiased and targeted metabolomic analysis of fasted mice with a conditional knockout of ACOT7 in the nervous system, Acot7(N-/-), revealed increased fatty acid flux into multiple long-chain acyl-CoA-dependent pathways. The alterations in brain fatty acid metabolism were concomitant with a loss of lean mass, hypermetabolism, hepatic steatosis, dyslipidemia, and behavioral hyperexcitability in Acot7(N-/-) mice. These failures in adaptive energy metabolism are common in neurodegenerative diseases. In agreement, Acot7(N-/-) mice exhibit neurological dysfunction and neurodegeneration. These data show that ACOT7 counterregulates fatty acid metabolism in neurons and protects against neurotoxicity.

  4. Fructose 1-phosphate is the preferred effector of the metabolic regulator Cra of Pseudomonas putida.

    Science.gov (United States)

    Chavarría, Max; Santiago, César; Platero, Raúl; Krell, Tino; Casasnovas, José M; de Lorenzo, Víctor

    2011-03-18

    The catabolite repressor/activator (Cra) protein is a global sensor and regulator of carbon fluxes through the central metabolic pathways of gram-negative bacteria. To examine the nature of the effector (or effectors) that signal such fluxes to the protein of Pseudomonas putida, the Cra factor of this soil microorganism has been purified and characterized and its three-dimensional structure determined. Analytical ultracentrifugation, gel filtration, and mobility shift assays showed that the effector-free Cra is a dimer that binds an operator DNA sequence in the promoter region of the fruBKA cluster. Furthermore, fructose 1-phosphate (F1P) was found to most efficiently dissociate the Cra-DNA complex. Thermodynamic parameters of the F1P-Cra-DNA interaction calculated by isothermal titration calorimetry revealed that the factor associates tightly to the DNA sequence 5'-TTAAACGTTTCA-3' (K(D) = 26.3 ± 3.1 nM) and that F1P binds the protein with an apparent stoichiometry of 1.06 ± 0.06 molecules per Cra monomer and a K(D) of 209 ± 20 nM. Other possible effectors, like fructose 1,6-bisphosphate, did not display a significant affinity for the regulator under the assay conditions. Moreover, the structure of Cra and its co-crystal with F1P at a 2-Å resolution revealed that F1P fits optimally the geometry of the effector pocket. Our results thus single out F1P as the preferred metabolic effector of the Cra protein of P. putida.

  5. Fructose 1-Phosphate Is the Preferred Effector of the Metabolic Regulator Cra of Pseudomonas putida*

    Science.gov (United States)

    Chavarría, Max; Santiago, César; Platero, Raúl; Krell, Tino; Casasnovas, José M.; de Lorenzo, Víctor

    2011-01-01

    The catabolite repressor/activator (Cra) protein is a global sensor and regulator of carbon fluxes through the central metabolic pathways of Gram-negative bacteria. To examine the nature of the effector (or effectors) that signal such fluxes to the protein of Pseudomonas putida, the Cra factor of this soil microorganism has been purified and characterized and its three-dimensional structure determined. Analytical ultracentrifugation, gel filtration, and mobility shift assays showed that the effector-free Cra is a dimer that binds an operator DNA sequence in the promoter region of the fruBKA cluster. Furthermore, fructose 1-phosphate (F1P) was found to most efficiently dissociate the Cra-DNA complex. Thermodynamic parameters of the F1P-Cra-DNA interaction calculated by isothermal titration calorimetry revealed that the factor associates tightly to the DNA sequence 5′-TTAAACGTTTCA-3′ (KD = 26.3 ± 3.1 nm) and that F1P binds the protein with an apparent stoichiometry of 1.06 ± 0.06 molecules per Cra monomer and a KD of 209 ± 20 nm. Other possible effectors, like fructose 1,6-bisphosphate, did not display a significant affinity for the regulator under the assay conditions. Moreover, the structure of Cra and its co-crystal with F1P at a 2-Å resolution revealed that F1P fits optimally the geometry of the effector pocket. Our results thus single out F1P as the preferred metabolic effector of the Cra protein of P. putida. PMID:21239488

  6. Activating Transcription Factor 3 Regulates Immune and Metabolic Homeostasis

    Science.gov (United States)

    Rynes, Jan; Donohoe, Colin D.; Frommolt, Peter; Brodesser, Susanne; Jindra, Marek

    2012-01-01

    Integration of metabolic and immune responses during animal development ensures energy balance, permitting both growth and defense. Disturbed homeostasis causes organ failure, growth retardation, and metabolic disorders. Here, we show that the Drosophila melanogaster activating transcription factor 3 (Atf3) safeguards metabolic and immune system homeostasis. Loss of Atf3 results in chronic inflammation and starvation responses mounted primarily by the larval gut epithelium, while the fat body suffers lipid overload, causing energy imbalance and death. Hyperactive proinflammatory and stress signaling through NF-κB/Relish, Jun N-terminal kinase, and FOXO in atf3 mutants deregulates genes important for immune defense, digestion, and lipid metabolism. Reducing the dose of either FOXO or Relish normalizes both lipid metabolism and gene expression in atf3 mutants. The function of Atf3 is conserved, as human ATF3 averts some of the Drosophila mutant phenotypes, improving their survival. The single Drosophila Atf3 may incorporate the diversified roles of two related mammalian proteins. PMID:22851689

  7. Natural Compounds as Regulators of the Cancer Cell Metabolism

    Directory of Open Access Journals (Sweden)

    Claudia Cerella

    2013-01-01

    Full Text Available Even though altered metabolism is an “old” physiological mechanism, only recently its targeting became a therapeutically interesting strategy and by now it is considered an emerging hallmark of cancer. Nevertheless, a very poor number of compounds are under investigation as potential modulators of cell metabolism. Candidate agents should display selectivity of action towards cancer cells without side effects. This ideal favorable profile would perfectly overlap the requisites of new anticancer therapies and chemopreventive strategies as well. Nature represents a still largely unexplored source of bioactive molecules with a therapeutic potential. Many of these compounds have already been characterized for their multiple anticancer activities. Many of them are absorbed with the diet and therefore possess a known profile in terms of tolerability and bioavailability compared to newly synthetized chemical compounds. The discovery of important cross-talks between mediators of the most therapeutically targeted aberrancies in cancer (i.e., cell proliferation, survival, and migration and the metabolic machinery allows to predict the possibility that many anticancer activities ascribed to a number of natural compounds may be due, in part, to their ability of modulating metabolic pathways. In this review, we attempt an overview of what is currently known about the potential of natural compounds as modulators of cancer cell metabolism.

  8. Perspectives in metabolic engineering: understanding cellular regulation towards the control of metabolic routes.

    Science.gov (United States)

    Zadran, Sohila; Levine, Raphael D

    2013-01-01

    Metabolic engineering seeks to redirect metabolic pathways through the modification of specific biochemical reactions or the introduction of new ones with the use of recombinant technology. Many of the chemicals synthesized via introduction of product-specific enzymes or the reconstruction of entire metabolic pathways into engineered hosts that can sustain production and can synthesize high yields of the desired product as yields of natural product-derived compounds are frequently low, and chemical processes can be both energy and material expensive; current endeavors have focused on using biologically derived processes as alternatives to chemical synthesis. Such economically favorable manufacturing processes pursue goals related to sustainable development and "green chemistry". Metabolic engineering is a multidisciplinary approach, involving chemical engineering, molecular biology, biochemistry, and analytical chemistry. Recent advances in molecular biology, genome-scale models, theoretical understanding, and kinetic modeling has increased interest in using metabolic engineering to redirect metabolic fluxes for industrial and therapeutic purposes. The use of metabolic engineering has increased the productivity of industrially pertinent small molecules, alcohol-based biofuels, and biodiesel. Here, we highlight developments in the practical and theoretical strategies and technologies available for the metabolic engineering of simple systems and address current limitations.

  9. A Status Report on the Global Research in Microbial Metabolic Engineering

    Energy Technology Data Exchange (ETDEWEB)

    Joe, Min Ho; Lim, Sang Yong; Kim, Dong Ho

    2008-09-15

    Biotechnology industry is now a global 'Mega-Trend' and metabolic engineering technology has important role is this area. Therefore, many countries has made efforts in this field to produce top value added bio-products efficiently using microorganisms. It has been applied to increase the production of chemicals that are already produced by the host organism, to produce desired chemical substances from less expensive feedstock, and to generate products that are new to the host organism. Recent experimental advances, the so-called '-omics' technologies, mainly functional genomics, proteomics and metabolomics, have enabled wholesale generation of new genomic, transcriptomic, proteomic, and metabolomic data. This report provides the insights of the integrated view of metabolism generated by metabolic engineering for biotechnological applications of microbial metabolic engineering.

  10. A Status Report on the Global Research in Microbial Metabolic Engineering

    International Nuclear Information System (INIS)

    Joe, Min Ho; Lim, Sang Yong; Kim, Dong Ho

    2008-09-01

    Biotechnology industry is now a global 'Mega-Trend' and metabolic engineering technology has important role is this area. Therefore, many countries has made efforts in this field to produce top value added bio-products efficiently using microorganisms. It has been applied to increase the production of chemicals that are already produced by the host organism, to produce desired chemical substances from less expensive feedstock, and to generate products that are new to the host organism. Recent experimental advances, the so-called '-omics' technologies, mainly functional genomics, proteomics and metabolomics, have enabled wholesale generation of new genomic, transcriptomic, proteomic, and metabolomic data. This report provides the insights of the integrated view of metabolism generated by metabolic engineering for biotechnological applications of microbial metabolic engineering

  11. A Status Report on the Global Research in Microbial Metabolic Engineering

    Energy Technology Data Exchange (ETDEWEB)

    Joe, Min Ho; Lim, Sang Yong; Kim, Dong Ho

    2008-09-15

    Biotechnology industry is now a global 'Mega-Trend' and metabolic engineering technology has important role is this area. Therefore, many countries has made efforts in this field to produce top value added bio-products efficiently using microorganisms. It has been applied to increase the production of chemicals that are already produced by the host organism, to produce desired chemical substances from less expensive feedstock, and to generate products that are new to the host organism. Recent experimental advances, the so-called '-omics' technologies, mainly functional genomics, proteomics and metabolomics, have enabled wholesale generation of new genomic, transcriptomic, proteomic, and metabolomic data. This report provides the insights of the integrated view of metabolism generated by metabolic engineering for biotechnological applications of microbial metabolic engineering.

  12. Proteolytic regulation of metabolic enzymes by E3 ubiquitin ligase complexes: lessons from yeast.

    Science.gov (United States)

    Nakatsukasa, Kunio; Okumura, Fumihiko; Kamura, Takumi

    2015-01-01

    Eukaryotic organisms use diverse mechanisms to control metabolic rates in response to changes in the internal and/or external environment. Fine metabolic control is a highly responsive, energy-saving process that is mediated by allosteric inhibition/activation and/or reversible modification of preexisting metabolic enzymes. In contrast, coarse metabolic control is a relatively long-term and expensive process that involves modulating the level of metabolic enzymes. Coarse metabolic control can be achieved through the degradation of metabolic enzymes by the ubiquitin-proteasome system (UPS), in which substrates are specifically ubiquitinated by an E3 ubiquitin ligase and targeted for proteasomal degradation. Here, we review select multi-protein E3 ligase complexes that directly regulate metabolic enzymes in Saccharomyces cerevisiae. The first part of the review focuses on the endoplasmic reticulum (ER) membrane-associated Hrd1 and Doa10 E3 ligase complexes. In addition to their primary roles in the ER-associated degradation pathway that eliminates misfolded proteins, recent quantitative proteomic analyses identified native substrates of Hrd1 and Doa10 in the sterol synthesis pathway. The second part focuses on the SCF (Skp1-Cul1-F-box protein) complex, an abundant prototypical multi-protein E3 ligase complex. While the best-known roles of the SCF complex are in the regulation of the cell cycle and transcription, accumulating evidence indicates that the SCF complex also modulates carbon metabolism pathways. The increasing number of metabolic enzymes whose stability is directly regulated by the UPS underscores the importance of the proteolytic regulation of metabolic processes for the acclimation of cells to environmental changes.

  13. Microbial Regulation of Glucose Metabolism and Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Silke Crommen

    2017-12-01

    Full Text Available Type 2 diabetes is a combined disease, resulting from a hyperglycemia and peripheral and hepatic insulin resistance. Recent data suggest that the gut microbiota is involved in diabetes development, altering metabolic processes including glucose and fatty acid metabolism. Thus, type 2 diabetes patients show a microbial dysbiosis, with reduced butyrate-producing bacteria and elevated potential pathogens compared to metabolically healthy individuals. Furthermore, probiotics are a known tool to modulate the microbiota, having a therapeutic potential. Current literature will be discussed to elucidate the complex interaction of gut microbiota, intestinal permeability and inflammation leading to peripheral and hepatic insulin resistance. Therefore, this review aims to generate a deeper understanding of the underlying mechanism of potential microbial strains, which can be used as probiotics.

  14. Pheromone-sensing neurons regulate peripheral lipid metabolism in Caenorhabditis elegans.

    Science.gov (United States)

    Hussey, Rosalind; Stieglitz, Jon; Mesgarzadeh, Jaleh; Locke, Tiffany T; Zhang, Ying K; Schroeder, Frank C; Srinivasan, Supriya

    2017-05-01

    It is now established that the central nervous system plays an important role in regulating whole body metabolism and energy balance. However, the extent to which sensory systems relay environmental information to modulate metabolic events in peripheral tissues has remained poorly understood. In addition, it has been challenging to map the molecular mechanisms underlying discrete sensory modalities with respect to their role in lipid metabolism. In previous work our lab has identified instructive roles for serotonin signaling as a surrogate for food availability, as well as oxygen sensing, in the control of whole body metabolism. In this study, we now identify a role for a pair of pheromone-sensing neurons in regulating fat metabolism in C. elegans, which has emerged as a tractable and highly informative model to study the neurobiology of metabolism. A genetic screen revealed that GPA-3, a member of the Gα family of G proteins, regulates body fat content in the intestine, the major metabolic organ for C. elegans. Genetic and reconstitution studies revealed that the potent body fat phenotype of gpa-3 null mutants is controlled from a pair of neurons called ADL(L/R). We show that cAMP functions as the second messenger in the ADL neurons, and regulates body fat stores via the neurotransmitter acetylcholine, from downstream neurons. We find that the pheromone ascr#3, which is detected by the ADL neurons, regulates body fat stores in a GPA-3-dependent manner. We define here a third sensory modality, pheromone sensing, as a major regulator of body fat metabolism. The pheromone ascr#3 is an indicator of population density, thus we hypothesize that pheromone sensing provides a salient 'denominator' to evaluate the amount of food available within a population and to accordingly adjust metabolic rate and body fat levels.

  15. NAD+ : A key metabolic regulator with great therapeutic potential.

    Science.gov (United States)

    Sultani, G; Samsudeen, A F; Osborne, B; Turner, N

    2017-10-01

    Nicotinamide adenine dinucleotide (NAD + ) is a ubiquitous metabolite that serves an essential role in the catabolism of nutrients. Recently, there has been a surge of interest in NAD + biology, with the recognition that NAD + influences many biological processes beyond metabolism, including transcription, signalling and cell survival. There are a multitude of pathways involved in the synthesis and breakdown of NAD + , and alterations in NAD + homeostasis have emerged as a common feature of a range of disease states. Here, we provide an overview of NAD + metabolism and summarise progress on the development of NAD + -related therapeutics. © 2017 British Society for Neuroendocrinology.

  16. Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Louise von Stechow

    Full Text Available The chemotherapeutic compound, cisplatin causes various kinds of DNA lesions but also triggers other pertubations, such as ER and oxidative stress. We and others have shown that treatment of pluripotent stem cells with cisplatin causes a plethora of transcriptional and post-translational alterations that, to a major extent, point to DNA damage response (DDR signaling. The orchestrated DDR signaling network is important to arrest the cell cycle and repair the lesions or, in case of damage beyond repair, eliminate affected cells. Failure to properly balance the various aspects of the DDR in stem cells contributes to ageing and cancer. Here, we performed metabolic profiling by mass spectrometry of embryonic stem (ES cells treated for different time periods with cisplatin. We then integrated metabolomics with transcriptomics analyses and connected cisplatin-regulated metabolites with regulated metabolic enzymes to identify enriched metabolic pathways. These included nucleotide metabolism, urea cycle and arginine and proline metabolism. Silencing of identified proline metabolic and catabolic enzymes indicated that altered proline metabolism serves as an adaptive, rather than a toxic response. A group of enriched metabolic pathways clustered around the metabolite S-adenosylmethionine, which is a hub for methylation and transsulfuration reactions and polyamine metabolism. Enzymes and metabolites with pro- or anti-oxidant functions were also enriched but enhanced levels of reactive oxygen species were not measured in cisplatin-treated ES cells. Lastly, a number of the differentially regulated metabolic enzymes were identified as target genes of the transcription factor p53, pointing to p53-mediated alterations in metabolism in response to genotoxic stress. Altogether, our findings reveal interconnecting metabolic pathways that are responsive to cisplatin and may serve as signaling modules in the DDR in pluripotent stem cells.

  17. Integrative Analysis of PRKAG2 Cardiomyopathy iPS and Microtissue Models Identifies AMPK as a Regulator of Metabolism, Survival, and Fibrosis

    Directory of Open Access Journals (Sweden)

    J. Travis Hinson

    2016-12-01

    Full Text Available AMP-activated protein kinase (AMPK is a metabolic enzyme that can be activated by nutrient stress or genetic mutations. Missense mutations in the regulatory subunit, PRKAG2, activate AMPK and cause left ventricular hypertrophy, glycogen accumulation, and ventricular pre-excitation. Using human iPS cell models combined with three-dimensional cardiac microtissues, we show that activating PRKAG2 mutations increase microtissue twitch force by enhancing myocyte survival. Integrating RNA sequencing with metabolomics, PRKAG2 mutations that activate AMPK remodeled global metabolism by regulating RNA transcripts to favor glycogen storage and oxidative metabolism instead of glycolysis. As in patients with PRKAG2 cardiomyopathy, iPS cell and mouse models are protected from cardiac fibrosis, and we define a crosstalk between AMPK and post-transcriptional regulation of TGFβ isoform signaling that has implications in fibrotic forms of cardiomyopathy. Our results establish critical connections among metabolic sensing, myocyte survival, and TGFβ signaling.

  18. Activating transcription factor 3 regulates immune and metabolic homeostasis

    Czech Academy of Sciences Publication Activity Database

    Ryneš, J.; Donohoe, C. D.; Frommolt, P.; Brodesser, S.; Jindra, Marek; Uhlířová, M.

    2012-01-01

    Roč. 32, č. 19 (2012), s. 3949-3962 ISSN 0270-7306 R&D Projects: GA ČR(CZ) GD204/09/H058 Institutional support: RVO:60077344 Keywords : metabolic homeostasis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.372, year: 2012

  19. Metabolic regulation in the facultative methylotroph arthrobacter P1

    NARCIS (Netherlands)

    1985-01-01

    Many microorganisms are able to utilize C1 compounds, i.e. compounds which do not contain carbon-carbon bonds, as carbon- and energy sources for growth. In order to synthesize cell constituents from these C1 compounds special metabolic pathways are employed by such organisms. Although a great deal

  20. Regulation of Metabolic Signaling in Human Skeletal Muscle

    DEFF Research Database (Denmark)

    Albers, Peter Hjorth

    sensitivity in type I muscle fibers possibly reflects a superior effect of insulin on metabolic signaling compared to type II muscle fibers. This was investigated in the present thesis by examining muscle biopsies from lean and obese healthy subjects as well as patients with type 2 diabetes. From these muscle...

  1. Krüppel-like factor 15: Regulator of BCAA metabolism and circadian protein rhythmicity.

    Science.gov (United States)

    Fan, Liyan; Hsieh, Paishiun N; Sweet, David R; Jain, Mukesh K

    2018-04-01

    Regulation of nutrient intake, utilization, and storage exhibits a circadian rhythmicity that allows organisms to anticipate and adequately respond to changes in the environment across day/night cycles. The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are important modulators of metabolism and metabolic health - for example, their catabolism yields carbon substrates for gluconeogenesis during periods of fasting. Krüppel-like factor 15 (KLF15) has recently emerged as a critical transcriptional regulator of BCAA metabolism, and the absence of this transcription factor contributes to severe pathologies such as Duchenne muscular dystrophy and heart failure. This review highlights KLF15's role as a central regulator of BCAA metabolism during periods of fasting, throughout day/night cycles, and in experimental models of muscle disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Co-regulation of metabolic genes is better explained by flux coupling than by network distance.

    Directory of Open Access Journals (Sweden)

    Richard A Notebaart

    2008-01-01

    Full Text Available To what extent can modes of gene regulation be explained by systems-level properties of metabolic networks? Prior studies on co-regulation of metabolic genes have mainly focused on graph-theoretical features of metabolic networks and demonstrated a decreasing level of co-expression with increasing network distance, a naïve, but widely used, topological index. Others have suggested that static graph representations can poorly capture dynamic functional associations, e.g., in the form of dependence of metabolic fluxes across genes in the network. Here, we systematically tested the relative importance of metabolic flux coupling and network position on gene co-regulation, using a genome-scale metabolic model of Escherichia coli. After validating the computational method with empirical data on flux correlations, we confirm that genes coupled by their enzymatic fluxes not only show similar expression patterns, but also share transcriptional regulators and frequently reside in the same operon. In contrast, we demonstrate that network distance per se has relatively minor influence on gene co-regulation. Moreover, the type of flux coupling can explain refined properties of the regulatory network that are ignored by simple graph-theoretical indices. Our results underline the importance of studying functional states of cellular networks to define physiologically relevant associations between genes and should stimulate future developments of novel functional genomic tools.

  3. Growth hormone regulation of metabolic gene expression in muscle: a microarray study in hypopituitary men.

    Science.gov (United States)

    Sjögren, Klara; Leung, Kin-Chuen; Kaplan, Warren; Gardiner-Garden, Margaret; Gibney, James; Ho, Ken K Y

    2007-07-01

    Muscle is a target of growth hormone (GH) action and a major contributor to whole body metabolism. Little is known about how GH regulates metabolic processes in muscle or the extent to which muscle contributes to changes in whole body substrate metabolism during GH treatment. To identify GH-responsive genes that regulate substrate metabolism in muscle, we studied six hypopituitary men who underwent whole body metabolic measurement and skeletal muscle biopsies before and after 2 wk of GH treatment (0.5 mg/day). Transcript profiles of four subjects were analyzed using Affymetrix GeneChips. Serum insulin-like growth factor I (IGF-I) and procollagens I and III were measured by RIA. GH increased serum IGF-I and procollagens I and III, enhanced whole body lipid oxidation, reduced carbohydrate oxidation, and stimulated protein synthesis. It induced gene expression of IGF-I and collagens in muscle. GH reduced expression of several enzymes regulating lipid oxidation and energy production. It reduced calpain 3, increased ribosomal protein L38 expression, and displayed mixed effects on genes encoding myofibrillar proteins. It increased expression of circadian gene CLOCK, and reduced that of PERIOD. In summary, GH exerted concordant effects on muscle expression and blood levels of IGF-I and collagens. It induced changes in genes regulating protein metabolism in parallel with a whole body anabolic effect. The discordance between muscle gene expression profiles and metabolic responses suggests that muscle is unlikely to contribute to GH-induced stimulation of whole body energy and lipid metabolism. GH may regulate circadian function in skeletal muscle by modulating circadian gene expression with possible metabolic consequences.

  4. Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes.

    Science.gov (United States)

    Jeong, Hyunyoung

    2010-06-01

    Medication use during pregnancy is prevalent, but pharmacokinetic information of most drugs used during pregnancy is lacking in spite of known effects of pregnancy on drug disposition. Accurate pharmacokinetic information is essential for optimal drug therapy in mother and fetus. Thus, understanding how pregnancy influences drug disposition is important for better prediction of pharmacokinetic changes of drugs in pregnant women. Pregnancy is known to affect hepatic drug metabolism, but the underlying mechanisms remain unknown. Physiological changes accompanying pregnancy are probably responsible for the reported alteration in drug metabolism during pregnancy. These include elevated concentrations of various hormones such as estrogen, progesterone, placental growth hormones and prolactin. This review covers how these hormones influence expression of drug-metabolizing enzymes (DMEs), thus potentially responsible for altered drug metabolism during pregnancy. The reader will gain a greater understanding of the altered drug metabolism in pregnant women and the regulatory effects of pregnancy hormones on expression of DMEs. In-depth studies in hormonal regulatory mechanisms as well as confirmatory studies in pregnant women are warranted for systematic understanding and prediction of the changes in hepatic drug metabolism during pregnancy.

  5. Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise

    DEFF Research Database (Denmark)

    Jørgensen, Sebastian Beck; Richter, Erik; Wojtaszewski, Jørgen

    2006-01-01

    The 5'-AMP-activated protein kinase (AMPK) is a potent regulator of skeletal muscle metabolism and gene expression. AMPK is activated both in response to in vivo exercise and ex vivo contraction. AMPK is therefore believed to be an important signalling molecule in regulating muscle metabolism...... during exercise as well as in adaptation of skeletal muscle to exercise training. The first part of this review is focused on different mechanisms regulating AMPK activity during muscle work such as alterations in nucleotide concentrations, availability of energy substrates and upstream AMPK kinases. We...... in relation to adaptation of skeletal muscle to exercise training....

  6. The Global Acetylome of the Human Pathogen Vibrio cholerae V52 Reveals Lysine Acetylation of Major Transcriptional Regulators

    DEFF Research Database (Denmark)

    Jers, Carsten; Ravikumar, Vaishnavi; Lezyk, Mateusz Jakub

    2018-01-01

    Protein lysine acetylation is recognized as an important reversible post translational modification in all domains of life. While its primary roles appear to reside in metabolic processes, lysine acetylation has also been implicated in regulating pathogenesis in bacteria. Several global lysine...... acetylome analyses have been carried out in various bacteria, but thus far there have been no reports of lysine acetylation taking place in the important human pathogen Vibrio cholerae. In this study, we analyzed the lysine acetylproteome of the human pathogen V. cholerae V52. By applying a combination...... in direct regulation of virulence in V. cholerae were acetylated. In conclusion, this is the first global protein lysine acetylome analysis of V. cholerae and should constitute a valuable resource for in-depth studies of the impact of lysine acetylation in pathogenesis and other cellular processes....

  7. The role of bile acids in metabolic regulation.

    Science.gov (United States)

    Vítek, Libor; Haluzík, Martin

    2016-03-01

    Bile acids (BA), long believed to only have lipid-digestive functions, have emerged as novel metabolic modulators. They have important endocrine effects through multiple cytoplasmic as well as nuclear receptors in various organs and tissues. BA affect multiple functions to control energy homeostasis, as well as glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor and the cytoplasmic G protein-coupled BA receptor TGR5 in a variety of tissues. However, BA also are aimed at many other cellular targets in a wide array of organs and cell compartments. Their role in the pathogenesis of diabetes, obesity and other 'diseases of civilization' becomes even more clear. They also interact with the gut microbiome, with important clinical implications, further extending the complexity of their biological functions. Therefore, it is not surprising that BA metabolism is substantially modulated by bariatric surgery, a phenomenon contributing favorably to the therapeutic effects of these surgical procedures. Based on these data, several therapeutic approaches to ameliorate obesity and diabetes have been proposed to affect the cellular targets of BA. © 2016 Society for Endocrinology.

  8. Cell signaling mechanisms and metabolic regulation of germination and dormancy in barley seeds

    Directory of Open Access Journals (Sweden)

    Zhenguo Ma

    2017-12-01

    Full Text Available During germination of barley (Hordeum vulgare L. seeds, important morphological and physiological changes take place, including development of organs and tissues and activation of metabolic pathways. Germination and dormancy of seeds are regulated by abscisic acid, gibberellins, reactive oxygen species (ROS, reactive nitrogen species (RNS and several other factors. Activities of ascorbate–glutathione cycle enzymes, responsible for scavenging ROS, strongly increase. Catalase and superoxide dismutase activities, also scavenging ROS, decrease at the onset of seed germination and then increase. With the increase in aerobic metabolism after radicle protrusion, the activities of the fermentation enzymes lactate and alcohol dehydrogenase decline rapidly. The RNS-scavenging activity of S-nitrosoglutathione reductase decreases in the course of seed germination, in concert with elevation of nitric oxide production and protein nitrosylation. This activity supports the role of RNS in regulating seed germination. Transcription of various genes at different phases of seed germination exhibits phase-specific changes. During imbibition, genes involved in cell wall metabolism are highly expressed; in the middle phase of seed germination before radicle protrusion, genes involved in amino acid synthesis, protein synthesis, and transport and nucleic acid synthesis are upregulated significantly, and after radicle protrusion, genes involved in photosynthetic metabolism are induced. In summary, signal transduction and metabolic regulation of seed germination involve diverse reactions and complex regulation at different levels of metabolic organization. Keywords: Seed germination, Reactive oxygen species, Reactive nitrogen species, Signal transduction, Gene expression

  9. Regulation of NAD+ metabolism, signaling and compartmentalization in the yeast Saccharomyces cerevisiae

    Science.gov (United States)

    Kato, Michiko; Lin, Su-Ju

    2014-01-01

    Pyridine nucleotides are essential coenzymes in many cellular redox reactions in all living systems. In addition to functioning as a redox carrier, NAD+ is also a required co-substrate for the conserved sirtuin deacetylases. Sirtuins regulate transcription, genome maintenance and metabolism and function as molecular links between cells and their environment. Maintaining NAD+ homeostasis is essential for proper cellular function and aberrant NAD+ metabolism has been implicated in a number of metabolic- and age-associated diseases. Recently, NAD+ metabolism has been linked to the phosphate-responsive signaling pathway (PHO pathway) in the budding yeast Saccharomyces cerevisiae. Activation of the PHO pathway is associated with the production and mobilization of the NAD+ metabolite nicotinamide riboside (NR), which is mediated in part by PHO-regulated nucleotidases. Cross-regulation between NAD+ metabolism and the PHO pathway has also been reported; however, detailed mechanisms remain to be elucidated. The PHO pathway also appears to modulate the activities of common downstream effectors of multiple nutrient-sensing pathways (Ras-PKA, TOR, Sch9/AKT). These signaling pathways were suggested to play a role in calorie restriction-mediated beneficial effects, which have also been linked to Sir2 function and NAD+ metabolism. Here, we discuss the interactions of these pathways and their potential roles in regulating NAD+ metabolism. In eukaryotic cells, intracellular compartmentalization facilitates the regulation of enzymatic functions and also concentrates or sequesters specific metabolites. Various NAD+-mediated cellular functions such as mitochondrial oxidative phosphorylation are compartmentalized. Therefore, we also discuss several key players functioning in mitochondrial, cytosolic and vacuolar compartmentalization of NAD+ intermediates, and their potential roles in NAD+ homeostasis. To date, it remains unclear how NAD+ and NAD+ intermediates shuttle between different

  10. Regulation of NAD+ metabolism, signaling and compartmentalization in the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Kato, Michiko; Lin, Su-Ju

    2014-11-01

    Pyridine nucleotides are essential coenzymes in many cellular redox reactions in all living systems. In addition to functioning as a redox carrier, NAD(+) is also a required co-substrate for the conserved sirtuin deacetylases. Sirtuins regulate transcription, genome maintenance and metabolism and function as molecular links between cells and their environment. Maintaining NAD(+) homeostasis is essential for proper cellular function and aberrant NAD(+) metabolism has been implicated in a number of metabolic- and age-associated diseases. Recently, NAD(+) metabolism has been linked to the phosphate-responsive signaling pathway (PHO pathway) in the budding yeast Saccharomyces cerevisiae. Activation of the PHO pathway is associated with the production and mobilization of the NAD(+) metabolite nicotinamide riboside (NR), which is mediated in part by PHO-regulated nucleotidases. Cross-regulation between NAD(+) metabolism and the PHO pathway has also been reported; however, detailed mechanisms remain to be elucidated. The PHO pathway also appears to modulate the activities of common downstream effectors of multiple nutrient-sensing pathways (Ras-PKA, TOR, Sch9/AKT). These signaling pathways were suggested to play a role in calorie restriction-mediated beneficial effects, which have also been linked to Sir2 function and NAD(+) metabolism. Here, we discuss the interactions of these pathways and their potential roles in regulating NAD(+) metabolism. In eukaryotic cells, intracellular compartmentalization facilitates the regulation of enzymatic functions and also concentrates or sequesters specific metabolites. Various NAD(+)-mediated cellular functions such as mitochondrial oxidative phosphorylation are compartmentalized. Therefore, we also discuss several key players functioning in mitochondrial, cytosolic and vacuolar compartmentalization of NAD(+) intermediates, and their potential roles in NAD(+) homeostasis. To date, it remains unclear how NAD(+) and NAD(+) intermediates

  11. DLK1 Regulates Whole-Body Glucose Metabolism

    DEFF Research Database (Denmark)

    Abdallah, Basem M; Ditzel, Nicholas; Laborda, Jorge

    2015-01-01

    due to impaired insulin signaling in OB and lowered Glu-OCN serum levels. Furthermore, Dlk1(-/-) mice treated with Glu-OC experienced significantly lower blood glucose levels than Glu-OCN-treated wild-type mice. The data suggest that Glu-OCN-controlled production of DLK1 by pancreatic β-cells acts...... metabolism. We show that Glu-OCN specifically stimulates Dlk1 expression by the pancreas. Conversely, Dlk1-deficient (Dlk1(-/-) ) mice exhibited increased circulating Glu-OCN levels and increased insulin sensitivity, whereas mice overexpressing Dlk1 in OB displayed reduced insulin secretion and sensitivity...

  12. Regulation of exercise-induced lipid metabolism in skeletal muscle

    DEFF Research Database (Denmark)

    Jordy, Andreas Børsting; Kiens, Bente

    2014-01-01

    Exercise increases the utilization of lipids in muscle. The sources of lipids are long-chain fatty acids taken up from the plasma and fatty acids released from stores of intramuscular triacylglycerol by the action of intramuscular lipases. In the present review, we focus on the role of fatty acid...... binding proteins, particularly fatty acid translocase/cluster of differentiation 36 (FAT/CD36), in the exercise- and contraction-induced increase in uptake of long-chain fatty acids in muscle. The FAT/CD36 translocates from intracellular depots to the surface membrane upon initiation of exercise/muscle...... triglyceride lipase in regulation of muscle lipolysis. Although the molecular regulation of the lipases in muscle is not understood, it is speculated that intramuscular lipolysis may be regulated in part by the availability of the plasma concentration of long-chain fatty acids....

  13. Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions.

    Science.gov (United States)

    Karigane, Daiki; Takubo, Keiyo

    2017-07-01

    Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

  14. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance.

    Science.gov (United States)

    López, Miguel; Varela, Luis; Vázquez, María J; Rodríguez-Cuenca, Sergio; González, Carmen R; Velagapudi, Vidya R; Morgan, Donald A; Schoenmakers, Erik; Agassandian, Khristofor; Lage, Ricardo; Martínez de Morentin, Pablo Blanco; Tovar, Sulay; Nogueiras, Rubén; Carling, David; Lelliott, Christopher; Gallego, Rosalía; Oresic, Matej; Chatterjee, Krishna; Saha, Asish K; Rahmouni, Kamal; Diéguez, Carlos; Vidal-Puig, Antonio

    2010-09-01

    Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.

  15. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance

    Science.gov (United States)

    López, Miguel; Varela, Luis; Vázquez, María J.; Rodríguez-Cuenca, Sergio; González, Carmen R.; Velagapudi, Vidya R.; Morgan, Donald A.; Schoenmakers, Erik; Agassandian, Khristofor; Lage, Ricardo; de Morentin, Pablo Blanco Martínez; Tovar, Sulay; Nogueiras, Rubén; Carling, David; Lelliott, Christopher; Gallego, Rosalía; Orešič, Matej; Chatterjee, Krishna; Saha, Asish K.; Rahmouni, Kamal; Diéguez, Carlos; Vidal-Puig, Antonio

    2010-01-01

    Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here, we demonstrate that either whole body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly inhibition of thyroid hormone receptors (TRs) in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation as genetic ablation of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid-hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is an important regulator of energy homeostasis. PMID:20802499

  16. Evidence for a Role of Proline and Hypothalamic Astrocytes in the Regulation of Glucose Metabolism in Rats

    OpenAIRE

    Arrieta-Cruz, Isabel; Su, Ya; Knight, Colette M.; Lam, Tony K.T.; Gutiérrez-Juárez, Roger

    2013-01-01

    The metabolism of lactate to pyruvate in the mediobasal hypothalamus (MBH) regulates hepatic glucose production. Because astrocytes and neurons are functionally linked by metabolic coupling through lactate transfer via the astrocyte-neuron lactate shuttle (ANLS), we reasoned that astrocytes might be involved in the hypothalamic regulation of glucose metabolism. To examine this possibility, we used the gluconeogenic amino acid proline, which is metabolized to pyruvate in astrocytes. Our result...

  17. Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle

    OpenAIRE

    Chao, Lily C.; Zhang, Zidong; Pei, Liming; Saito, Tsugumichi; Tontonoz, Peter; Pilch, Paul F.

    2007-01-01

    Innervation is important for normal metabolism in skeletal muscle, including insulin-sensitive glucose uptake. However, the transcription factors that transduce signals from the neuromuscular junction to the nucleus and affect changes in metabolic gene expression are not well defined. We demonstrate here that the orphan nuclear receptor Nur77 is a regulator of gene expression linked to glucose utilization in muscle. In vivo, Nur77 is preferentially expressed in glycolytic compared to oxidativ...

  18. Increased fat oxidation and regulation of metabolic genes with ultraendurance exercise

    DEFF Research Database (Denmark)

    Helge, Jørn Wulff; Rehrer, N J; Pilegaard, H

    2007-01-01

    AIM: Regular endurance exercise stimulates muscle metabolic capacity, but effects of very prolonged endurance exercise are largely unknown. This study examined muscle substrate availability and utilization during prolonged endurance exercise, and associated metabolic genes. METHODS: Data were...... exercise markedly increases plasma fatty acid availability and fat utilization during exercise. Exercise-induced regulation of genes encoding proteins involved in fatty acid recruitment and oxidation may contribute to these changes....

  19. The genome sequence of Geobacter metallireducens: features of metabolism, physiology and regulation common and dissimilar to Geobacter sulfurreducens

    Energy Technology Data Exchange (ETDEWEB)

    Aklujkar, Muktak; Krushkal, Julia; DiBartolo, Genevieve; Lapidus, Alla; Land, Miriam L.; Lovley, Derek R.

    2008-12-01

    Background: The genome sequence of Geobacter metallireducens is the second to be completed from the metal-respiring genus Geobacter, and is compared in this report to that of Geobacter sulfurreducens in order to understand their metabolic, physiological and regulatory similarities and differences. Results: The experimentally observed greater metabolic versatility of G. metallireducens versus G. sulfurreducens is borne out by the presence of more numerous genes for metabolism of organic acids including acetate, propionate, and pyruvate. Although G. metallireducens lacks a dicarboxylic acid transporter, it has acquired a second succinate dehydrogenase/fumarate reductase complex, suggesting that respiration of fumarate was important until recently in its evolutionary history. Vestiges of the molybdate (ModE) regulon of G. sulfurreducens can be detected in G. metallireducens, which has lost the global regulatory protein ModE but retained some putative ModE-binding sites and multiplied certain genes of molybdenum cofactor biosynthesis. Several enzymes of amino acid metabolism are of different origin in the two species, but significant patterns of gene organization are conserved. Whereas most Geobacteraceae are predicted to obtain biosynthetic reducing equivalents from electron transfer pathways via a ferredoxin oxidoreductase, G. metallireducens can derive them from the oxidative pentose phosphate pathway. In addition to the evidence of greater metabolic versatility, the G. metallireducens genome is also remarkable for the abundance of multicopy nucleotide sequences found in intergenic regions and even within genes. Conclusion: The genomic evidence suggests that metabolism, physiology and regulation of gene expression in G. metallireducens may be dramatically different from other Geobacteraceae.

  20. Modulation of intestinal sulfur assimilation metabolism regulates iron homeostasis

    Science.gov (United States)

    Hudson, Benjamin H.; Hale, Andrew T.; Irving, Ryan P.; Li, Shenglan; York, John D.

    2018-01-01

    Sulfur assimilation is an evolutionarily conserved pathway that plays an essential role in cellular and metabolic processes, including sulfation, amino acid biosynthesis, and organismal development. We report that loss of a key enzymatic component of the pathway, bisphosphate 3′-nucleotidase (Bpnt1), in mice, both whole animal and intestine-specific, leads to iron-deficiency anemia. Analysis of mutant enterocytes demonstrates that modulation of their substrate 3′-phosphoadenosine 5′-phosphate (PAP) influences levels of key iron homeostasis factors involved in dietary iron reduction, import and transport, that in part mimic those reported for the loss of hypoxic-induced transcription factor, HIF-2α. Our studies define a genetic basis for iron-deficiency anemia, a molecular approach for rescuing loss of nucleotidase function, and an unanticipated link between nucleotide hydrolysis in the sulfur assimilation pathway and iron homeostasis. PMID:29507250

  1. Regulation of host metabolism and immunity by the gut microbiome

    DEFF Research Database (Denmark)

    Laursen, Janne Marie

    During recent years, central roles of the gut microbiome in metabolic and immunological diseases have been uncovered, and multiple studies have shown that bacterial-derived components shape host physiology and immune responses via direct cellular interactions. The intestinal immune system...... developed a computational framework for identifying bacteria that produce specific endotoxin variants with opposing immunological effects in metagenomic fecal samples. This framework was used to identify the endotoxin variant distribution amongst bacteria in the gut microbiome of Danes and Chinese...... with obesity and type 2 diabetes. We show for the first time that species producing pro-inflammatory endotoxin variants are vastly underrepresented in the gut microbiome compared to species producing non-inflammatory endotoxin and we identify country-specific gram-negative bacterial modules associated...

  2. Transcriptional regulation and steady-state modeling of metabolic networks

    DEFF Research Database (Denmark)

    Zelezniak, Aleksej

    Biological systems are characterized by a high degree of complexity wherein the individual components (e.g. proteins) are inter-linked in a way that leads to emergent behaviors that are difficult to decipher. Uncovering system complexity requires, at least, answers to the following three questions......: what are the components of the systems, how are the different components interconnected and how do these networks perform the functions that make the resulting system behavior? Modern analytical technologies allow us to unravel the constituents and interactions happening in a given system; however......, the third question is the ultimate challenge for systems biology. The work of this thesis systematically addresses this question in the context of metabolic networks, which are arguably the most well characterized cellular networks in terms of their constituting components and interactions among them...

  3. Differential regulation of metabolic parameters by energy deficit and hunger.

    Science.gov (United States)

    Kitka, Tamás; Tuza, Sebestyén; Varga, Balázs; Horváth, Csilla; Kovács, Péter

    2015-10-01

    Hypocaloric diet decreases both energy expenditure (EE) and respiratory exchange rate (RER), affecting the efficacy of dieting inversely. Energy deficit and hunger may be modulated separately both in human and animal studies by drug treatment or food restriction. Thus it is important to separate the effects of energy deficit and hunger on EE and RER. Three parallel and analogous experiments were performed using three pharmacologically distinct anorectic drugs: rimonabant, sibutramine and tramadol. Metabolic parameters of vehicle- and drug-treated and pair-fed diet-induced obese mice from the three experiments underwent common statistical analysis to identify effects independent of the mechanisms of action. Diet-induced obesity (DIO) test of tramadol was also performed to examine its anti-obesity efficacy. RER was decreased similarly by drug treatments and paired feeding throughout the experiment irrespective of the cause of reduced food intake. Contrarily, during the passive phase, EE was decreased more by paired feeding than by both vehicle and drug treatment irrespective of the drug used. In the active phase, EE was influenced by the pharmacological mechanisms of action. Tramadol decreased body weight in the DIO test. Our results suggest that RER is mainly affected by the actual state of energy balance; conversely, EE is rather influenced by hunger. Therefore, pharmacological medications that decrease hunger may enhance the efficacy of a hypocaloric diet by maintaining metabolic rate. Furthermore, our results yield the proposal that effects of anorectic drugs on EE and RER should be determined compared to vehicle and pair-fed groups, respectively, in animal models. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Jasmonate-responsive transcription factors regulating plant secondary metabolism.

    Science.gov (United States)

    Zhou, Meiliang; Memelink, Johan

    2016-01-01

    Plants produce a large variety of secondary metabolites including alkaloids, glucosinolates, terpenoids and phenylpropanoids. These compounds play key roles in plant-environment interactions and many of them have pharmacological activity in humans. Jasmonates (JAs) are plant hormones which induce biosynthesis of many secondary metabolites. JAs-responsive transcription factors (TFs) that regulate the JAs-induced accumulation of secondary metabolites belong to different families including AP2/ERF, bHLH, MYB and WRKY. Here, we give an overview of the types and functions of TFs that have been identified in JAs-induced secondary metabolite biosynthesis, and highlight their similarities and differences in regulating various biosynthetic pathways. We review major recent developments regarding JAs-responsive TFs mediating secondary metabolite biosynthesis, and provide suggestions for further studies. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Untreated pain, narcotics regulation, and global health ideologies.

    Science.gov (United States)

    King, Nicholas B; Fraser, Veronique

    2013-01-01

    Pain management is marginalized or ignored, with millions of people worldwide unnecessarily living with untreated pain. Reducing global inequalities in untreated pain requires a concerted global effort, say Veronique Fraser and colleagues, which must attend to the complexity of pain and promote multimodal, multidisciplinary pain management.

  6. Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes

    Energy Technology Data Exchange (ETDEWEB)

    Last, Jerold A [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States); Gohil, Kishorchandra [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States); Mathrani, Vivek C [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States); Kenyon, Nicholas J [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States)

    2005-10-15

    Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-{kappa}B in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.

  7. Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes

    International Nuclear Information System (INIS)

    Last, Jerold A.; Gohil, Kishorchandra; Mathrani, Vivek C.; Kenyon, Nicholas J.

    2005-01-01

    Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-κB in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone

  8. Rev-erbα and the circadian transcriptional regulation of metabolism

    DEFF Research Database (Denmark)

    Gerhart-Hines, Z.; Lazar, M. A.

    2015-01-01

    The circadian clock orchestrates the coordinated rhythmicity of numerous metabolic pathways to anticipate daily and seasonal changes in energy demand. This vital physiol. function is controlled by a set of individual clock components that are present in each cell of the body, and regulate each ot...... between circadian rhythm and tissue-specific biol. networks and its relevance to organismal physiology.......The circadian clock orchestrates the coordinated rhythmicity of numerous metabolic pathways to anticipate daily and seasonal changes in energy demand. This vital physiol. function is controlled by a set of individual clock components that are present in each cell of the body, and regulate each...

  9. Danqi Pill regulates lipid metabolism disorder induced by myocardial ischemia through FATP-CPTI pathway.

    Science.gov (United States)

    Wang, Yong; Li, Chun; Wang, Qiyan; Shi, Tianjiao; Wang, Jing; Chen, Hui; Wu, Yan; Han, Jing; Guo, Shuzhen; Wang, Yuanyuan; Wang, Wei

    2015-02-21

    Danqi Pill (DQP), which contains Chinese herbs Salvia miltiorrhiza Bunge and Panax notoginseng, is widely used in the treatment of myocardial ischemia (MI) in China. Its regulatory effects on MI-associated lipid metabolism disorders haven't been comprehensively studied so far. We aimed to systematically investigate the regulatory mechanism of DQP on myocardial ischemia-induced lipid metabolism disorders. Myocardial ischemia rat model was induced by left anterior descending coronary artery ligation. The rat models were divided into three groups: model group with administration of normal saline, study group with administration of DanQi aqueous solution (1.5 mg/kg) and positive-control group with administration of pravastatin aqueous solution (1.2 mg/kg). In addition, another sham-operated group was set as negative control. At 28 days after treatment, cardiac function and degree of lipid metabolism disorders in rats of different groups were measured. Plasma lipid disorders were induced by myocardial ischemia, with manifestation of up-regulation of triglyceride (TG), low density lipoprotein (LDL), Apolipoprotein B (Apo-B) and 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR). DQP could down-regulate the levels of TG, LDL, Apo-B and HMGCR. The Lipid transport pathway, fatty acids transport protein (FATP) and Carnitine palmitoyltransferase I (CPTI) were down-regulated in model group. DQP could improve plasma lipid metabolism by up-regulating this lipid transport pathway. The transcription factors peroxisome proliferator-activated receptor α (PPARα) and retinoid X receptors (RXRs), which regulate lipid metabolism, were also up-regulated by DQP. Furthermore, DQP was able to improve heart function and up-regulate ejection fraction (EF) by increasing the cardiac diastolic volume. Our study reveals that DQP would be an ideal alternative drug for the treatment of dyslipidemia which is induced by myocardial ischemia.

  10. Retinol Dehydrogenases Regulate Vitamin A Metabolism for Visual Function

    Directory of Open Access Journals (Sweden)

    Bhubanananda Sahu

    2016-11-01

    Full Text Available The visual system produces visual chromophore, 11-cis-retinal from dietary vitamin A, all-trans-retinol making this vitamin essential for retinal health and function. These metabolic events are mediated by a sequential biochemical process called the visual cycle. Retinol dehydrogenases (RDHs are responsible for two reactions in the visual cycle performed in retinal pigmented epithelial (RPE cells, photoreceptor cells and Müller cells in the retina. RDHs in the RPE function as 11-cis-RDHs, which oxidize 11-cis-retinol to 11-cis-retinal in vivo. RDHs in rod photoreceptor cells in the retina work as all-trans-RDHs, which reduce all-trans-retinal to all-trans-retinol. Dysfunction of RDHs can cause inherited retinal diseases in humans. To facilitate further understanding of human diseases, mouse models of RDHs-related diseases have been carefully examined and have revealed the physiological contribution of specific RDHs to visual cycle function and overall retinal health. Herein we describe the function of RDHs in the RPE and the retina, particularly in rod photoreceptor cells, their regulatory properties for retinoid homeostasis and future therapeutic strategy for treatment of retinal diseases.

  11. Optimality principles in the regulation of metabolic networks.

    Science.gov (United States)

    Berkhout, Jan; Bruggeman, Frank J; Teusink, Bas

    2012-08-29

    One of the challenging tasks in systems biology is to understand how molecular networks give rise to emergent functionality and whether universal design principles apply to molecular networks. To achieve this, the biophysical, evolutionary and physiological constraints that act on those networks need to be identified in addition to the characterisation of the molecular components and interactions. Then, the cellular "task" of the network-its function-should be identified. A network contributes to organismal fitness through its function. The premise is that the same functions are often implemented in different organisms by the same type of network; hence, the concept of design principles. In biology, due to the strong forces of selective pressure and natural selection, network functions can often be understood as the outcome of fitness optimisation. The hypothesis of fitness optimisation to understand the design of a network has proven to be a powerful strategy. Here, we outline the use of several optimisation principles applied to biological networks, with an emphasis on metabolic regulatory networks. We discuss the different objective functions and constraints that are considered and the kind of understanding that they provide.

  12. Optimality Principles in the Regulation of Metabolic Networks

    Directory of Open Access Journals (Sweden)

    Jan Berkhout

    2012-08-01

    Full Text Available One of the challenging tasks in systems biology is to understand how molecular networks give rise to emergent functionality and whether universal design principles apply to molecular networks. To achieve this, the biophysical, evolutionary and physiological constraints that act on those networks need to be identified in addition to the characterisation of the molecular components and interactions. Then, the cellular “task” of the network—its function—should be identified. A network contributes to organismal fitness through its function. The premise is that the same functions are often implemented in different organisms by the same type of network; hence, the concept of design principles. In biology, due to the strong forces of selective pressure and natural selection, network functions can often be understood as the outcome of fitness optimisation. The hypothesis of fitness optimisation to understand the design of a network has proven to be a powerful strategy. Here, we outline the use of several optimisation principles applied to biological networks, with an emphasis on metabolic regulatory networks. We discuss the different objective functions and constraints that are considered and the kind of understanding that they provide.

  13. Metabolic regulation of cellular plasticity in the pancreas.

    Science.gov (United States)

    Ninov, Nikolay; Hesselson, Daniel; Gut, Philipp; Zhou, Amy; Fidelin, Kevin; Stainier, Didier Y R

    2013-07-08

    Obese individuals exhibit an increase in pancreatic β cell mass; conversely, scarce nutrition during pregnancy has been linked to β cell insufficiency in the offspring [reviewed in 1, 2]. These phenomena are thought to be mediated mainly through effects on β cell proliferation, given that a nutrient-sensitive β cell progenitor population in the pancreas has not been identified. Here, we employed the fluorescent ubiquitination-based cell-cycle indicator system to investigate β cell replication in real time and found that high nutrient concentrations induce rapid β cell proliferation. Importantly, we found that high nutrient concentrations also stimulate β cell differentiation from progenitors in the intrapancreatic duct (IPD). Furthermore, using a new zebrafish line where β cells are constitutively ablated, we show that β cell loss and high nutrient intake synergistically activate these progenitors. At the cellular level, this activation process causes ductal cell reorganization as it stimulates their proliferation and differentiation. Notably, we link the nutrient-dependent activation of these progenitors to a downregulation of Notch signaling specifically within the IPD. Furthermore, we show that the nutrient sensor mechanistic target of rapamycin (mTOR) is required for endocrine differentiation from the IPD under physiological conditions as well as in the diabetic state. Thus, this study reveals critical insights into how cells modulate their plasticity in response to metabolic cues and identifies nutrient-sensitive progenitors in the mature pancreas. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Regulation of iron metabolism during Neisseria meningitidis infection in mice

    Energy Technology Data Exchange (ETDEWEB)

    Letendre, E.D.

    1984-01-01

    Bacterial invasion of vertebrates triggers a marked reduction in the levels of iron associated with the plasma transferrin (Tf) pool. This hypoferremic response has been regarded as a host attempt to withhold essential iron from the invading pathogen. The exact nature of the mechanisms involved remains obscure. The kinetics of iron processing by the RE system were studied by labeling the RE compartments with /sup 59/Fe-labeled denatured red blood cells. Uptake and redistribution of the label indicated the RE-processed iron was not returned to the plasma Tf pool during the hypoferremia. Fractionation of hepatic cellular compartments showed that this impaired release of iron resulted from a preferential incorporation of home-derived iron into the intracellular ferritin pool and this produces the hypoferremia. The role of ceruloplasmin (ferroxidase I,EC.1.16.3.1) (Cp) in iron metabolism during meningococcal infection was investigated. Plasma Cp ferroxidase activity was found to increase greatly in mice during the convalescence phase.

  15. Nanocellulose size regulates microalgal flocculation and lipid metabolism

    Science.gov (United States)

    Yu, Sun Il; Min, Seul Ki; Shin, Hwa Sung

    2016-01-01

    Harvesting of microalgae is a cost-consuming step for biodiesel production. Cellulose has recently been studied as a biocompatible and inexpensive flocculant for harvesting microalgae via surface modifications such as cation-modifications. In this study, we demonstrated that cellulose nanofibrils (CNF) played a role as a microalgal flocculant via its network geometry without cation modification. Sulfur acid-treated tunicate CNF flocculated microalgae, but cellulose nanocrystals (CNC) did not. In addition, desulfurization did not significantly influence the flocculation efficiency of CNF. This mechanism is likely related to encapsulation of microalgae by nanofibrous structure formation, which is derived from nanofibrils entanglement and intra-hydrogen bonding. Moreover, flocculated microalgae were subject to mechanical stress resulting in changes in metabolism induced by calcium ion influx, leading to upregulated lipid synthesis. CNF do not require surface modifications such as cation modified CNC and flocculation is derived from network geometry related to nanocellulose size; accordingly, CNF is one of the least expensive cellulose-based flocculants ever identified. If this flocculant is applied to the biodiesel process, it could decrease the cost of harvest, which is one of the most expensive steps, while increasing lipid production. PMID:27796311

  16. Evolution of Microbial Quorum Sensing to Human Global Quorum Sensing: An Insight into How Gap Junctional Intercellular Communication Might Be Linked to the Global Metabolic Disease Crisis.

    Science.gov (United States)

    Trosko, James E

    2016-06-15

    The first anaerobic organism extracted energy for survival and reproduction from its source of nutrients, with the genetic means to ensure protection of its individual genome but also its species survival. While it had a means to communicate with its community via simple secreted molecules ("quorum sensing"), the eventual shift to an aerobic environment led to multi-cellular metazoan organisms, with evolutionary-selected genes to form extracellular matrices, stem cells, stem cell niches, and a family of gap junction or "connexin" genes. These germinal and somatic stem cells responded to extracellular signals that triggered intra-cellular signaling to regulate specific genes out of the total genome. These extra-cellular induced intra-cellular signals also modulated gap junctional intercellular communication (GJIC) in order to regulate the new cellular functions of symmetrical and asymmetrical cell division, cell differentiation, modes of cell death, and senescence. Within the hierarchical and cybernetic concepts, differentiated by neurons organized in the brain of the Homo sapiens, the conscious mind led to language, abstract ideas, technology, myth-making, scientific reasoning, and moral decision-making, i.e., the creation of culture. Over thousands of years, this has created the current collision between biological and cultural evolution, leading to the global "metabolic disease" crisis.

  17. Evolution of Microbial Quorum Sensing to Human Global Quorum Sensing: An Insight into How Gap Junctional Intercellular Communication Might Be Linked to the Global Metabolic Disease Crisis

    Directory of Open Access Journals (Sweden)

    James E. Trosko

    2016-06-01

    Full Text Available The first anaerobic organism extracted energy for survival and reproduction from its source of nutrients, with the genetic means to ensure protection of its individual genome but also its species survival. While it had a means to communicate with its community via simple secreted molecules (“quorum sensing”, the eventual shift to an aerobic environment led to multi-cellular metazoan organisms, with evolutionary-selected genes to form extracellular matrices, stem cells, stem cell niches, and a family of gap junction or “connexin” genes. These germinal and somatic stem cells responded to extracellular signals that triggered intra-cellular signaling to regulate specific genes out of the total genome. These extra-cellular induced intra-cellular signals also modulated gap junctional intercellular communication (GJIC in order to regulate the new cellular functions of symmetrical and asymmetrical cell division, cell differentiation, modes of cell death, and senescence. Within the hierarchical and cybernetic concepts, differentiated by neurons organized in the brain of the Homo sapiens, the conscious mind led to language, abstract ideas, technology, myth-making, scientific reasoning, and moral decision–making, i.e., the creation of culture. Over thousands of years, this has created the current collision between biological and cultural evolution, leading to the globalmetabolic disease” crisis.

  18. Conserved Metabolic Changes in Nondiabetic and Type 2 Diabetic Bariatric Surgery Patients: Global Metabolomic Pilot Study

    Directory of Open Access Journals (Sweden)

    Konrad Sarosiek

    2016-01-01

    Full Text Available The goal of this study was to provide insight into the mechanism by which bariatric surgical procedures led to weight loss and improvement or resolution of diabetes. Global biochemical profiling was used to evaluate changes occurring in nondiabetic and type 2 diabetic (T2D patients experiencing either less extreme sleeve gastrectomy or a full gastric bypass. We were able to identify changes in metabolism that were affected by standard preoperation liquid weight loss diet as well as by bariatric surgery itself. Preoperation weight-loss diet was associated with a strong lipid metabolism signature largely related to the consumption of adipose reserves for energy production. Glucose usage shift away from glycolytic pyruvate production toward pentose phosphate pathway, via glucose-6-phosphate, appeared to be shared across all patients regardless of T2D status or bariatric surgery procedure. Our results suggested that bariatric surgery might promote antioxidant defense and insulin sensitivity through both increased heme synthesis and HO activity or expression. Changes in histidine and its metabolites following surgery might be an indication of altered gut microbiome ecology or liver function. This initial study provided broad understanding of how metabolism changed globally in morbidly obese nondiabetic and T2D patients following weight-loss surgery.

  19. Genome-Wide RNAi Ionomics Screen Reveals New Genes and Regulation of Human Trace Element Metabolism

    OpenAIRE

    Malinouski, Mikalai; Hasan, Nesrin M.; Zhang, Yan; Seravalli, Javier; Lin, Jie; Avanesov, Andrei; Lutsenko, Svetlana; Gladyshev, Vadim N.

    2017-01-01

    Trace elements are essential for human metabolism and dysregulation of their homeostasis is associated with numerous disorders. Here we characterize mechanisms that regulate trace elements in human cells by designing and performing a genome-wide high-throughput siRNA/ionomics screen, and examining top hits in cellular and biochemical assays. The screen reveals high stability of the ionomes, especially the zinc ionome, and yields known regulators and novel candidates. We further uncover fundam...

  20. Kynurenine acid - metabolism and regulation of kynurenine pathway

    Directory of Open Access Journals (Sweden)

    Piotr Kozłowski

    2017-07-01

    Full Text Available Kynurenic acid (KYNA was first isolated from the dog's urine in 1853 by german chemist Justus von Liebig. KYNA probably plays an important role in the pathogenesis of many neurodegenerative and psychiatric diseases. Its elevated concentration were found in the brain (post mortem or in the cerebrospinal fluid patients  with schizophrenia, bipolar disorder, Alzheimer's disease, meningitis, autoimmune diseases, inflammatory processes and memory and learning disorders. The reduced KYNA concentration is characteristic for multiple sclerosis, Parkinson's disease, Huntington's disease and epilepsy. KYNA is an organic compound naturally occurring in nature. This amino acid belongs to the group of exogenous amino acids and can be synthesized by plants and bacteria alone. The largest amount of tryptophan about 95%is  metabolised by the kynurenine pathway. Only 1% of tryptophan supplied in the diet serves to produce serotonin in the brain. The process of regulation of KYNA synthesis in both the CNS and the periphery is complicated.

  1. Systems assessment of transcriptional regulation on central carbon metabolism by Cra and CRP.

    Science.gov (United States)

    Kim, Donghyuk; Seo, Sang Woo; Gao, Ye; Nam, Hojung; Guzman, Gabriela I; Cho, Byung-Kwan; Palsson, Bernhard O

    2018-04-06

    Two major transcriptional regulators of carbon metabolism in bacteria are Cra and CRP. CRP is considered to be the main mediator of catabolite repression. Unlike for CRP, in vivo DNA binding information of Cra is scarce. Here we generate and integrate ChIP-exo and RNA-seq data to identify 39 binding sites for Cra and 97 regulon genes that are regulated by Cra in Escherichia coli. An integrated metabolic-regulatory network was formed by including experimentally-derived regulatory information and a genome-scale metabolic network reconstruction. Applying analysis methods of systems biology to this integrated network showed that Cra enables optimal bacterial growth on poor carbon sources by redirecting and repressing glycolysis flux, by activating the glyoxylate shunt pathway, and by activating the respiratory pathway. In these regulatory mechanisms, the overriding regulatory activity of Cra over CRP is fundamental. Thus, elucidation of interacting transcriptional regulation of core carbon metabolism in bacteria by two key transcription factors was possible by combining genome-wide experimental measurement and simulation with a genome-scale metabolic model.

  2. Myogenin regulates exercise capacity and skeletal muscle metabolism in the adult mouse.

    Directory of Open Access Journals (Sweden)

    Jesse M Flynn

    2010-10-01

    Full Text Available Although skeletal muscle metabolism is a well-studied physiological process, little is known about how it is regulated at the transcriptional level. The myogenic transcription factor myogenin is required for skeletal muscle development during embryonic and fetal life, but myogenin's role in adult skeletal muscle is unclear. We sought to determine myogenin's function in adult muscle metabolism. A Myog conditional allele and Cre-ER transgene were used to delete Myog in adult mice. Mice were analyzed for exercise capacity by involuntary treadmill running. To assess oxidative and glycolytic metabolism, we performed indirect calorimetry, monitored blood glucose and lactate levels, and performed histochemical analyses on muscle fibers. Surprisingly, we found that Myog-deleted mice performed significantly better than controls in high- and low-intensity treadmill running. This enhanced exercise capacity was due to more efficient oxidative metabolism during low- and high-intensity exercise and more efficient glycolytic metabolism during high-intensity exercise. Furthermore, Myog-deleted mice had an enhanced response to long-term voluntary exercise training on running wheels. We identified several candidate genes whose expression was altered in exercise-stressed muscle of mice lacking myogenin. The results suggest that myogenin plays a critical role as a high-level transcriptional regulator to control the energy balance between aerobic and anaerobic metabolism in adult skeletal muscle.

  3. Osteopontin regulates the cross-talk between phosphatidylcholine and cholesterol metabolism in mouse liver.

    Science.gov (United States)

    Nuñez-Garcia, Maitane; Gomez-Santos, Beatriz; Buqué, Xabier; García-Rodriguez, Juan L; Romero, Marta R; Marin, Jose J G; Arteta, Beatriz; García-Monzón, Carmelo; Castaño, Luis; Syn, Wing-Kin; Fresnedo, Olatz; Aspichueta, Patricia

    2017-09-01

    Osteopontin (OPN) is involved in different liver pathologies in which metabolic dysregulation is a hallmark. Here, we investigated whether OPN could alter liver, and more specifically hepatocyte, lipid metabolism and the mechanism involved. In mice, lack of OPN enhanced cholesterol 7α-hydroxylase (CYP7A1) levels and promoted loss of phosphatidylcholine (PC) content in liver; in vivo treatment with recombinant (r)OPN caused opposite effects. rOPN directly decreased CYP7A1 levels through activation of focal adhesion kinase-AKT signaling in hepatocytes. PC content was also decreased in OPN-deficient (OPN-KO) hepatocytes in which de novo FA and PC synthesis was lower, whereas cholesterol (CHOL) synthesis was higher, than in WT hepatocytes. In vivo inhibition of cholesterogenesis normalized liver PC content in OPN-KO mice, demonstrating that OPN regulates the cross-talk between liver CHOL and PC metabolism. Matched liver and serum samples showed a positive correlation between serum OPN levels and liver PC and CHOL concentration in nonobese patients with nonalcoholic fatty liver. In conclusion, OPN regulates CYP7A1 levels and the metabolic fate of liver acetyl-CoA as a result of CHOL and PC metabolism interplay. The results suggest that CYP7A1 is a main axis and that serum OPN could disrupt liver PC and CHOL metabolism, contributing to nonalcoholic fatty liver disease progression in nonobese patients.

  4. PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation.

    Science.gov (United States)

    Strand, D W; Jiang, M; Murphy, T A; Yi, Y; Konvinse, K C; Franco, O E; Wang, Y; Young, J D; Hayward, S W

    2012-08-09

    Recent observations indicate prostatic diseases are comorbidities of systemic metabolic dysfunction. These discoveries revealed fundamental questions regarding the nature of prostate metabolism. We previously showed that prostate-specific ablation of PPARγ in mice resulted in tumorigenesis and active autophagy. Here, we demonstrate control of overlapping and distinct aspects of prostate epithelial metabolism by ectopic expression of individual PPARγ isoforms in PPARγ knockout prostate epithelial cells. Expression and activation of either PPARγ 1 or 2 reduced de novo lipogenesis and oxidative stress and mediated a switch from glucose to fatty acid oxidation through regulation of genes including Pdk4, Fabp4, Lpl, Acot1 and Cd36. Differential effects of PPARγ isoforms included decreased basal cell differentiation, Scd1 expression and triglyceride fatty acid desaturation and increased tumorigenicity by PPARγ1. In contrast, PPARγ2 expression significantly increased basal cell differentiation, Scd1 expression and AR expression and responsiveness. Finally, in confirmation of in vitro data, a PPARγ agonist versus high-fat diet (HFD) regimen in vivo confirmed that PPARγ agonization increased prostatic differentiation markers, whereas HFD downregulated PPARγ-regulated genes and decreased prostate differentiation. These data provide a rationale for pursuing a fundamental metabolic understanding of changes to glucose and fatty acid metabolism in benign and malignant prostatic diseases associated with systemic metabolic stress.

  5. Hypothalamic carnitine metabolism integrates nutrient and hormonal feedback to regulate energy homeostasis.

    Science.gov (United States)

    Stark, Romana; Reichenbach, Alex; Andrews, Zane B

    2015-12-15

    The maintenance of energy homeostasis requires the hypothalamic integration of nutrient feedback cues, such as glucose, fatty acids, amino acids, and metabolic hormones such as insulin, leptin and ghrelin. Although hypothalamic neurons are critical to maintain energy homeostasis research efforts have focused on feedback mechanisms in isolation, such as glucose alone, fatty acids alone or single hormones. However this seems rather too simplistic considering the range of nutrient and endocrine changes associated with different metabolic states, such as starvation (negative energy balance) or diet-induced obesity (positive energy balance). In order to understand how neurons integrate multiple nutrient or hormonal signals, we need to identify and examine potential intracellular convergence points or common molecular targets that have the ability to sense glucose, fatty acids, amino acids and hormones. In this review, we focus on the role of carnitine metabolism in neurons regulating energy homeostasis. Hypothalamic carnitine metabolism represents a novel means for neurons to facilitate and control both nutrient and hormonal feedback. In terms of nutrient regulation, carnitine metabolism regulates hypothalamic fatty acid sensing through the actions of CPT1 and has an underappreciated role in glucose sensing since carnitine metabolism also buffers mitochondrial matrix levels of acetyl-CoA, an allosteric inhibitor of pyruvate dehydrogenase and hence glucose metabolism. Studies also show that hypothalamic CPT1 activity also controls hormonal feedback. We hypothesis that hypothalamic carnitine metabolism represents a key molecular target that can concurrently integrate nutrient and hormonal information, which is critical to maintain energy homeostasis. We also suggest this is relevant to broader neuroendocrine research as it predicts that hormonal signaling in the brain varies depending on current nutrient status. Indeed, the metabolic action of ghrelin, leptin or insulin

  6. Studies on the mechanism of quinone action on hormonal regulation of metabolism in the rat liver

    International Nuclear Information System (INIS)

    Cheng, E.Y.

    1989-01-01

    The mechanism of quinone actions in liver cell metabolism had been investigated using menadione as a model compound. Previous reports suggested that quinones and free radicals could produce perturbations in cellular calcium homeostasis. Since calcium plays an important role in the regulation of cellular metabolic processes, then regulation of cytosolic calcium concentrations, and thus of cellular metabolism, by calcium-mobilizing hormones such as phenylephrine and vasopressin could possibly be modified by quinones such as menadione. Methods used to approach this hypothesis included the assay for activation of glycogen phosphorylase, an indirect index of calcium mobilization; the determination of calcium mobilization with 45 Ca efflux exchange and with fluorescent calcium indicator fura-2; and the measurement of phosphatidylinositides, an important link in the membrane-associated receptor-mediated signal transduction mechanism

  7. [Dry immersion effects on the mechanisms of metabolic-reflex regulation of hemodynamics during muscular work].

    Science.gov (United States)

    Bravyĭ, Ia R; Bersenev, E Iu; Missina, S S; Borovik, A S; Sharova, A P; Vinogradova, O L

    2008-01-01

    Effects of 4-d dry immersion on metabolic-reflex regulation of hemodynamics were evaluated during local static work (30% of maximum voluntary effort) of the talocrural extensors. One group of immersed test-subjects received low-frequency electrostimulation of leg muscles to offset the immersion effect on EMG of working muscles. Metabolic-reflex regulation was evaluated through comparison of cardiovascular responses to physical tests with and w/o post-exercise vascular occlusion. Immersion vaguely increased heart rate and reduced systolic arterial pressure in resting subjects; however, it did not have a distinct effect on arterial pressure and HR during muscular work or metabolic-reflex potentiation of hemodynamic shifts.

  8. Metabolic Regulation of CaMKII Protein and Caspases in Xenopus laevis Egg Extracts*

    Science.gov (United States)

    McCoy, Francis; Darbandi, Rashid; Chen, Si-Ing; Eckard, Laura; Dodd, Keela; Jones, Kelly; Baucum, Anthony J.; Gibbons, Jennifer A.; Lin, Sue-Hwa; Colbran, Roger J.; Nutt, Leta K.

    2013-01-01

    The metabolism of the Xenopus laevis egg provides a cell survival signal. We found previously that increased carbon flux from glucose-6-phosphate (G6P) through the pentose phosphate pathway in egg extracts maintains NADPH levels and calcium/calmodulin regulated protein kinase II (CaMKII) activity to phosphorylate caspase 2 and suppress cell death pathways. Here we show that the addition of G6P to oocyte extracts inhibits the dephosphorylation/inactivation of CaMKII bound to caspase 2 by protein phosphatase 1. Thus, G6P sustains the phosphorylation of caspase 2 by CaMKII at Ser-135, preventing the induction of caspase 2-mediated apoptotic pathways. These findings expand our understanding of oocyte biology and clarify mechanisms underlying the metabolic regulation of CaMKII and apoptosis. Furthermore, these findings suggest novel approaches to disrupt the suppressive effects of the abnormal metabolism on cell death pathways. PMID:23400775

  9. Overexpression of Jazf1 reduces body weight gain and regulates lipid metabolism in high fat diet

    International Nuclear Information System (INIS)

    Jang, Woo Young; Bae, Ki Beom; Kim, Sung Hyun; Yu, Dong Hun; Kim, Hei Jung; Ji, Young Rae; Park, Seo Jin; Park, Si Jun; Kang, Min-Cheol; Jeong, Ja In; Park, Sang-Joon; Lee, Sang Gyu; Lee, Inkyu; Kim, Myoung Ok; Yoon, Duhak; Ryoo, Zae Young

    2014-01-01

    Highlights: • The expression of Jazf1 in the liver suppressed lipid accumulation. • Jazf1 significantly increases transcription of fatty acid synthase. • Jazf1 plays a critical role in the regulation of energy and lipid homeostasis. • Jazf1 associates the development of metabolic disorder. • Jazf1 may provide a new therapeutic target in the management of metabolic disorder. - Abstract: Jazf1 is a 27 kDa nuclear protein containing three putative zinc finger motifs that is associated with diabetes mellitus and prostate cancer; however, little is known about the role that this gene plays in regulation of metabolism. Recent evidence indicates that Jazf1 transcription factors bind to the nuclear orphan receptor TR4. This receptor regulates PEPCK, the key enzyme involved in gluconeogenesis. To elucidate Jazf1’s role in metabolism, we fed a 60% fat diet for up to 15 weeks. In Jazf1 overexpression mice, weight gain was found to be significantly decreased. The expression of Jazf1 in the liver also suppressed lipid accumulation and decreased droplet size. These results suggest that Jazf1 plays a critical role in the regulation of lipid homeostasis. Finally, Jazf1 may provide a new therapeutic target in the management of obesity and diabetes

  10. PPAR-alpha dependent regulation of vanin-1 mediates hepatic lipid metabolism

    NARCIS (Netherlands)

    Diepen, van J.A.; Jansen, P.A.; Ballak, D.B.; Hijmans, A.; Hooiveld, G.J.E.J.; Rommelaere, S.; Kersten, A.H.; Stienstra, R.

    2014-01-01

    Background & Aims Peroxisome proliferator-activated receptor alpha (PPARa) is a key regulator of hepatic fat oxidation that serves as an energy source during starvation. Vanin-1 has been described as a putative PPARa target gene in liver, but its function in hepatic lipid metabolism is unknown.

  11. Overexpression of Jazf1 reduces body weight gain and regulates lipid metabolism in high fat diet

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Woo Young; Bae, Ki Beom; Kim, Sung Hyun; Yu, Dong Hun; Kim, Hei Jung; Ji, Young Rae; Park, Seo Jin; Park, Si Jun; Kang, Min-Cheol; Jeong, Ja In [School of Life Science and Biotechnology, Kyungpook National University, 1370 Sankyuk-dong, Buk-ku, Daegu 702-701 (Korea, Republic of); Park, Sang-Joon [College of Veterinary Medicine, Kyungpook National University, 1370 Sankyuk-dong, Buk-ku, Daegu 702-701 (Korea, Republic of); Lee, Sang Gyu [School of Life Science and Biotechnology, Kyungpook National University, 1370 Sankyuk-dong, Buk-ku, Daegu 702-701 (Korea, Republic of); Lee, Inkyu [School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 700-842 (Korea, Republic of); Kim, Myoung Ok [School of Animal BT Sciences, Sangju Campus, Kyungpook National University, 386 Gajang-dong, Sangju, Gyeongsangbuk-do 742-211 (Korea, Republic of); Yoon, Duhak, E-mail: dhyoon@knu.ac.kr [School of Animal BT Sciences, Sangju Campus, Kyungpook National University, 386 Gajang-dong, Sangju, Gyeongsangbuk-do 742-211 (Korea, Republic of); Ryoo, Zae Young, E-mail: jaewoong64@hanmail.net [School of Life Science and Biotechnology, Kyungpook National University, 1370 Sankyuk-dong, Buk-ku, Daegu 702-701 (Korea, Republic of)

    2014-02-14

    Highlights: • The expression of Jazf1 in the liver suppressed lipid accumulation. • Jazf1 significantly increases transcription of fatty acid synthase. • Jazf1 plays a critical role in the regulation of energy and lipid homeostasis. • Jazf1 associates the development of metabolic disorder. • Jazf1 may provide a new therapeutic target in the management of metabolic disorder. - Abstract: Jazf1 is a 27 kDa nuclear protein containing three putative zinc finger motifs that is associated with diabetes mellitus and prostate cancer; however, little is known about the role that this gene plays in regulation of metabolism. Recent evidence indicates that Jazf1 transcription factors bind to the nuclear orphan receptor TR4. This receptor regulates PEPCK, the key enzyme involved in gluconeogenesis. To elucidate Jazf1’s role in metabolism, we fed a 60% fat diet for up to 15 weeks. In Jazf1 overexpression mice, weight gain was found to be significantly decreased. The expression of Jazf1 in the liver also suppressed lipid accumulation and decreased droplet size. These results suggest that Jazf1 plays a critical role in the regulation of lipid homeostasis. Finally, Jazf1 may provide a new therapeutic target in the management of obesity and diabetes.

  12. Regulation of lipid metabolism by energy availability: a role for the central nervous system.

    Science.gov (United States)

    Nogueiras, R; López, M; Diéguez, C

    2010-03-01

    The central nervous system (CNS) is crucial in the regulation of energy homeostasis. Many neuroanatomical studies have shown that the white adipose tissue (WAT) is innervated by the sympathetic nervous system, which plays a critical role in adipocyte lipid metabolism. Therefore, there are currently numerous reports indicating that signals from the CNS control the amount of fat by modulating the storage or oxidation of fatty acids. Importantly, some CNS pathways regulate adipocyte metabolism independently of food intake, suggesting that some signals possess alternative mechanisms to regulate energy homeostasis. In this review, we mainly focus on how neuronal circuits within the hypothalamus, such as leptin- ghrelin-and resistin-responsive neurons, as well as melanocortins, neuropeptide Y, and the cannabinoid system exert their actions on lipid metabolism in peripheral tissues such as WAT, liver or muscle. Dissecting the complicated interactions between peripheral signals and neuronal circuits regulating lipid metabolism might open new avenues for the development of new therapies preventing and treating obesity and its associated cardiometabolic sequelae.

  13. Methanol Metabolism in Yeasts : Regulation of the Synthesis of Catabolic Enzymes

    NARCIS (Netherlands)

    Egli, Th.; Dijken, J.P. van; Veenhuis, M.; Harder, W.; Fiechter, A.

    1980-01-01

    The regulation of the synthesis of four dissimilatory enzymes involved in methanol metabolism, namely alcohol oxidase, formaldehyde dehydrogenase, formate dehydrogenase and catalase was investigated in the yeasts Hansenula polymorpha and Kloeckera sp. 2201. Enzyme profiles in cell-free extracts of

  14. Body weight regulation and obesity: dietary strategies to improve the metabolic profile.

    Science.gov (United States)

    Munsters, M J M; Saris, W H M

    2014-01-01

    This review discusses dietary strategies that may improve the metabolic profile and body weight regulation in obesity. Recent evidence demonstrated that long-term health effects seem to be more beneficial for low-glycemic index (GI) diets compared to high-protein diets. Still, these results need to be confirmed by other prospective cohort studies and long-term clinical trials, and the discrepancy between these study designs needs to be explored in more detail. Furthermore, the current literature is mixed with regard to the efficacy of increased meal frequency (or snacking) regimens in causing metabolic alterations, particularly in relation to body weight control. In conclusion, a growing body of evidence suggests that dietary strategies with the aim to reduce postprandial insulin response and increase fat oxidation, and that tend to restore metabolic flexibility, have a place in the prevention and treatment of obesity and associated metabolic disorders.

  15. Metabolic regulation of the plant hormone indole-3-acetic acid

    Energy Technology Data Exchange (ETDEWEB)

    Jerry D. Cohen

    2009-11-01

    The phytohormone indole-3-acetic acid (IAA, auxin) is important for many aspects of plant growth, development and responses to the environment yet the routes to is biosynthesis and mechanisms for regulation of IAA levels remain important research questions. A critical issue concerning the biosynthesis if IAA in plants is that redundant pathways for IAA biosynthesis exist in plants. We showed that these redundant pathways and their relative contribution to net IAA production are under both developmental and environmental control. We worked on three fundamental problems related to how plants get their IAA: 1) An in vitro biochemical approach was used to define the tryptophan dependent pathway to IAA using maize endosperm, where relatively large amounts of IAA are produced over a short developmental period. Both a stable isotope dilution and a protein MS approach were used to identify intermediates and enzymes in the reactions. 2) We developed an in vitro system for analysis of tryptophan-independent IAA biosynthesis in maize seedlings and we used a metabolite profiling approach to isolate intermediates in this reaction. 3) Arabidopsis contains a small family of genes that encode potential indolepyruvate decarboxylase enzymes. We cloned these genes and studied plants that are mutant in these genes and that over-express each member in the family in terms of the level and route of IAA biosynthesis. Together, these allowed further development of a comprehensive picture of the pathways and regulatory components that are involved in IAA homeostasis in higher plants.

  16. PGC-1α regulates alanine metabolism in muscle cells.

    Science.gov (United States)

    Hatazawa, Yukino; Qian, Kun; Gong, Da-Wei; Kamei, Yasutomi

    2018-01-01

    The skeletal muscle is the largest organ in the human body, depositing energy as protein/amino acids, which are degraded in catabolic conditions such as fasting. Alanine is synthesized and secreted from the skeletal muscle that is used as substrates of gluconeogenesis in the liver. During fasting, the expression of PGC-1α, a transcriptional coactivator of nuclear receptors, is increased in the liver and regulates gluconeogenesis. In the present study, we observed increased mRNA expression of PGC-1α and alanine aminotransferase 2 (ALT2) in the skeletal muscle during fasting. In C2C12 myoblast cells overexpressing PGC-1α, ALT2 expression was increased concomitant with an increased alanine level in the cells and medium. In addition, PGC-1α, along with nuclear receptor ERR, dose-dependently enhanced the ALT2 promoter activity in reporter assay using C2C12 cells. In the absence of glucose in the culture medium, mRNA levels of PGC-1α and ALT2 increased. Endogenous PGC-1α knockdown in C2C12 cells reduced ALT2 gene expression level, induced by the no-glucose medium. Taken together, in the skeletal muscle, PGC-1α activates ALT2 gene expression, and alanine production may play roles in adaptation to fasting.

  17. Role of Glycolytic Intermediates in Global Regulation and Signal Transduction. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Liao, J.C.

    2000-05-08

    The goal of this project is to determine the role of glycolytic intermediates in regulation of cell physiology. It is known that many glycolytic intermediates are involved in regulation of enzyme activities at the kinetic level. However, little is known regarding the role of these metabolites in global regulation and signal transduction. This project aims to investigate the role of glycolytic intermediates in the regulation of gene expression.

  18. Systems biology of adipose tissue metabolism: regulation of growth, signaling and inflammation.

    Science.gov (United States)

    Manteiga, Sara; Choi, Kyungoh; Jayaraman, Arul; Lee, Kyongbum

    2013-01-01

    Adipose tissue (AT) depots actively regulate whole body energy homeostasis by orchestrating complex communications with other physiological systems as well as within the tissue. Adipocytes readily respond to hormonal and nutritional inputs to store excess nutrients as intracellular lipids or mobilize the stored fat for utilization. Co-ordinated regulation of metabolic pathways balancing uptake, esterification, and hydrolysis of lipids is accomplished through positive and negative feedback interactions of regulatory hubs comprising several pleiotropic protein kinases and nuclear receptors. Metabolic regulation in adipocytes encompasses biogenesis and remodeling of uniquely large lipid droplets (LDs). The regulatory hubs also function as energy and nutrient sensors, and integrate metabolic regulation with intercellular signaling. Over-nutrition causes hypertrophic expansion of adipocytes, which, through incompletely understood mechanisms, initiates a cascade of metabolic and signaling events leading to tissue remodeling and immune cell recruitment. Macrophage activation and polarization toward a pro-inflammatory phenotype drives a self-reinforcing cycle of pro-inflammatory signals in the AT, establishing an inflammatory state. Sustained inflammation accelerates lipolysis and elevates free fatty acids in circulation, which robustly correlates with development of obesity-related diseases. The adipose regulatory network coupling metabolism, growth, and signaling of multiple cell types is exceedingly complex. While components of the regulatory network have been individually studied in exquisite detail, systems approaches have rarely been utilized to comprehensively assess the relative engagements of the components. Thus, need and opportunity exist to develop quantitative models of metabolic and signaling networks to achieve a more complete understanding of AT biology in both health and disease. Copyright © 2013 Wiley Periodicals, Inc.

  19. Hydrogen sulfide metabolism regulates endothelial solute barrier function

    Directory of Open Access Journals (Sweden)

    Shuai Yuan

    2016-10-01

    Full Text Available Hydrogen sulfide (H2S is an important gaseous signaling molecule in the cardiovascular system. In addition to free H2S, H2S can be oxidized to polysulfide which can be biologically active. Since the impact of H2S on endothelial solute barrier function is not known, we sought to determine whether H2S and its various metabolites affect endothelial permeability. In vitro permeability was evaluated using albumin flux and transendothelial electrical resistance. Different H2S donors were used to examine the effects of exogenous H2S. To evaluate the role of endogenous H2S, mouse aortic endothelial cells (MAECs were isolated from wild type mice and mice lacking cystathionine γ-lyase (CSE, a predominant source of H2S in endothelial cells. In vivo permeability was evaluated using the Miles assay. We observed that polysulfide donors induced rapid albumin flux across endothelium. Comparatively, free sulfide donors increased permeability only with higher concentrations and at later time points. Increased solute permeability was associated with disruption of endothelial junction proteins claudin 5 and VE-cadherin, along with enhanced actin stress fiber formation. Importantly, sulfide donors that increase permeability elicited a preferential increase in polysulfide levels within endothelium. Similarly, CSE deficient MAECs showed enhanced solute barrier function along with reduced endogenous bound sulfane sulfur. CSE siRNA knockdown also enhanced endothelial junction structures with increased claudin 5 protein expression. In vivo, CSE genetic deficiency significantly blunted VEGF induced hyperpermeability revealing an important role of the enzyme for barrier function. In summary, endothelial solute permeability is critically regulated via exogenous and endogenous sulfide bioavailability with a prominent role of polysulfides.

  20. Carbohydrate Metabolism in Archaea: Current Insights into Unusual Enzymes and Pathways and Their Regulation

    Science.gov (United States)

    Esser, Dominik; Rauch, Bernadette

    2014-01-01

    SUMMARY The metabolism of Archaea, the third domain of life, resembles in its complexity those of Bacteria and lower Eukarya. However, this metabolic complexity in Archaea is accompanied by the absence of many “classical” pathways, particularly in central carbohydrate metabolism. Instead, Archaea are characterized by the presence of unique, modified variants of classical pathways such as the Embden-Meyerhof-Parnas (EMP) pathway and the Entner-Doudoroff (ED) pathway. The pentose phosphate pathway is only partly present (if at all), and pentose degradation also significantly differs from that known for bacterial model organisms. These modifications are accompanied by the invention of “new,” unusual enzymes which cause fundamental consequences for the underlying regulatory principles, and classical allosteric regulation sites well established in Bacteria and Eukarya are lost. The aim of this review is to present the current understanding of central carbohydrate metabolic pathways and their regulation in Archaea. In order to give an overview of their complexity, pathway modifications are discussed with respect to unusual archaeal biocatalysts, their structural and mechanistic characteristics, and their regulatory properties in comparison to their classic counterparts from Bacteria and Eukarya. Furthermore, an overview focusing on hexose metabolic, i.e., glycolytic as well as gluconeogenic, pathways identified in archaeal model organisms is given. Their energy gain is discussed, and new insights into different levels of regulation that have been observed so far, including the transcript and protein levels (e.g., gene regulation, known transcription regulators, and posttranslational modification via reversible protein phosphorylation), are presented. PMID:24600042

  1. Proteomic evidences for rex regulation of metabolism in toxin-producing Bacillus cereus ATCC 14579.

    Directory of Open Access Journals (Sweden)

    Sabrina Laouami

    Full Text Available The facultative anaerobe, Bacillus cereus, causes diarrheal diseases in humans. Its ability to deal with oxygen availability is recognized to be critical for pathogenesis. The B. cereus genome comprises a gene encoding a protein with high similarities to the redox regulator, Rex, which is a central regulator of anaerobic metabolism in Bacillus subtilis and other Gram-positive bacteria. Here, we showed that B. cereus rex is monocistronic and down-regulated in the absence of oxygen. The protein encoded by rex is an authentic Rex transcriptional factor since its DNA binding activity depends on the NADH/NAD+ ratio. Rex deletion compromised the ability of B. cereus to cope with external oxidative stress under anaerobiosis while increasing B. cereus resistance against such stress under aerobiosis. The deletion of rex affects anaerobic fermentative and aerobic respiratory metabolism of B. cereus by decreasing and increasing, respectively, the carbon flux through the NADH-recycling lactate pathway. We compared both the cellular proteome and exoproteome of the wild-type and Δrex cells using a high throughput shotgun label-free quantitation approach and identified proteins that are under control of Rex-mediated regulation. Proteomics data have been deposited to the ProteomeXchange with identifier PXD000886. The data suggest that Rex regulates both the cross-talk between metabolic pathways that produce NADH and NADPH and toxinogenesis, especially in oxic conditions.

  2. Global metabolic rewiring for improved CO2 fixation and chemical production in cyanobacteria

    Science.gov (United States)

    Kanno, Masahiro; Carroll, Austin L.; Atsumi, Shota

    2017-03-01

    Cyanobacteria have attracted much attention as hosts to recycle CO2 into valuable chemicals. Although cyanobacteria have been engineered to produce various compounds, production efficiencies are too low for commercialization. Here we engineer the carbon metabolism of Synechococcus elongatus PCC 7942 to improve glucose utilization, enhance CO2 fixation and increase chemical production. We introduce modifications in glycolytic pathways and the Calvin Benson cycle to increase carbon flux and redirect it towards carbon fixation. The engineered strain efficiently uses both CO2 and glucose, and produces 12.6 g l-1 of 2,3-butanediol with a rate of 1.1 g l-1 d-1 under continuous light conditions. Removal of native regulation enables carbon fixation and 2,3-butanediol production in the absence of light. This represents a significant step towards industrial viability and an excellent example of carbon metabolism plasticity.

  3. Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption

    Science.gov (United States)

    Patel, Chirag; Douard, Veronique; Yu, Shiyan; Gao, Nan; Ferraris, Ronaldo P.

    2015-01-01

    Dietary fructose that is linked to metabolic abnormalities can up-regulate its own absorption, but the underlying regulatory mechanisms are not known. We hypothesized that glucose transporter (GLUT) protein, member 5 (GLUT5) is the primary fructose transporter and that fructose absorption via GLUT5, metabolism via ketohexokinase (KHK), as well as GLUT5 trafficking to the apical membrane via the Ras-related protein-in-brain 11 (Rab11)a-dependent endosomes are each required for regulation. Introducing fructose but not lysine and glucose solutions into the lumen increased by 2- to 10-fold the heterogeneous nuclear RNA, mRNA, protein, and activity levels of GLUT5 in adult wild-type mice consuming chow. Levels of GLUT5 were >100-fold that of candidate apical fructose transporters GLUTs 7, 8, and 12 whose expression, and that of GLUT 2 and the sodium-dependent glucose transporter protein 1 (SGLT1), was not regulated by luminal fructose. GLUT5-knockout (KO) mice exhibited no facilitative fructose transport and no compensatory increases in activity and expression of SGLT1 and other GLUTs. Fructose could not up-regulate GLUT5 in GLUT5-KO, KHK-KO, and intestinal epithelial cell-specific Rab11a-KO mice. The fructose-specific metabolite glyceraldehyde did not increase GLUT5 expression. GLUT5 is the primary transporter responsible for facilitative absorption of fructose, and its regulation specifically requires fructose uptake and metabolism and normal GLUT5 trafficking to the apical membrane.—Patel, C., Douard, V., Yu, S., Gao, N., Ferraris, R. P. Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption. PMID:26071406

  4. An AICD-based functional screen to identify APP metabolism regulators

    Directory of Open Access Journals (Sweden)

    Lee Jeremy C

    2007-08-01

    Full Text Available Abstract Background A central event in Alzheimer's disease (AD is the regulated intramembraneous proteolysis of the β-amyloid precursor protein (APP, to generate the β-amyloid (Aβ peptide and the APP intracellular domain (AICD. Aβ is the major component of amyloid plaques and AICD displays transcriptional activation properties. We have taken advantage of AICD transactivation properties to develop a genetic screen to identify regulators of APP metabolism. This screen relies on an APP-Gal4 fusion protein, which upon normal proteolysis, produces AICD-Gal4. Production of AICD-Gal4 induces Gal4-UAS driven luciferase expression. Therefore, when regulators of APP metabolism are modulated, luciferase expression is altered. Results To validate this experimental approach we modulated α-, β-, and γ-secretase levels and activities. Changes in AICD-Gal4 levels as measured by Western blot analysis were strongly and significantly correlated to the observed changes in AICD-Gal4 mediated luciferase activity. To determine if a known regulator of APP trafficking/maturation and Presenilin1 endoproteolysis could be detected using the AICD-Gal4 mediated luciferase assay, we knocked-down Ubiquilin 1 and observed decreased luciferase activity. We confirmed that Ubiquilin 1 modulated AICD-Gal4 levels by Western blot analysis and also observed that Ubiquilin 1 modulated total APP levels, the ratio of mature to immature APP, as well as PS1 endoproteolysis. Conclusion Taken together, we have shown that this screen can identify known APP metabolism regulators that control proteolysis, intracellular trafficking, maturation and levels of APP and its proteolytic products. We demonstrate for the first time that Ubiquilin 1 regulates APP metabolism in the human neuroblastoma cell line, SH-SY5Y.

  5. Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors.

    Science.gov (United States)

    Montgomery, David C; Sorum, Alexander W; Guasch, Laura; Nicklaus, Marc C; Meier, Jordan L

    2015-08-20

    The finding that chromatin modifications are sensitive to changes in cellular cofactor levels potentially links altered tumor cell metabolism and gene expression. However, the specific enzymes and metabolites that connect these two processes remain obscure. Characterizing these metabolic-epigenetic axes is critical to understanding how metabolism supports signaling in cancer, and developing therapeutic strategies to disrupt this process. Here, we describe a chemical approach to define the metabolic regulation of lysine acetyltransferase (KAT) enzymes. Using a novel chemoproteomic probe, we identify a previously unreported interaction between palmitoyl coenzyme A (palmitoyl-CoA) and KAT enzymes. Further analysis reveals that palmitoyl-CoA is a potent inhibitor of KAT activity and that fatty acyl-CoA precursors reduce cellular histone acetylation levels. These studies implicate fatty acyl-CoAs as endogenous regulators of histone acetylation, and suggest novel strategies for the investigation and metabolic modulation of epigenetic signaling. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Study of AMPK-Regulated Metabolic Fluxes in Neurons Using the Seahorse XFe Analyzer.

    Science.gov (United States)

    Marinangeli, Claudia; Kluza, Jérome; Marchetti, Philippe; Buée, Luc; Vingtdeux, Valérie

    2018-01-01

    AMP-activated protein kinase (AMPK) is the intracellular master energy sensor and metabolic regulator. AMPK is involved in cell energy homeostasis through the regulation of glycolytic flux and mitochondrial biogenesis. Interestingly, metabolic dysfunctions and AMPK deregulations are observed in many neurodegenerative diseases, including Alzheimer's. While these deregulations could play a key role in the development of these diseases, the study of metabolic fluxes has remained quite challenging and time-consuming. In this chapter, we describe the Seahorse XFe respirometry assay as a fundamental experimental tool to investigate the role of AMPK in controlling and modulating cell metabolic fluxes in living and intact differentiated primary neurons. The Seahorse XFe respirometry assay allows the real-time monitoring of glycolytic flux and mitochondrial respiration from different kind of cells, tissues, and isolated mitochondria. Here, we specify a protocol optimized for primary neuronal cells using several energy substrates such as glucose, pyruvate, lactate, glutamine, and ketone bodies. Nevertheless, this protocol can easily be adapted to monitor metabolic fluxes from other types of cells, tissues, or isolated mitochondria by taking into account the notes proposed for each key step of this assay.

  7. TRAP1 Regulation of Cancer Metabolism: Dual Role as Oncogene or Tumor Suppressor

    Directory of Open Access Journals (Sweden)

    Danilo Swann Matassa

    2018-04-01

    Full Text Available Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1 is a molecular chaperone involved in the regulation of energetic metabolism in cancer cells. This protein is highly expressed in several cancers, such as glioblastoma, colon, breast, prostate and lung cancers and is often associated with drug resistance. However, TRAP1 is also downregulated in specific tumors, such as ovarian, bladder and renal cancers, where its lower expression is correlated with the worst prognoses and chemoresistance. TRAP1 is the only mitochondrial member of the Heat Shock Protein 90 (HSP90 family that directly interacts with respiratory complexes, contributing to their stability and activity but it is still unclear if such interactions lead to reduced or increased respiratory capacity. The role of TRAP1 is to enhance or suppress oxidative phosphorylation; the effects of such regulation on tumor development and progression are controversial. These observations encourage the study of the mechanisms responsible for the dualist role of TRAP1 as an oncogene or oncosuppressor in specific tumor types. In this review, TRAP1 puzzling functions were recapitulated with a special focus on the correlation between metabolic reprogramming and tumor outcome. We wanted to investigate whether metabolism-targeting drugs can efficiently interfere with tumor progression and whether they might be combined with chemotherapeutics or molecular-targeted agents to counteract drug resistance and reduce therapeutic failure.

  8. De novo Transcriptome Assembly of Chinese Kale and Global Expression Analysis of Genes Involved in Glucosinolate Metabolism in Multiple Tissues

    Science.gov (United States)

    Wu, Shuanghua; Lei, Jianjun; Chen, Guoju; Chen, Hancai; Cao, Bihao; Chen, Changming

    2017-01-01

    Chinese kale, a vegetable of the cruciferous family, is a popular crop in southern China and Southeast Asia due to its high glucosinolate content and nutritional qualities. However, there is little research on the molecular genetics and genes involved in glucosinolate metabolism and its regulation in Chinese kale. In this study, we sequenced and characterized the transcriptomes and expression profiles of genes expressed in 11 tissues of Chinese kale. A total of 216 million 150-bp clean reads were generated using RNA-sequencing technology. From the sequences, 98,180 unigenes were assembled for the whole plant, and 49,582~98,423 unigenes were assembled for each tissue. Blast analysis indicated that a total of 80,688 (82.18%) unigenes exhibited similarity to known proteins. The functional annotation and classification tools used in this study suggested that genes principally expressed in Chinese kale, were mostly involved in fundamental processes, such as cellular and molecular functions, the signal transduction, and biosynthesis of secondary metabolites. The expression levels of all unigenes were analyzed in various tissues of Chinese kale. A large number of candidate genes involved in glucosinolate metabolism and its regulation were identified, and the expression patterns of these genes were analyzed. We found that most of the genes involved in glucosinolate biosynthesis were highly expressed in the root, petiole, and in senescent leaves. The expression patterns of ten glucosinolate biosynthetic genes from RNA-seq were validated by quantitative RT-PCR in different tissues. These results provided an initial and global overview of Chinese kale gene functions and expression activities in different tissues. PMID:28228764

  9. Chromatin-Bound MDM2 Regulates Serine Metabolism and Redox Homeostasis Independently of p53.

    Science.gov (United States)

    Riscal, Romain; Schrepfer, Emilie; Arena, Giuseppe; Cissé, Madi Y; Bellvert, Floriant; Heuillet, Maud; Rambow, Florian; Bonneil, Eric; Sabourdy, Frédérique; Vincent, Charles; Ait-Arsa, Imade; Levade, Thierry; Thibaut, Pierre; Marine, Jean-Christophe; Portais, Jean-Charles; Sarry, Jean-Emmanuel; Le Cam, Laurent; Linares, Laetitia K

    2016-06-16

    The mouse double minute 2 (MDM2) oncoprotein is recognized as a major negative regulator of the p53 tumor suppressor, but growing evidence indicates that its oncogenic activities extend beyond p53. Here, we show that MDM2 is recruited to chromatin independently of p53 to regulate a transcriptional program implicated in amino acid metabolism and redox homeostasis. Identification of MDM2 target genes at the whole-genome level highlights an important role for ATF3/4 transcription factors in tethering MDM2 to chromatin. MDM2 recruitment to chromatin is a tightly regulated process that occurs during oxidative stress and serine/glycine deprivation and is modulated by the pyruvate kinase M2 (PKM2) metabolic enzyme. Depletion of endogenous MDM2 in p53-deficient cells impairs serine/glycine metabolism, the NAD(+)/NADH ratio, and glutathione (GSH) recycling, impacting their redox state and tumorigenic potential. Collectively, our data illustrate a previously unsuspected function of chromatin-bound MDM2 in cancer cell metabolism. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Free fatty acid receptors and their role in regulation of energy metabolism.

    Science.gov (United States)

    Hara, Takafumi; Kimura, Ikuo; Inoue, Daisuke; Ichimura, Atsuhiko; Hirasawa, Akira

    2013-01-01

    The free fatty acid receptor (FFAR) is a G protein-coupled receptor (GPCR) activated by free fatty acids (FFAs), which play important roles not only as essential nutritional components but also as signaling molecules in numerous physiological processes. In the last decade, FFARs have been identified by the GPCR deorphanization strategy derived from the human genome database. To date, several FFARs have been identified and characterized as critical components in various physiological processes. FFARs are categorized according to the chain length of FFA ligands that activate each FFAR; FFA2 and FFA3 are activated by short chain FFAs, GPR84 is activated by medium-chain FFAs, whereas FFA1 and GPR120 are activated by medium- or long-chain FFAs. FFARs appear to act as physiological sensors for food-derived FFAs and digestion products in the gastrointestinal tract. Moreover, they are considered to be involved in the regulation of energy metabolism mediated by the secretion of insulin and incretin hormones and by the regulation of the sympathetic nerve systems, taste preferences, and inflammatory responses related to insulin resistance. Therefore, because FFARs can be considered to play important roles in physiological processes and various pathophysiological processes, FFARs have been targeted in therapeutic strategies for the treatment of metabolic disorders including type 2 diabetes and metabolic syndrome. In this review, we present a summary of recent progress regarding the understanding of their physiological roles in the regulation of energy metabolism and their potential as therapeutic targets.

  11. Regulation of water resources for sustaining global future socioeconomic development

    Science.gov (United States)

    Chen, J.; SHI, H.; Sivakumar, B.

    2016-12-01

    With population projections indicating continued growth during this century, socio-economic problems (e.g., water, food, and energy shortages) will be most likely to occur, especially if proper planning, development, and management strategies are not adopted. In the present study, firstly, we explore the vital role of dams in promoting economic growth through analyzing the relationship between dams and Gross Domestic Product (GDP) at both global and national scales. Secondly, we analyze the current situation of global water scarcity based on the data representing water resources availability, dam development, and the level of economic development. Third, with comprehensive consideration of population growth as the major driving force, water resources availability as the basic supporting factor, and topography as the important constraint, this study addresses the question of dam development in the future and predicts the locations of future dams around the world.

  12. Life-stage-associated remodelling of lipid metabolism regulation in Atlantic salmon.

    Science.gov (United States)

    Gillard, Gareth; Harvey, Thomas N; Gjuvsland, Arne; Jin, Yang; Thomassen, Magny; Lien, Sigbjørn; Leaver, Michael; Torgersen, Jacob S; Hvidsten, Torgeir R; Vik, Jon Olav; Sandve, Simen R

    2018-03-01

    Atlantic salmon migrates from rivers to sea to feed, grow and develop gonads before returning to spawn in freshwater. The transition to marine habitats is associated with dramatic changes in the environment, including water salinity, exposure to pathogens and shift in dietary lipid availability. Many changes in physiology and metabolism occur across this life-stage transition, but little is known about the molecular nature of these changes. Here, we use a long-term feeding experiment to study transcriptional regulation of lipid metabolism in Atlantic salmon gut and liver in both fresh- and saltwater. We find that lipid metabolism becomes significantly less plastic to differences in dietary lipid composition when salmon transitions to saltwater and experiences increased dietary lipid availability. Expression of genes in liver relating to lipogenesis and lipid transport decreases overall and becomes less responsive to diet, while genes for lipid uptake in gut become more highly expressed. Finally, analyses of evolutionary consequences of the salmonid-specific whole-genome duplication on lipid metabolism reveal several pathways with significantly different (p < .05) duplicate retention or duplicate regulatory conservation. We also find a limited number of cases where the whole-genome duplication has resulted in an increased gene dosage. In conclusion, we find variable and pathway-specific effects of the salmonid genome duplication on lipid metabolism genes. A clear life-stage-associated shift in lipid metabolism regulation is evident, and we hypothesize this to be, at least partly, driven by nondietary factors such as the preparatory remodelling of gene regulation and physiology prior to sea migration. © 2018 John Wiley & Sons Ltd.

  13. Global regulation of robots using only position measurements

    NARCIS (Netherlands)

    Berghuis, Harry; Berghuis, Harry; Nijmeijer, Henk

    1993-01-01

    In this note we propose a simple solution to the regulation problem of rigid robots based on the availability of only joint position measurements. The controller consists of two parts: (1) a gravitation compensation, (2) a linear dynamic first-order compensator. The gravitation compensation part can

  14. Thermodynamic analysis of regulation in metabolic networks using constraint-based modeling

    Directory of Open Access Journals (Sweden)

    Mahadevan Radhakrishnan

    2010-05-01

    Full Text Available Abstract Background Geobacter sulfurreducens is a member of the Geobacter species, which are capable of oxidation of organic waste coupled to the reduction of heavy metals and electrode with applications in bioremediation and bioenergy generation. While the metabolism of this organism has been studied through the development of a stoichiometry based genome-scale metabolic model, the associated regulatory network has not yet been well studied. In this manuscript, we report on the implementation of a thermodynamics based metabolic flux model for Geobacter sulfurreducens. We use this updated model to identify reactions that are subject to regulatory control in the metabolic network of G. sulfurreducens using thermodynamic variability analysis. Findings As a first step, we have validated the regulatory sites and bottleneck reactions predicted by the thermodynamic flux analysis in E. coli by evaluating the expression ranges of the corresponding genes. We then identified ten reactions in the metabolic network of G. sulfurreducens that are predicted to be candidates for regulation. We then compared the free energy ranges for these reactions with the corresponding gene expression fold changes under conditions of different environmental and genetic perturbations and show that the model predictions of regulation are consistent with data. In addition, we also identify reactions that operate close to equilibrium and show that the experimentally determined exchange coefficient (a measure of reversibility is significant for these reactions. Conclusions Application of the thermodynamic constraints resulted in identification of potential bottleneck reactions not only from the central metabolism but also from the nucleotide and amino acid subsystems, thereby showing the highly coupled nature of the thermodynamic constraints. In addition, thermodynamic variability analysis serves as a valuable tool in estimating the ranges of ΔrG' of every reaction in the model

  15. Inflammation and ER Stress Regulate Branched-Chain Amino Acid Uptake and Metabolism in Adipocytes

    Science.gov (United States)

    Burrill, Joel S.; Long, Eric K.; Reilly, Brian; Deng, Yingfeng; Armitage, Ian M.; Scherer, Philipp E.

    2015-01-01

    Inflammation plays a critical role in the pathology of obesity-linked insulin resistance and is mechanistically linked to the effects of macrophage-derived cytokines on adipocyte energy metabolism, particularly that of the mitochondrial branched-chain amino acid (BCAA) and tricarboxylic acid (TCA) pathways. To address the role of inflammation on energy metabolism in adipocytes, we used high fat-fed C57BL/6J mice and lean controls and measured the down-regulation of genes linked to BCAA and TCA cycle metabolism selectively in visceral but not in subcutaneous adipose tissue, brown fat, liver, or muscle. Using 3T3-L1 cells, TNFα, and other proinflammatory cytokine treatments reduced the expression of the genes linked to BCAA transport and oxidation. Consistent with this, [14C]-leucine uptake and conversion to triglycerides was markedly attenuated in TNFα-treated adipocytes, whereas the conversion to protein was relatively unaffected. Because inflammatory cytokines lead to the induction of endoplasmic reticulum stress, we evaluated the effects of tunicamycin or thapsigargin treatment of 3T3-L1 cells and measured a similar down-regulation in the BCAA/TCA cycle pathway. Moreover, transgenic mice overexpressing X-box binding protein 1 in adipocytes similarly down-regulated genes of BCAA and TCA metabolism in vivo. These results indicate that inflammation and endoplasmic reticulum stress attenuate lipogenesis in visceral adipose depots by down-regulating the BCAA/TCA metabolism pathway and are consistent with a model whereby the accumulation of serum BCAA in the obese insulin-resistant state is linked to adipose inflammation. PMID:25635940

  16. The disturbances of lipid metabolism regulation after the prenatal low-level irradiation

    International Nuclear Information System (INIS)

    Rogov, Yu.I.; Danil'chik, V.S.; Spivak, L.V.; Rubchenya, I.N.

    2000-01-01

    The objective of this study was to assess the influence of low-level irradiation on lipid metabolism in rats after prenatal exposure. Pregnant rats were irradiated during the period of gestation with the whole final dose 0,5 Gy/rat. The blood lipid fractions were investigated in newborn rats and in 6-month age rats. In irradiated offspring the lipo synthesis processes exceeded lipolysis in comparison with that of the control. The negative consequences of embryo low-level irradiation in the lipid metabolism regulation are discussed in this report. (authors)

  17. Effect of antibiotics on gut microbiota, glucose metabolism and bodyweight regulation

    DEFF Research Database (Denmark)

    Mikkelsen, Kristian Hallundbaek; Allin, Kristine Højgaard; Knop, Filip Krag

    2016-01-01

    Gut bacteria are involved in a number of host metabolic processes and have been implicated in the development of obesity and type 2 diabetes in humans. Use of antibiotics changes the composition of the gut microbiota and there is accumulating evidence from observational studies for an association...... between exposure to antibiotics and development of obesity and type 2 diabetes. Here we review human studies examining effects of antibiotics on bodyweight regulation and glucose metabolism and discuss whether the observed findings may relate to alterations in the composition and function of the gut...

  18. Connexin 43-Mediated Astroglial Metabolic Networks Contribute to the Regulation of the Sleep-Wake Cycle.

    Science.gov (United States)

    Clasadonte, Jerome; Scemes, Eliana; Wang, Zhongya; Boison, Detlev; Haydon, Philip G

    2017-09-13

    Astrocytes produce and supply metabolic substrates to neurons through gap junction-mediated astroglial networks. However, the role of astroglial metabolic networks in behavior is unclear. Here, we demonstrate that perturbation of astroglial networks impairs the sleep-wake cycle. Using a conditional Cre-Lox system in mice, we show that knockout of the gap junction subunit connexin 43 in astrocytes throughout the brain causes excessive sleepiness and fragmented wakefulness during the nocturnal active phase. This astrocyte-specific genetic manipulation silenced the wake-promoting orexin neurons located in the lateral hypothalamic area (LHA) by impairing glucose and lactate trafficking through astrocytic networks. This global wakefulness instability was mimicked with viral delivery of Cre recombinase to astrocytes in the LHA and rescued by in vivo injections of lactate. Our findings propose a novel regulatory mechanism critical for maintaining normal daily cycle of wakefulness and involving astrocyte-neuron metabolic interactions. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. A Transcript-Specific eIF3 Complex Mediates Global Translational Control of Energy Metabolism.

    Science.gov (United States)

    Shah, Meera; Su, Dan; Scheliga, Judith S; Pluskal, Tomáš; Boronat, Susanna; Motamedchaboki, Khatereh; Campos, Alexandre Rosa; Qi, Feng; Hidalgo, Elena; Yanagida, Mitsuhiro; Wolf, Dieter A

    2016-08-16

    The multi-subunit eukaryotic translation initiation factor eIF3 is thought to assist in the recruitment of ribosomes to mRNA. The expression of eIF3 subunits is frequently disrupted in human cancers, but the specific roles of individual subunits in mRNA translation and cancer remain elusive. Using global transcriptomic, proteomic, and metabolomic profiling, we found a striking failure of Schizosaccharomyces pombe cells lacking eIF3e and eIF3d to synthesize components of the mitochondrial electron transport chain, leading to a defect in respiration, endogenous oxidative stress, and premature aging. Energy balance was maintained, however, by a switch to glycolysis with increased glucose uptake, upregulation of glycolytic enzymes, and strict dependence on a fermentable carbon source. This metabolic regulatory function appears to be conserved in human cells where eIF3e binds metabolic mRNAs and promotes their translation. Thus, via its eIF3d-eIF3e module, eIF3 orchestrates an mRNA-specific translational mechanism controlling energy metabolism that may be disrupted in cancer. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. A Transcript-Specific eIF3 Complex Mediates Global Translational Control of Energy Metabolism

    Directory of Open Access Journals (Sweden)

    Meera Shah

    2016-08-01

    Full Text Available The multi-subunit eukaryotic translation initiation factor eIF3 is thought to assist in the recruitment of ribosomes to mRNA. The expression of eIF3 subunits is frequently disrupted in human cancers, but the specific roles of individual subunits in mRNA translation and cancer remain elusive. Using global transcriptomic, proteomic, and metabolomic profiling, we found a striking failure of Schizosaccharomyces pombe cells lacking eIF3e and eIF3d to synthesize components of the mitochondrial electron transport chain, leading to a defect in respiration, endogenous oxidative stress, and premature aging. Energy balance was maintained, however, by a switch to glycolysis with increased glucose uptake, upregulation of glycolytic enzymes, and strict dependence on a fermentable carbon source. This metabolic regulatory function appears to be conserved in human cells where eIF3e binds metabolic mRNAs and promotes their translation. Thus, via its eIF3d-eIF3e module, eIF3 orchestrates an mRNA-specific translational mechanism controlling energy metabolism that may be disrupted in cancer.

  1. Regulation of glucose metabolism in T cells; new insight into the role of Phosphoinositide 3-kinases

    Directory of Open Access Journals (Sweden)

    David K Finlay

    2012-08-01

    Full Text Available Naïve T cells are relatively quiescent cells that only require energy to prevent atrophy and for survival and migration. However, in response to developmental or extrinsic cues T cells can engage in rapid growth and robust proliferation, produce of a range of effector molecules and migrate through peripheral tissues. To meet the significantly increased metabolic demands of these activities, T cells switch from primarily metabolizing glucose to carbon dioxide through oxidative phosphorylation to utilizing glycolysis to convert glucose to lactate (termed aerobic glycolysis. This metabolic switch allows glucose to be used as a source of carbon to generate biosynthetic precursors for the production of protein, DNA and phospholipids, and is crucial for T cells to meet metabolic demands. Phosphoinositide 3-kinases (PI3K are a family of inositol lipid kinases linked with a broad range of cellular functions in T lymphocytes that include cell growth, proliferation, metabolism, differentiation, survival and migration. Initial research described a critical role for PI3K signaling through Akt (also called Protein kinase B for the increased glucose uptake and glycolysis that accompanies T cell activation. This review article relates this original research with more recent data and discusses the evidence for and against a role for PI3K in regulating the metabolic switch to aerobic glycolysis in T cells.

  2. Impact of training state on fasting-induced regulation of adipose tissue metabolism in humans

    DEFF Research Database (Denmark)

    Bertholdt, Lærke; Gudiksen, Anders; Stankiewicz, Tomasz

    2018-01-01

    Recruitment of fatty acids from adipose tissue is essential during fasting. However, the molecular mechanisms behind fasting-induced metabolic regulation in human adipose tissue and the potential impact of training state in this are unknown. Therefore, the aim of the present study was to investig......Recruitment of fatty acids from adipose tissue is essential during fasting. However, the molecular mechanisms behind fasting-induced metabolic regulation in human adipose tissue and the potential impact of training state in this are unknown. Therefore, the aim of the present study...... was to investigate 1) fasting-induced regulation of lipolysis and glyceroneogenesis in human adipose tissue as well as 2) the impact of training state on basal oxidative capacity and fasting-induced metabolic regulation in human adipose tissue. Untrained (VO2max 55ml......RNA content were higher in trained subjects than untrained subjects. In addition, trained subjects had higher adipose tissue hormone sensitive lipase Ser660 phosphorylation and adipose triglyceride lipase protein content as well as higher plasma free fatty acids concentration than untrained subjects during...

  3. SEEDSTICK is a master regulator of development and metabolism in the Arabidopsis seed coat.

    Directory of Open Access Journals (Sweden)

    Chiara Mizzotti

    2014-12-01

    Full Text Available The role of secondary metabolites in the determination of cell identity has been an area of particular interest over recent years, and studies strongly indicate a connection between cell fate and the regulation of enzymes involved in secondary metabolism. In Arabidopsis thaliana, the maternally derived seed coat plays pivotal roles in both the protection of the developing embryo and the first steps of germination. In this regard, a characteristic feature of seed coat development is the accumulation of proanthocyanidins (PAs - a class of phenylpropanoid metabolites in the innermost layer of the seed coat. Our genome-wide transcriptomic analysis suggests that the ovule identity factor SEEDSTICK (STK is involved in the regulation of several metabolic processes, providing a strong basis for a connection between cell fate determination, development and metabolism. Using phenotypic, genetic, biochemical and transcriptomic approaches, we have focused specifically on the role of STK in PA biosynthesis. Our results indicate that STK exerts its effect by direct regulation of the gene encoding BANYULS/ANTHOCYANIDIN REDUCTASE (BAN/ANR, which converts anthocyanidins into their corresponding 2,3-cis-flavan-3-ols. Our study also demonstrates that the levels of H3K9ac chromatin modification directly correlate with the active state of BAN in an STK-dependent way. This is consistent with the idea that MADS-domain proteins control the expression of their target genes through the modification of chromatin states. STK might thus recruit or regulate histone modifying factors to control their activity. In addition, we show that STK is able to regulate other BAN regulators. Our study demonstrates for the first time how a floral homeotic gene controls tissue identity through the regulation of a wide range of processes including the accumulation of secondary metabolites.

  4. Forkhead, a new cross regulator of metabolism and innate immunity downstream of TOR in Drosophila.

    Science.gov (United States)

    Varma, Disha; Bülow, Margret H; Pesch, Yanina-Yasmin; Loch, Gerrit; Hoch, Michael

    2014-10-01

    Antimicrobial peptides (AMPs) are conserved cationic peptides which act both as defense molecules of the host immune system and as regulators of the commensal microbiome. Expression of AMPs is induced in response to infection by the Toll and Imd pathway. Under non-infected conditions, the transcription factor dFOXO directly regulates a set of AMP expression at low levels when nutrients are limited. Here we have analyzed whether target of rapamycin (TOR), another major regulator of growth and metabolism, also modulates AMP responses in Drosophila. We found that downregulation of TOR by feeding the drug rapamycin or by overexpressing the negative TOR regulators TSC1/TSC2, resulted in a specific induction of the AMPs Diptericin (Dpt) and Metchnikowin (Mtk). In contrast, overexpression of Rheb, which positively regulates TOR led to a repression of the two AMPs. Genetic and pharmacological experiments indicate that Dpt and Mtk activation is controlled by the transcription factor Forkhead (FKH), the founding member of the FoxO family. Shuttling of FKH from the cytoplasm to the nucleus is induced in the fat body and in the posterior midgut in response to TOR downregulation. The FKH-dependent induction of Dpt and Mtk can be triggered in dFOXO null mutants and in immune-compromised Toll and IMD pathway mutants indicating that FKH acts in parallel to these regulators. Together, we have discovered that FKH is the second conserved member of the FoxO family cross-regulating metabolism and innate immunity. dFOXO and FKH, which are activated upon downregulation of insulin or TOR activities, respectively, act in parallel to induce different sets of AMPs, thereby modulating the immune status of metabolic tissues such as the fat body or the gut in response to the oscillating energy status of the organism. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Mitochondrial metabolism of pyruvate is essential for regulating glucose-stimulated insulin secretion.

    Science.gov (United States)

    Patterson, Jessica N; Cousteils, Katelyn; Lou, Jennifer W; Manning Fox, Jocelyn E; MacDonald, Patrick E; Joseph, Jamie W

    2014-05-09

    It is well known that mitochondrial metabolism of pyruvate is critical for insulin secretion; however, we know little about how pyruvate is transported into mitochondria in β-cells. Part of the reason for this lack of knowledge is that the carrier gene was only discovered in 2012. In the current study, we assess the role of the recently identified carrier in the regulation of insulin secretion. Our studies show that β-cells express both mitochondrial pyruvate carriers (Mpc1 and Mpc2). Using both pharmacological inhibitors and siRNA-mediated knockdown of the MPCs we show that this carrier plays a key role in regulating insulin secretion in clonal 832/13 β-cells as well as rat and human islets. We also show that the MPC is an essential regulator of both the ATP-regulated potassium (KATP) channel-dependent and -independent pathways of insulin secretion. Inhibition of the MPC blocks the glucose-stimulated increase in two key signaling molecules involved in regulating insulin secretion, the ATP/ADP ratio and NADPH/NADP(+) ratio. The MPC also plays a role in in vivo glucose homeostasis as inhibition of MPC by the pharmacological inhibitor α-cyano-β-(1-phenylindol-3-yl)-acrylate (UK5099) resulted in impaired glucose tolerance. These studies clearly show that the newly identified mitochondrial pyruvate carrier sits at an important branching point in nutrient metabolism and that it is an essential regulator of insulin secretion.

  6. Conserved regulators of nucleolar size revealed by global phenotypic analyses.

    Science.gov (United States)

    Neumüller, Ralph A; Gross, Thomas; Samsonova, Anastasia A; Vinayagam, Arunachalam; Buckner, Michael; Founk, Karen; Hu, Yanhui; Sharifpoor, Sara; Rosebrock, Adam P; Andrews, Brenda; Winston, Fred; Perrimon, Norbert

    2013-08-20

    Regulation of cell growth is a fundamental process in development and disease that integrates a vast array of extra- and intracellular information. A central player in this process is RNA polymerase I (Pol I), which transcribes ribosomal RNA (rRNA) genes in the nucleolus. Rapidly growing cancer cells are characterized by increased Pol I-mediated transcription and, consequently, nucleolar hypertrophy. To map the genetic network underlying the regulation of nucleolar size and of Pol I-mediated transcription, we performed comparative, genome-wide loss-of-function analyses of nucleolar size in Saccharomyces cerevisiae and Drosophila melanogaster coupled with mass spectrometry-based analyses of the ribosomal DNA (rDNA) promoter. With this approach, we identified a set of conserved and nonconserved molecular complexes that control nucleolar size. Furthermore, we characterized a direct role of the histone information regulator (HIR) complex in repressing rRNA transcription in yeast. Our study provides a full-genome, cross-species analysis of a nuclear subcompartment and shows that this approach can identify conserved molecular modules.

  7. Conserved Regulators of Nucleolar Size Revealed by Global Phenotypic Analyses

    Science.gov (United States)

    Neumüller, Ralph A.; Gross, Thomas; Samsonova, Anastasia A.; Vinayagam, Arunachalam; Buckner, Michael; Founk, Karen; Hu, Yanhui; Sharifpoor, Sara; Rosebrock, Adam P.; Andrews, Brenda; Winston, Fred; Perrimon, Norbert

    2014-01-01

    Regulation of cell growth is a fundamental process in development and disease that integrates a vast array of extra- and intracellular information. A central player in this process is RNA polymerase I (Pol I), which transcribes ribosomal RNA (rRNA) genes in the nucleolus. Rapidly growing cancer cells are characterized by increased Pol I–mediated transcription and, consequently, nucleolar hypertrophy. To map the genetic network underlying the regulation of nucleolar size and of Pol I–mediated transcription, we performed comparative, genome-wide loss-of-function analyses of nucleolar size in Saccharomyces cerevisiae and Drosophila melanogaster coupled with mass spectrometry–based analyses of the ribosomal DNA (rDNA) promoter. With this approach, we identified a set of conserved and nonconserved molecular complexes that control nucleolar size. Furthermore, we characterized a direct role of the histone information regulator (HIR) complex in repressing rRNA transcription in yeast. Our study provides a full-genome, cross-species analysis of a nuclear subcompartment and shows that this approach can identify conserved molecular modules. PMID:23962978

  8. Regulators of nonsulfur purple phototrophic bacteria and the interactive control of CO2 assimilation, nitrogen fixation, hydrogen metabolism and energy generation.

    Science.gov (United States)

    Dubbs, James M; Tabita, F Robert

    2004-06-01

    For the metabolically diverse nonsulfur purple phototrophic bacteria, maintaining redox homeostasis requires balancing the activities of energy supplying and energy-utilizing pathways, often in the face of drastic changes in environmental conditions. These organisms, members of the class Alphaproteobacteria, primarily use CO2 as an electron sink to achieve redox homeostasis. After noting the consequences of inactivating the capacity for CO2 reduction through the Calvin-Benson-Bassham (CBB) pathway, it was shown that the molecular control of many additional important biological processes catalyzed by nonsulfur purple bacteria is linked to expression of the CBB genes. Several regulator proteins are involved, with the two component Reg/Prr regulatory system playing a major role in maintaining redox poise in these organisms. Reg/Prr was shown to be a global regulator involved in the coordinate control of a number of metabolic processes including CO2 assimilation, nitrogen fixation, hydrogen metabolism and energy-generation pathways. Accumulating evidence suggests that the Reg/Prr system senses the oxidation/reduction state of the cell by monitoring a signal associated with electron transport. The response regulator RegA/PrrA activates or represses gene expression through direct interaction with target gene promoters where it often works in concert with other regulators that can be either global or specific. For the key CO2 reduction pathway, which clearly triggers whether other redox balancing mechanisms are employed, the ability to activate or inactivate the specific regulator CbbR is of paramount importance. From these studies, it is apparent that a detailed understanding of how diverse regulatory elements integrate and control metabolism will eventually be achieved.

  9. Internet governance and global self regulation: theoretical and empirical building blocks for a general theory of self regulation

    NARCIS (Netherlands)

    Vey Mestdagh, C.; Rijgersberg, R.

    2010-01-01

    The following exposition sets out to identify the basic theoretical and empirical building blocks for a general theory of self-regulation. It uses the Internet as an empirical basis since its global reach and technical characteristics create interdependencies between actors that transcend national

  10. Dietary exposure to the endocrine disruptor tolylfluanid promotes global metabolic dysfunction in male mice.

    Science.gov (United States)

    Regnier, Shane M; Kirkley, Andrew G; Ye, Honggang; El-Hashani, Essam; Zhang, Xiaojie; Neel, Brian A; Kamau, Wakanene; Thomas, Celeste C; Williams, Ayanna K; Hayes, Emily T; Massad, Nicole L; Johnson, Daniel N; Huang, Lei; Zhang, Chunling; Sargis, Robert M

    2015-03-01

    Environmental endocrine disruptors are implicated as putative contributors to the burgeoning metabolic disease epidemic. Tolylfluanid (TF) is a commonly detected fungicide in Europe, and previous in vitro and ex vivo work has identified it as a potent endocrine disruptor with the capacity to promote adipocyte differentiation and induce adipocytic insulin resistance, effects likely resulting from activation of glucocorticoid receptor signaling. The present study extends these findings to an in vivo mouse model of dietary TF exposure. After 12 weeks of consumption of a normal chow diet supplemented with 100 parts per million TF, mice exhibited increased body weight gain and an increase in total fat mass, with a specific augmentation in visceral adipose depots. This increased adipose accumulation is proposed to occur through a reduction in lipolytic and fatty acid oxidation gene expression. Dietary TF exposure induced glucose intolerance, insulin resistance, and metabolic inflexibility, while also disrupting diurnal rhythms of energy expenditure and food consumption. Adipose tissue endocrine function was also impaired with a reduction in serum adiponectin levels. Moreover, adipocytes from TF-exposed mice exhibited reduced insulin sensitivity, an effect likely mediated through a specific down-regulation of insulin receptor substrate-1 expression, mirroring effects of ex vivo TF exposure. Finally, gene set enrichment analysis revealed an increase in adipose glucocorticoid receptor signaling with TF treatment. Taken together, these findings identify TF as a novel in vivo endocrine disruptor and obesogen in mice, with dietary exposure leading to alterations in energy homeostasis that recapitulate many features of the metabolic syndrome.

  11. Calcium Regulation and Bone Mineral Metabolism in Elderly Patients with Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Vickram Tejwani

    2013-05-01

    Full Text Available The elderly chronic kidney disease (CKD population is growing. Both aging and CKD can disrupt calcium (Ca2+ homeostasis and cause alterations of multiple Ca2+-regulatory mechanisms, including parathyroid hormone, vitamin D, fibroblast growth factor-23/Klotho, calcium-sensing receptor and Ca2+-phosphate product. These alterations can be deleterious to bone mineral metabolism and soft tissue health, leading to metabolic bone disease and vascular calcification and aging, termed CKD-mineral and bone disorder (MBD. CKD-MBD is associated with morbid clinical outcomes, including fracture, cardiovascular events and all-cause mortality. In this paper, we comprehensively review Ca2+ regulation and bone mineral metabolism, with a special emphasis on elderly CKD patients. We also present the current treatment-guidelines and management options for CKD-MBD.

  12. Regulation of metabolic products and gene expression in Fusarium asiaticum by agmatine addition.

    Science.gov (United States)

    Suzuki, Tadahiro; Kim, Young-Kyung; Yoshioka, Hifumi; Iwahashi, Yumiko

    2013-05-01

    The metabolic products resulting from the cultivation of F. asiaticum in agmatine were identified using capillary electrophoresis-time of flight mass spectrometry. Glyoxylic acid was detected from fungal cultures grown in agmatine, while it was absent in control cells. The abundance of other metabolic products of the glycolytic pathway also increased because of agmatine; however, there was no increase in the amounts of pyruvic acid or metabolites from the tricarboxylic acid cycle. Moreover, gene expression levels within Fusarium asiaticum exposed to agmatine were analyzed by DNA microarray. Changes in gene expression levels directed the changes in metabolic products. Our results suggest that acetyl coenzyme A, which is a starting substrate for the biosynthesis of deoxynivalenol (DON), was simultaneously produced by activated β-oxidation. Furthermore, the content of 4-aminobutyrate (GABA) was increased in the agmatine addition culture medium. GABA can be synthesized from agmatine through putrescine and might influence the regulation of DON-related genes.

  13. Heat stress induced changes in metabolic regulators of donkeys from arid tracts in India

    Directory of Open Access Journals (Sweden)

    Kataria N.

    2012-05-01

    Full Text Available To find out heat stress induced changes in metabolic regulators of donkeys from arid tracts in India, blood samples were collected to harvest the serum during moderate and extreme hot ambiences. The metabolic enzymes determined were sorbitol dehydrogenase, malate dehydrogenase, glucose-6-phosphate dehydrogenase, glutamate dehydrogenase, ornithine carbamoyl transferase, gammaglutamayl transferase, 5’nucleotidase, glucose-6-phosphatase, arginase, and aldolase. The mean values of all the serum enzymes increased significantly (p≤0.05 during hot ambience as compared to respective values during moderate ambience. It was concluded that increased activity of all the enzymes in the serum was due to modulation of metabolic reactions to combat the effect of hot ambience on the animals. Activation of gluconeogenesis along with hexose monophosphate shunt and urea cycle probably helped the animals to combat the heat stress.

  14. SirT1 regulates energy metabolism and response to caloric restriction in mice.

    Directory of Open Access Journals (Sweden)

    Gino Boily

    Full Text Available The yeast sir2 gene and its orthologues in Drosophila and C. elegans have well-established roles in lifespan determination and response to caloric restriction. We have studied mice carrying two null alleles for SirT1, the mammalian orthologue of sir2, and found that these animals inefficiently utilize ingested food. These mice are hypermetabolic, contain inefficient liver mitochondria, and have elevated rates of lipid oxidation. When challenged with a 40% reduction in caloric intake, normal mice maintained their metabolic rate and increased their physical activity while the metabolic rate of SirT1-null mice dropped and their activity did not increase. Moreover, CR did not extend lifespan of SirT1-null mice. Thus, SirT1 is an important regulator of energy metabolism and, like its orthologues from simpler eukaryotes, the SirT1 protein appears to be required for a normal response to caloric restriction.

  15. Local flow regulation and irrigation raise global human water consumption and footprint.

    Science.gov (United States)

    Jaramillo, Fernando; Destouni, Georgia

    2015-12-04

    Flow regulation and irrigation alter local freshwater conditions, but their global effects are highly uncertain. We investigated these global effects from 1901 to 2008, using hydroclimatic observations in 100 large hydrological basins. Globally, we find consistent and dominant effects of increasing relative evapotranspiration from both activities, and decreasing temporal runoff variability from flow regulation. The evapotranspiration effect increases the long-term average human consumption of fresh water by 3563 ± 979 km(3)/year from 1901-1954 to 1955-2008. This increase raises a recent estimate of the current global water footprint of humanity by around 18%, to 10,688 ± 979 km(3)/year. The results highlight the global impact of local water-use activities and call for their relevant account in Earth system modeling. Copyright © 2015, American Association for the Advancement of Science.

  16. New opportunities for the regulation of secondary metabolism in plants: focus on microRNAs.

    Science.gov (United States)

    Bulgakov, Victor P; Avramenko, Tatiana V

    2015-09-01

    Plant cell cultures are of particular interest in industrial applications as a source of biologically active substances. It is difficult, however, to achieve stable production of secondary metabolites for many plant cell cultures using classical techniques. Novel approaches should be developed for removal of the inhibitor blocks that prevent pathway activation and shift the regulatory balance to the activation of entire biosynthetic pathways. MicroRNAs (miRNAs) are small RNAs that play important regulatory roles in various biological processes. Only recently miRNAs have been demonstrated as active in secondary metabolism regulation. In this work, we summarize recent data on the emerging approaches based on regulation of secondary metabolism by miRNAs.

  17. Role of glycolytic intermediate in regulation: Improving lycopene production in Escherichia coli by engineering metabolic control

    Energy Technology Data Exchange (ETDEWEB)

    Farmer, W.R.; Liao, J.C.

    2001-06-01

    Metabolic engineering in the postgenomic era is expected to benefit from a full understanding of the biosynthetic capability of microorganisms as a result of the progress being made in bioinformatics and functional genomics. The immediate advantage of such information is to allow the rational design of novel pathways and the elimination of native reactions that are detrimental or unnecessary for the desired purpose. However, with the ability to manipulate metabolic pathways becoming more effective, metabolic engineering will need to face a new challenge: the reengineering of the regulatory hierarchy that controls gene expression in those pathways. In addition to constructing the genetic composition of a metabolic pathway, they propose that it will become just as important to consider the dynamics of pathways gene expression. It has been widely observed that high-level induction of a recombinant protein or pathway leads to growth retardation and reduced metabolic activity. These phenotypic characteristics result from the fact that the constant demands of production placed upon the cell interfere with its changing requirements for growth. They believe that this common situation in metabolic engineering can be alleviated by designing a dynamic controller that is able to sense the metabolic state of the cell and regulate the expression of the recombinant pathway accordingly. This approach, which is termed metabolic control engineering, involves redesigning the native regulatory circuits and applying them to the recombinant pathway. The general goal of such an effort will be to control the flux to the recombinant pathway adaptively according to the cell's metabolic state. The dynamically controlled recombinant pathway can potentially lead to enhanced production, minimized growth retardation, and reduced toxic by-product formation. The regulation of gene expression in response to the physiological state is also essential to the success of gene therapy. Here they

  18. Regulation of abscisic acid metabolism in relation to the dormancy and germination of cereal grains

    Directory of Open Access Journals (Sweden)

    Justyna Fidler

    2015-03-01

    Full Text Available Seed dormancy is of particular importance in the cultivation of cereals, as it directly affects the quality of crop yield. If the dormancy period is too short, this may lead to pre-harvest sprouting, whereas a dormancy period that is too long may cause uneven germination; both of these scenarios are associated with economic losses. Most enzymes engaged in the metabolism of abscisic acid (ABA have been identified, and significant progress has been made in understanding the role of this phytohormone in the induction and maintenance of dormancy, mainly as a result of research conducted in Arabidopsis. Much less is known about the metabolism and function of ABA in cereal grains, especially in relation to dormancy and germination. This review focuses on the regulation of ABA metabolism in dormant and non-dormant cereal grains, in both the dry state and upon imbibition. Moreover, this review describes the influence of factors such as after-ripening, light, temperature, nitric oxide, and reactive oxygen species (ROS on the dormancy and germination of cereal grains. These factors, with the exception of ROS, appear to affect the level of dormancy and germination of grains through regulation of ABA metabolism.

  19. Dendrobium nobile Lindl. alkaloids regulate metabolism gene expression in livers of mice.

    Science.gov (United States)

    Xu, Yun-Yan; Xu, Ya-Sha; Wang, Yuan; Wu, Qin; Lu, Yuan-Fu; Liu, Jie; Shi, Jing-Shan

    2017-10-01

    In our previous studies, Dendrobium nobile Lindl. alkaloids (DNLA) has been shown to have glucose-lowering and antihyperlipidaemia effects in diabetic rats, in rats fed with high-fat diets, and in mice challenged with adrenaline. This study aimed to examine the effects of DNLA on the expression of glucose and lipid metabolism genes in livers of mice. Mice were given DNLA at doses of 10-80 mg/kg, po for 8 days, and livers were removed for total RNA and protein isolation to perform real-time RT-PCR and Western blot analysis. Dendrobium nobile Lindl. alkaloids increased PGC1α at mRNA and protein levels and increased glucose metabolism gene Glut2 and FoxO1 expression. DNLA also increased the expression of fatty acid β-oxidation genes Acox1 and Cpt1a. The lipid synthesis regulator Srebp1 (sterol regulatory element-binding protein-1) was decreased, while the lipolysis gene ATGL was increased. Interestingly, DNLA increased the expression of antioxidant gene metallothionein-1 and NADPH quinone oxidoreductase-1 (Nqo1) in livers of mice. Western blot on selected proteins confirmed these changes including the increased expression of GLUT4 and PPARα. DNLA has beneficial effects on liver glucose and lipid metabolism gene expressions, and enhances the Nrf2-antioxidant pathway gene expressions, which could play integrated roles in regulating metabolic disorders. © 2017 Royal Pharmaceutical Society.

  20. Impact of global transcriptional regulation by ArcA, ArcB, Cra, Crp, Cya, Fnr, and Mlc on glucose catabolism in Escherichia coli.

    Science.gov (United States)

    Perrenoud, Annik; Sauer, Uwe

    2005-05-01

    Even though transcriptional regulation plays a key role in establishing the metabolic network, the extent to which it actually controls the in vivo distribution of metabolic fluxes through different pathways is essentially unknown. Based on metabolism-wide quantification of intracellular fluxes, we systematically elucidated the relevance of global transcriptional regulation by ArcA, ArcB, Cra, Crp, Cya, Fnr, and Mlc for aerobic glucose catabolism in batch cultures of Escherichia coli. Knockouts of ArcB, Cra, Fnr, and Mlc were phenotypically silent, while deletion of the catabolite repression regulators Crp and Cya resulted in a pronounced slow-growth phenotype but had only a nonspecific effect on the actual flux distribution. Knockout of ArcA-dependent redox regulation, however, increased the aerobic tricarboxylic acid (TCA) cycle activity by over 60%. Like aerobic conditions, anaerobic derepression of TCA cycle enzymes in an ArcA mutant significantly increased the in vivo TCA flux when nitrate was present as an electron acceptor. The in vivo and in vitro data demonstrate that ArcA-dependent transcriptional regulation directly or indirectly controls TCA cycle flux in both aerobic and anaerobic glucose batch cultures of E. coli. This control goes well beyond the previously known ArcA-dependent regulation of the TCA cycle during microaerobiosis.

  1. Metabolic profiling of a mapping population exposes new insights in the regulation of seed metabolism and seed, fruit, and plant relations.

    Directory of Open Access Journals (Sweden)

    David Toubiana

    Full Text Available To investigate the regulation of seed metabolism and to estimate the degree of metabolic natural variability, metabolite profiling and network analysis were applied to a collection of 76 different homozygous tomato introgression lines (ILs grown in the field in two consecutive harvest seasons. Factorial ANOVA confirmed the presence of 30 metabolite quantitative trait loci (mQTL. Amino acid contents displayed a high degree of variability across the population, with similar patterns across the two seasons, while sugars exhibited significant seasonal fluctuations. Upon integration of data for tomato pericarp metabolite profiling, factorial ANOVA identified the main factor for metabolic polymorphism to be the genotypic background rather than the environment or the tissue. Analysis of the coefficient of variance indicated greater phenotypic plasticity in the ILs than in the M82 tomato cultivar. Broad-sense estimate of heritability suggested that the mode of inheritance of metabolite traits in the seed differed from that in the fruit. Correlation-based metabolic network analysis comparing metabolite data for the seed with that for the pericarp showed that the seed network displayed tighter interdependence of metabolic processes than the fruit. Amino acids in the seed metabolic network were shown to play a central hub-like role in the topology of the network, maintaining high interactions with other metabolite categories, i.e., sugars and organic acids. Network analysis identified six exceptionally highly co-regulated amino acids, Gly, Ser, Thr, Ile, Val, and Pro. The strong interdependence of this group was confirmed by the mQTL mapping. Taken together these results (i reflect the extensive redundancy of the regulation underlying seed metabolism, (ii demonstrate the tight co-ordination of seed metabolism with respect to fruit metabolism, and (iii emphasize the centrality of the amino acid module in the seed metabolic network. Finally, the study

  2. Role of vitamin D3 active metabolites in the regulation of calcium metabolism in hypokinetic rats

    International Nuclear Information System (INIS)

    Sergeev, I.N.; Afonin, B.V.; Blazhevich, N.V.

    1985-01-01

    The rats exposed to prolonged hypokinesia showed hypocalciemia, lower PTH and higher calcitonin concentrations in the serum, decreased calcium absorption in the small intestine, and a trend toward nephro- and arteriocalcinosis. Prophylactic administration of 24, 25-hydroxy D 3 , 1, 25-hydroxy D 3 and their combinations enhanced calcium absorption and alleviated hypocalciemia. The changes in the hormonal regulation of calcium homeostasis can be viewed as a factor responsible for calcium metabolic disorders associated with hypokinesia

  3. JAZF1 can regulate the expression of lipid metabolic genes and inhibit lipid accumulation in adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Ming, Guang-feng [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China); Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China); Xiao, Di; Gong, Wei-jing [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China); Liu, Hui-xia; Liu, Jun [Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China); Zhou, Hong-hao [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China); Liu, Zhao-qian, E-mail: liuzhaoqian63@126.com [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China)

    2014-03-14

    Highlights: • JAZF1 was significantly upregulated during the differentiation of 3T3-L1 preadipocytes. • JAZF1 overexpression inhibited lipid accumulation in differentiated mature 3T3-L1 adipocytes. • JAZF1 overexpression inhibited the expression of SREBP1, ACC, and FAS. • JAZF1 overexpression upregulated the expression of HSL and ATGL. • SREBP1 and JAZF1 could regulate each other in adipocytes. - Abstract: JAZF1 is a newly identified gene with unknown functions. A recent genome-wide association study showed that JAZF1 is associated with type 2 diabetes and is highly expressed in liver and adipose tissue. Studies have demonstrated that JAZF1 is the co-repressor for nuclear orphan receptor TAK1, whereas most nuclear orphan receptor family members are involved in the regulation of lipid metabolism. Therefore, JAZF1 could be closely related to glycolipid metabolism. In this study, JAZF1 was significantly upregulated during the induced differentiation process of 3T3-L1 preadipocytes. The overexpression of JAZF1 inhibited lipid accumulation in differentiated mature 3T3-L1 adipocytes and significantly inhibited the expression of SREBPl, ACC, and FAS, which were important in lipid synthesis, while upregulating the expression of key enzyme hormone-sensitive lipase in lipoclasis. Moreover, SREBPl exhibited an inhibitory function on the expression of JAZF1. SREBP1 reversed the inhibitory action on lipid accumulation of JAZF1. SREBP1 and JAZF1 were observed to regulate each other in adipocytes. Therefore, JAZF1 could regulate the expression of particular genes related to lipid metabolism and inhibit lipid accumulation in adipocytes. This result suggests that JAZF1 may be a potential target for the treatment of diseases, such as obesity and lipid metabolism disorders.

  4. JAZF1 can regulate the expression of lipid metabolic genes and inhibit lipid accumulation in adipocytes

    International Nuclear Information System (INIS)

    Ming, Guang-feng; Xiao, Di; Gong, Wei-jing; Liu, Hui-xia; Liu, Jun; Zhou, Hong-hao; Liu, Zhao-qian

    2014-01-01

    Highlights: • JAZF1 was significantly upregulated during the differentiation of 3T3-L1 preadipocytes. • JAZF1 overexpression inhibited lipid accumulation in differentiated mature 3T3-L1 adipocytes. • JAZF1 overexpression inhibited the expression of SREBP1, ACC, and FAS. • JAZF1 overexpression upregulated the expression of HSL and ATGL. • SREBP1 and JAZF1 could regulate each other in adipocytes. - Abstract: JAZF1 is a newly identified gene with unknown functions. A recent genome-wide association study showed that JAZF1 is associated with type 2 diabetes and is highly expressed in liver and adipose tissue. Studies have demonstrated that JAZF1 is the co-repressor for nuclear orphan receptor TAK1, whereas most nuclear orphan receptor family members are involved in the regulation of lipid metabolism. Therefore, JAZF1 could be closely related to glycolipid metabolism. In this study, JAZF1 was significantly upregulated during the induced differentiation process of 3T3-L1 preadipocytes. The overexpression of JAZF1 inhibited lipid accumulation in differentiated mature 3T3-L1 adipocytes and significantly inhibited the expression of SREBPl, ACC, and FAS, which were important in lipid synthesis, while upregulating the expression of key enzyme hormone-sensitive lipase in lipoclasis. Moreover, SREBPl exhibited an inhibitory function on the expression of JAZF1. SREBP1 reversed the inhibitory action on lipid accumulation of JAZF1. SREBP1 and JAZF1 were observed to regulate each other in adipocytes. Therefore, JAZF1 could regulate the expression of particular genes related to lipid metabolism and inhibit lipid accumulation in adipocytes. This result suggests that JAZF1 may be a potential target for the treatment of diseases, such as obesity and lipid metabolism disorders

  5. Zebrafish as a Model System for Investigating the Compensatory Regulation of Ionic Balance during Metabolic Acidosis

    Directory of Open Access Journals (Sweden)

    Lletta Lewis

    2018-04-01

    Full Text Available Zebrafish (Danio rerio have become an important model for integrative physiological research. Zebrafish inhabit a hypo-osmotic environment; to maintain ionic and acid-base homeostasis, they must actively take up ions and secrete acid to the water. The gills in the adult and the skin at larval stage are the primary sites of ionic regulation in zebrafish. The uptake of ions in zebrafish is mediated by specific ion transporting cells termed ionocytes. Similarly, in mammals, ion reabsorption and acid excretion occur in specific cell types in the terminal region of the renal tubules (distal convoluted tubule and collecting duct. Previous studies have suggested that functional regulation of several ion transporters/channels in the zebrafish ionocytes resembles that in the mammalian renal cells. Additionally, several mechanisms involved in regulating the epithelial ion transport during metabolic acidosis are found to be similar between zebrafish and mammals. In this article, we systemically review the similarities and differences in ionic regulation between zebrafish and mammals during metabolic acidosis. We summarize the available information on the regulation of epithelial ion transporters during acidosis, with a focus on epithelial Na+, Cl− and Ca2+ transporters in zebrafish ionocytes and mammalian renal cells. We also discuss the neuroendocrine responses to acid exposure, and their potential role in ionic compensation. Finally, we identify several knowledge gaps that would benefit from further study.

  6. Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis

    Energy Technology Data Exchange (ETDEWEB)

    May, R.C.; Hara, Y.; Kelly, R.A.; Block, K.P.; Buse, M.G.; Mitch, W.E.

    1987-06-01

    Branched-chain amino acid (BCAA) metabolism is frequently abnormal in pathological conditions accompanied by chronic metabolic acidosis. To study how metabolic acidosis affects BCAA metabolism in muscle, rats were gavage fed a 14% protein diet with or without 4 mmol NH/sub 4/Cl x 100 g body wt/sup -1/ x day/sup -1/. Epitrochlearis muscles were incubated with L-(1-/sup 14/C)-valine and L-(1-/sup 14/C)leucine, and rates of decarboxylation, net transamination, and incorporation into muscle protein were measured. Plasma and muscle BCAA levels were lower in acidotic rats. Rates of valine and leucine decarboxylation and net transamination were higher in muscles from acidotic rats; these differences were associated with a 79% increase in the total activity of branched-chain ..cap alpha..-keto acid dehydrogenase and a 146% increase in the activated form of the enzyme. They conclude that acidosis affects the regulation of BCAA metabolism by enhancing flux through the transaminase and by directly stimulating oxidative catabolism through activation of branched-chain ..cap alpha..-keto acid dehydrogenase.

  7. Resistin Regulates Pituitary Lipid Metabolism and Inflammation In Vivo and In Vitro

    Directory of Open Access Journals (Sweden)

    F. Rodriguez-Pacheco

    2013-01-01

    Full Text Available The adipokine resistin is an insulin-antagonizing factor that also plays a regulatory role in inflammation, immunity, food intake, and gonadal function and also regulates growth hormone (GH secretion in rat adenopituitary cells cultures with the adipokine. Although adipose tissue is the primary source of resistin, it is also expressed in other tissues, including the pituitary. The aim of this study is to investigate the possible action of resistin on the lipid metabolism in the pituitary gland in vivo (rats in two different nutritional status, fed and fast, treated with resistin on acute and a chronic way and in vitro (adenopituitary cell cultures treated with the adipokine. Here, by a combination of in vivo and in vitro experimental models, we demonstrated that central acute and chronic administration of resistin enhance mRNA levels of the lipid metabolic enzymes which participated on lipolysis and moreover inhibiting mRNA levels of the lipid metabolic enzymes involved in lipogenesis. Taken together, our results demonstrate for the first time that resistin has a regulatory role on lipid metabolism in the pituitary gland providing a novel insight in relation to the mechanism by which this adipokine can participate in the integrated control of lipid metabolism.

  8. Calcium Co-regulates Oxidative Metabolism and ATP Synthase-dependent Respiration in Pancreatic Beta Cells

    Science.gov (United States)

    De Marchi, Umberto; Thevenet, Jonathan; Hermant, Aurelie; Dioum, Elhadji; Wiederkehr, Andreas

    2014-01-01

    Mitochondrial energy metabolism is essential for glucose-induced calcium signaling and, therefore, insulin granule exocytosis in pancreatic beta cells. Calcium signals are sensed by mitochondria acting in concert with mitochondrial substrates for the full activation of the organelle. Here we have studied glucose-induced calcium signaling and energy metabolism in INS-1E insulinoma cells and human islet beta cells. In insulin secreting cells a surprisingly large fraction of total respiration under resting conditions is ATP synthase-independent. We observe that ATP synthase-dependent respiration is markedly increased after glucose stimulation. Glucose also causes a very rapid elevation of oxidative metabolism as was followed by NAD(P)H autofluorescence. However, neither the rate of the glucose-induced increase nor the new steady-state NAD(P)H levels are significantly affected by calcium. Our findings challenge the current view, which has focused mainly on calcium-sensitive dehydrogenases as the target for the activation of mitochondrial energy metabolism. We propose a model of tight calcium-dependent regulation of oxidative metabolism and ATP synthase-dependent respiration in beta cell mitochondria. Coordinated activation of matrix dehydrogenases and respiratory chain activity by calcium allows the respiratory rate to change severalfold with only small or no alterations of the NAD(P)H/NAD(P)+ ratio. PMID:24554722

  9. Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle.

    Science.gov (United States)

    Chao, Lily C; Zhang, Zidong; Pei, Liming; Saito, Tsugumichi; Tontonoz, Peter; Pilch, Paul F

    2007-09-01

    Innervation is important for normal metabolism in skeletal muscle, including insulin-sensitive glucose uptake. However, the transcription factors that transduce signals from the neuromuscular junction to the nucleus and affect changes in metabolic gene expression are not well defined. We demonstrate here that the orphan nuclear receptor Nur77 is a regulator of gene expression linked to glucose utilization in muscle. In vivo, Nur77 is preferentially expressed in glycolytic compared with oxidative muscle and is responsive to beta-adrenergic stimulation. Denervation of rat muscle compromises expression of Nur77 in parallel with that of numerous genes linked to glucose metabolism, including glucose transporter 4 and genes involved in glycolysis, glycogenolysis, and the glycerophosphate shuttle. Ectopic expression of Nur77, either in rat muscle or in C2C12 muscle cells, induces expression of a highly overlapping set of genes, including glucose transporter 4, muscle phosphofructokinase, and glycogen phosphorylase. Furthermore, selective knockdown of Nur77 in rat muscle by small hairpin RNA or genetic deletion of Nur77 in mice reduces the expression of a battery of genes involved in skeletal muscle glucose utilization in vivo. Finally, we show that Nur77 binds the promoter regions of multiple genes involved in glucose metabolism in muscle. These results identify Nur77 as a potential mediator of neuromuscular signaling in the control of metabolic gene expression.

  10. Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis

    International Nuclear Information System (INIS)

    May, R.C.; Hara, Y.; Kelly, R.A.; Block, K.P.; Buse, M.G.; Mitch, W.E.

    1987-01-01

    Branched-chain amino acid (BCAA) metabolism is frequently abnormal in pathological conditions accompanied by chronic metabolic acidosis. To study how metabolic acidosis affects BCAA metabolism in muscle, rats were gavage fed a 14% protein diet with or without 4 mmol NH 4 Cl x 100 g body wt -1 x day -1 . Epitrochlearis muscles were incubated with L-[1- 14 C]-valine and L-[1- 14 C]leucine, and rates of decarboxylation, net transamination, and incorporation into muscle protein were measured. Plasma and muscle BCAA levels were lower in acidotic rats. Rates of valine and leucine decarboxylation and net transamination were higher in muscles from acidotic rats; these differences were associated with a 79% increase in the total activity of branched-chain α-keto acid dehydrogenase and a 146% increase in the activated form of the enzyme. They conclude that acidosis affects the regulation of BCAA metabolism by enhancing flux through the transaminase and by directly stimulating oxidative catabolism through activation of branched-chain α-keto acid dehydrogenase

  11. Resistin Regulates Pituitary Lipid Metabolism and Inflammation In Vivo and In Vitro

    Science.gov (United States)

    Rodriguez-Pacheco, F.; Novelle, M. G.; Vazquez, M. J.; Garcia-Escobar, E.; Soriguer, F.; Rojo-Martinez, G.; García-Fuentes, E.; Malagon, M. M.; Dieguez, C.

    2013-01-01

    The adipokine resistin is an insulin-antagonizing factor that also plays a regulatory role in inflammation, immunity, food intake, and gonadal function and also regulates growth hormone (GH) secretion in rat adenopituitary cells cultures with the adipokine. Although adipose tissue is the primary source of resistin, it is also expressed in other tissues, including the pituitary. The aim of this study is to investigate the possible action of resistin on the lipid metabolism in the pituitary gland in vivo (rats in two different nutritional status, fed and fast, treated with resistin on acute and a chronic way) and in vitro (adenopituitary cell cultures treated with the adipokine). Here, by a combination of in vivo and in vitro experimental models, we demonstrated that central acute and chronic administration of resistin enhance mRNA levels of the lipid metabolic enzymes which participated on lipolysis and moreover inhibiting mRNA levels of the lipid metabolic enzymes involved in lipogenesis. Taken together, our results demonstrate for the first time that resistin has a regulatory role on lipid metabolism in the pituitary gland providing a novel insight in relation to the mechanism by which this adipokine can participate in the integrated control of lipid metabolism. PMID:23710116

  12. miR-182 Regulates Metabolic Homeostasis by Modulating Glucose Utilization in Muscle

    Directory of Open Access Journals (Sweden)

    Duo Zhang

    2016-07-01

    Full Text Available Understanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC. Short-term high-fat diet (HFD feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα, which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control.

  13. The Roles of Vitamin A in the Regulation of Carbohydrate, Lipid, and Protein Metabolism

    Directory of Open Access Journals (Sweden)

    Wei Chen

    2014-05-01

    Full Text Available Currently, two-thirds of American adults are overweight or obese. This high prevalence of overweight/obesity negatively affects the health of the population, as obese individuals tend to develop several chronic diseases, such as type 2 diabetes and cardiovascular diseases. Due to obesity’s impact on health, medical costs, and longevity, the rise in the number of obese people has become a public health concern. Both genetic and environmental/dietary factors play a role in the development of metabolic diseases. Intuitively, it seems to be obvious to link over-nutrition to the development of obesity and other metabolic diseases. However, the underlying mechanisms are still unclear. Dietary nutrients not only provide energy derived from macronutrients, but also factors such as micronutrients with regulatory roles. How micronutrients, such as vitamin A (VA; retinol, regulate macronutrient homeostasis is still an ongoing research topic. As an essential micronutrient, VA plays a key role in the general health of an individual. This review summarizes recent research progress regarding VA’s role in carbohydrate, lipid, and protein metabolism. Due to the large amount of information regarding VA functions, this review focusses on metabolism in metabolic active organs and tissues. Additionally, some perspectives for future studies will be provided.

  14. The Microbiological Memory, an Epigenetic Regulator Governing the Balance Between Good Health and Metabolic Disorders

    Directory of Open Access Journals (Sweden)

    Christian A. Devaux

    2018-06-01

    Full Text Available If the transmission of biological information from one generation to the next is based on DNA, most heritable phenotypic traits such as chronic metabolic diseases, are not linked to genetic variation in DNA sequences. Non-genetic heritability might have several causes including epigenetic, parental effect, adaptive social learning, and influence of the ecological environment. Distinguishing among these causes is crucial to resolve major phenotypic enigmas. Strong evidence indicates that changes in DNA expression through various epigenetic mechanisms can be linked to parent-offspring resemblance in terms of sensitivity to metabolic diseases. Among non-genetic heritable traits, early nutrition could account for a long term deviant programming of genes expression responsible for metabolic diseases in adulthood. Nutrition could shape an inadequate gut microbiota (dysbiosis, triggering epigenetic deregulation of transcription which can be observed in chronic metabolic diseases. We review herein the evidence that dysbiosis might be a major cause of heritable epigenetic patterns found to be associated with metabolic diseases. By taking into account the recent advances on the gut microbiome, we have aggregated together different observations supporting the hypothesis that the gut microbiota could promote the molecular crosstalk between bacteria and surrounding host cells which controls the pathological epigenetic signature. We introduce for the first time the concept of “microbiological memory” as the main regulator of the epigenetic signatures, thereby indicating that different causes of non-genetic heritability can interact in complex pathways to produce inheritance.

  15. Metabolic reprogramming as a novel regulator of skeletal muscle development and regeneration.

    Science.gov (United States)

    Ryall, James G

    2013-09-01

    Adult skeletal muscle contains a resident population of stem cells, termed satellite cells, that exist in a quiescent state. In response to an activating signal (such as physical trauma), satellite cells enter the cell cycle and undergo multiple rounds of proliferation, followed by differentiation, fusion, and maturation. Over the last 10-15 years, our understanding of the transcriptional regulation of this stem cell population has greatly expanded, but there remains a dearth of knowledge with regard to the initiating signal leading to these changes in transcription. The recent renewed interest in the metabolic regulation of both cancer and stem cells, combined with previous findings indicating that satellite cells preferentially colocalize with blood vessels, suggests that satellite cell function may be regulated by changes in cellular metabolism. This review aims to describe what is currently known about satellite cell metabolism during changes in cell fate, as well as to describe some of the exciting findings in other cell types and how these might relate to satellite cells. © 2013 The Author Journal compilation © 2013 FEBS.

  16. Metabolic Regulation of Manganese Superoxide Dismutase Expression via Essential Amino Acid Deprivation*

    Science.gov (United States)

    Aiken, Kimberly J.; Bickford, Justin S.; Kilberg, Michael S.; Nick, Harry S.

    2008-01-01

    Organisms respond to available nutrient levels by rapidly adjusting metabolic flux, in part through changes in gene expression. A consequence of adaptations in metabolic rate is the production of mitochondria-derived reactive oxygen species. Therefore, we hypothesized that nutrient sensing could regulate the synthesis of the primary defense of the cell against superoxide radicals, manganese superoxide dismutase. Our data establish a novel nutrient-sensing pathway for manganese superoxide dismutase expression mediated through essential amino acid depletion concurrent with an increase in cellular viability. Most relevantly, our results are divergent from current mechanisms governing amino acid-dependent gene regulation. This pathway requires the presence of glutamine, signaling via the tricarboxylic acid cycle/electron transport chain, an intact mitochondrial membrane potential, and the activity of both the MEK/ERK and mammalian target of rapamycin kinases. Our results provide evidence for convergence of metabolic cues with nutrient control of antioxidant gene regulation, revealing a potential signaling strategy that impacts free radical-mediated mutations with implications in cancer and aging. PMID:18187411

  17. Metabolic regulation of manganese superoxide dismutase expression via essential amino acid deprivation.

    Science.gov (United States)

    Aiken, Kimberly J; Bickford, Justin S; Kilberg, Michael S; Nick, Harry S

    2008-04-18

    Organisms respond to available nutrient levels by rapidly adjusting metabolic flux, in part through changes in gene expression. A consequence of adaptations in metabolic rate is the production of mitochondria-derived reactive oxygen species. Therefore, we hypothesized that nutrient sensing could regulate the synthesis of the primary defense of the cell against superoxide radicals, manganese superoxide dismutase. Our data establish a novel nutrient-sensing pathway for manganese superoxide dismutase expression mediated through essential amino acid depletion concurrent with an increase in cellular viability. Most relevantly, our results are divergent from current mechanisms governing amino acid-dependent gene regulation. This pathway requires the presence of glutamine, signaling via the tricarboxylic acid cycle/electron transport chain, an intact mitochondrial membrane potential, and the activity of both the MEK/ERK and mammalian target of rapamycin kinases. Our results provide evidence for convergence of metabolic cues with nutrient control of antioxidant gene regulation, revealing a potential signaling strategy that impacts free radical-mediated mutations with implications in cancer and aging.

  18. Genome-Wide RNAi Ionomics Screen Reveals New Genes and Regulation of Human Trace Element Metabolism

    Science.gov (United States)

    Malinouski, Mikalai; Hasan, Nesrin M.; Zhang, Yan; Seravalli, Javier; Lin, Jie; Avanesov, Andrei; Lutsenko, Svetlana; Gladyshev, Vadim N.

    2017-01-01

    Trace elements are essential for human metabolism and dysregulation of their homeostasis is associated with numerous disorders. Here we characterize mechanisms that regulate trace elements in human cells by designing and performing a genome-wide high-throughput siRNA/ionomics screen, and examining top hits in cellular and biochemical assays. The screen reveals high stability of the ionomes, especially the zinc ionome, and yields known regulators and novel candidates. We further uncover fundamental differences in the regulation of different trace elements. Specifically, selenium levels are controlled through the selenocysteine machinery and expression of abundant selenoproteins; copper balance is affected by lipid metabolism and requires machinery involved in protein trafficking and posttranslational modifications; and the iron levels are influenced by iron import and expression of the iron/heme-containing enzymes. Our approach can be applied to a variety of disease models and/or nutritional conditions, and the generated dataset opens new directions for studies of human trace element metabolism. PMID:24522796

  19. Dynamic Metabolite Profiling in an Archaeon Connects Transcriptional Regulation to Metabolic Consequences.

    Directory of Open Access Journals (Sweden)

    Horia Todor

    Full Text Available Previous work demonstrated that the TrmB transcription factor is responsible for regulating the expression of many enzyme-coding genes in the hypersaline-adapted archaeon Halobacterium salinarum via a direct interaction with a cis-regulatory sequence in their promoters. This interaction is abolished in the presence of glucose. Although much is known about the effects of TrmB at the transcriptional level, it remains unclear whether and to what extent changes in mRNA levels directly affect metabolite levels. In order to address this question, here we performed a high-resolution metabolite profiling time course during a change in nutrients using a combination of targeted and untargeted methods in wild-type and ΔtrmB strain backgrounds. We found that TrmB-mediated transcriptional changes resulted in widespread and significant changes to metabolite levels across the metabolic network. Additionally, the pattern of growth complementation using various purines suggests that the mis-regulation of gluconeogenesis in the ΔtrmB mutant strain in the absence of glucose results in low phosphoribosylpyrophosphate (PRPP levels. We confirmed these low PRPP levels using a quantitative mass spectrometric technique and found that they are associated with a metabolic block in de novo purine synthesis, which is partially responsible for the growth defect of the ΔtrmB mutant strain in the absence of glucose. In conclusion, we show how transcriptional regulation of metabolism affects metabolite levels and ultimately, phenotypes.

  20. Tribbles-1: a novel regulator of hepatic lipid metabolism in humans.

    Science.gov (United States)

    Bauer, Robert C; Yenilmez, Batuhan O; Rader, Daniel J

    2015-10-01

    The protein tribbles-1, encoded by the gene TRIB1, is increasingly recognized as a major regulator of multiple cellular and physiological processes in humans. Recent human genetic studies, as well as molecular biological approaches, have implicated this intriguing protein in the aetiology of multiple human diseases, including myeloid leukaemia, Crohn's disease, non-alcoholic fatty liver disease (NAFLD), dyslipidaemia and coronary artery disease (CAD). Genome-wide association studies (GWAS) have repeatedly identified variants at the genomic TRIB1 locus as being significantly associated with multiple plasma lipid traits and cardiovascular disease (CVD) in humans. The involvement of TRIB1 in hepatic lipid metabolism has been validated through viral-mediated hepatic overexpression of the gene in mice; increasing levels of TRIB1 decreased plasma lipids in a dose-dependent manner. Additional studies have implicated TRIB1 in the regulation of hepatic lipogenesis and NAFLD. The exact mechanisms of TRIB1 regulation of both plasma lipids and hepatic lipogenesis remain undetermined, although multiple signalling pathways and transcription factors have been implicated in tribbles-1 function. Recent reports have been aimed at developing TRIB1-based lipid therapeutics. In summary, tribbles-1 is an important modulator of human energy metabolism and metabolic syndromes and worthy of future studies aimed at investigating its potential as a therapeutic target. © 2015 Authors; published by Portland Press Limited.

  1. Dynamic Metabolite Profiling in an Archaeon Connects Transcriptional Regulation to Metabolic Consequences.

    Science.gov (United States)

    Todor, Horia; Gooding, Jessica; Ilkayeva, Olga R; Schmid, Amy K

    2015-01-01

    Previous work demonstrated that the TrmB transcription factor is responsible for regulating the expression of many enzyme-coding genes in the hypersaline-adapted archaeon Halobacterium salinarum via a direct interaction with a cis-regulatory sequence in their promoters. This interaction is abolished in the presence of glucose. Although much is known about the effects of TrmB at the transcriptional level, it remains unclear whether and to what extent changes in mRNA levels directly affect metabolite levels. In order to address this question, here we performed a high-resolution metabolite profiling time course during a change in nutrients using a combination of targeted and untargeted methods in wild-type and ΔtrmB strain backgrounds. We found that TrmB-mediated transcriptional changes resulted in widespread and significant changes to metabolite levels across the metabolic network. Additionally, the pattern of growth complementation using various purines suggests that the mis-regulation of gluconeogenesis in the ΔtrmB mutant strain in the absence of glucose results in low phosphoribosylpyrophosphate (PRPP) levels. We confirmed these low PRPP levels using a quantitative mass spectrometric technique and found that they are associated with a metabolic block in de novo purine synthesis, which is partially responsible for the growth defect of the ΔtrmB mutant strain in the absence of glucose. In conclusion, we show how transcriptional regulation of metabolism affects metabolite levels and ultimately, phenotypes.

  2. CTRP3 attenuates diet-induced hepatic steatosis by regulating triglyceride metabolism.

    Science.gov (United States)

    Peterson, Jonathan M; Seldin, Marcus M; Wei, Zhikui; Aja, Susan; Wong, G William

    2013-08-01

    CTRP3 is a secreted plasma protein of the C1q family that helps regulate hepatic gluconeogenesis and is downregulated in a diet-induced obese state. However, the role of CTRP3 in regulating lipid metabolism has not been established. Here, we used a transgenic mouse model to address the potential function of CTRP3 in ameliorating high-fat diet-induced metabolic stress. Both transgenic and wild-type mice fed a high-fat diet showed similar body weight gain, food intake, and energy expenditure. Despite similar adiposity to wild-type mice upon diet-induced obesity (DIO), CTRP3 transgenic mice were strikingly resistant to the development of hepatic steatosis, had reduced serum TNF-α levels, and demonstrated a modest improvement in systemic insulin sensitivity. Additionally, reduced hepatic triglyceride levels were due to decreased expression of enzymes (GPAT, AGPAT, and DGAT) involved in triglyceride synthesis. Importantly, short-term daily administration of recombinant CTRP3 to DIO mice for 5 days was sufficient to improve the fatty liver phenotype, evident as reduced hepatic triglyceride content and expression of triglyceride synthesis genes. Consistent with a direct effect on liver cells, recombinant CTRP3 treatment reduced fatty acid synthesis and neutral lipid accumulation in cultured rat H4IIE hepatocytes. Together, these results establish a novel role for CTRP3 hormone in regulating hepatic lipid metabolism and highlight its protective function and therapeutic potential in attenuating hepatic steatosis.

  3. Irradiation of protoporphyric mice induces down-regulation of epidermal eicosanoid metabolism

    International Nuclear Information System (INIS)

    He, D.; Lim, H.W.

    1991-01-01

    This study investigated the effect of radiation on clinical and histologic changes, and on cutaneous eicosanoid metabolism, in Skh:HR-1 hairless albino mice rendered protoporphyric by the administration of collidine. At 0.1-18 h after exposure to 12 kJ/m2 of 396-406 nm irradiation, thicknesses of back skin and ears were measured, and histologic changes were evaluated by using hematoxylin and eosin (H-E) and Giemsa's stains. Activities of eicosanoid-metabolizing enzymes in epidermal and dermal homogenates were assessed by incubating the tissue homogenates with 3H-AA, followed by quantitation of the eicosanoids generated by radio-TLC. In irradiated protoporphyric mice, an increase of back-skin thickness was noted at 0.1 h, reaching a peak at 18 h, whereas maximal increase in ear thickness was observed at 12 h. Histologic changes included dermal edema, increased mast cell degranulation, and mononuclear cells in the dermis. In these irradiated protoporphyric animals, generations of 6 keto-PGF1a, PGF2a, PGE2, PGD2, and HETE by epidermal eicosanoid-metabolizing enzymes were markedly suppressed at all the timepoints studied. Dermal eicosanoid-metabolizing enzymes of irradiated protoporphyric mice generated increased amounts of PGE2 and HETE at 18 h, probably reflecting the presence of dermal cellular infiltrates. The suppression of the activities of epidermal eicosanoid-metabolizing enzymes was prevented by intraperitoneal injection of WR-2721, a sulfhydryl group generator, prior to irradiation, suggesting that the suppression was secondary to photo-oxidative damage of the enzymes during the in vivo phototoxic response. These results suggest that the effect of protoporphyrin and radiation on cutaneous eicosanoid metabolism in this animal model in vivo is that of a down regulation of the activities of epidermal eicosanoid-metabolizing enzymes

  4. Proteomics Reveals Global Regulation of Protein SUMOylation by ATM and ATR Kinases during Replication Stress

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    Stephanie Munk

    2017-10-01

    Full Text Available The mechanisms that protect eukaryotic DNA during the cumbersome task of replication depend on the precise coordination of several post-translational modification (PTM-based signaling networks. Phosphorylation is a well-known regulator of the replication stress response, and recently an essential role for SUMOs (small ubiquitin-like modifiers has also been established. Here, we investigate the global interplay between phosphorylation and SUMOylation in response to replication stress. Using SUMO and phosphoproteomic technologies, we identify thousands of regulated modification sites. We find co-regulation of central DNA damage and replication stress responders, of which the ATR-activating factor TOPBP1 is the most highly regulated. Using pharmacological inhibition of the DNA damage response kinases ATR and ATM, we find that these factors regulate global protein SUMOylation in the protein networks that protect DNA upon replication stress and fork breakage, pointing to integration between phosphorylation and SUMOylation in the cellular systems that protect DNA integrity.

  5. Functional analysis of the global repressor Tup1 for maltose metabolism in Saccharomyces cerevisiae: different roles of the functional domains.

    Science.gov (United States)

    Lin, Xue; Yu, Ai-Qun; Zhang, Cui-Ying; Pi, Li; Bai, Xiao-Wen; Xiao, Dong-Guang

    2017-11-09

    Tup1 is a general transcriptional repressor of diverse gene families coordinately controlled by glucose repression, mating type, and other mechanisms in Saccharomyces cerevisiae. Several functional domains of Tup1 have been identified, each of which has differing effects on transcriptional repression. In this study, we aim to investigate the role of Tup1 and its domains in maltose metabolism of industrial baker's yeast. To this end, a battery of in-frame truncations in the TUP1 gene coding region were performed in the industrial baker's yeasts with different genetic background, and the maltose metabolism, leavening ability, MAL gene expression levels, and growth characteristics were investigated. The results suggest that the TUP1 gene is essential to maltose metabolism in industrial baker's yeast. Importantly, different domains of Tup1 play different roles in glucose repression and maltose metabolism of industrial baker's yeast cells. The Ssn6 interaction, N-terminal repression and C-terminal repression domains might play roles in the regulation of MAL transcription by Tup1 for maltose metabolism of baker's yeast. The WD region lacking the first repeat could influence the regulation of maltose metabolism directly, rather than indirectly through glucose repression. These findings lay a foundation for the optimization of industrial baker's yeast strains for accelerated maltose metabolism and facilitate future research on glucose repression in other sugar metabolism.

  6. Identification of Proteins Involved in Carbohydrate Metabolism and Energy Metabolism Pathways and Their Regulation of Cytoplasmic Male Sterility in Wheat

    Directory of Open Access Journals (Sweden)

    Xingxia Geng

    2018-01-01

    Full Text Available Cytoplasmic male sterility (CMS where no functional pollen is produced has important roles in wheat breeding. The anther is a unique organ for male gametogenesis and its abnormal development can cause male sterility. However, the mechanisms and regulatory networks related to plant male sterility are poorly understood. In this study, we conducted comparative analyses using isobaric tags for relative and absolute quantification (iTRAQ of the pollen proteins in a CMS line and its wheat maintainer. Differentially abundant proteins (DAPs were analyzed based on Gene Ontology classifications, metabolic pathways and transcriptional regulation networks using Blast2GO. We identified 5570 proteins based on 23,277 peptides, which matched with 73,688 spectra, including proteins in key pathways such as glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase and 6-phosphofructokinase 1 in the glycolysis pathway, isocitrate dehydrogenase and citrate synthase in the tricarboxylic acid cycle and nicotinamide adenine dinucleotide (NADH-dehydrogenase and adenosine-triphosphate (ATP synthases in the oxidative phosphorylation pathway. These proteins may comprise a network that regulates male sterility in wheat. Quantitative real time polymerase chain reaction (qRT-PCR analysis, ATP assays and total sugar assays validated the iTRAQ results. These DAPs could be associated with abnormal pollen grain formation and male sterility. Our findings provide insights into the molecular mechanism related to male sterility in wheat.

  7. Identification of Proteins Involved in Carbohydrate Metabolism and Energy Metabolism Pathways and Their Regulation of Cytoplasmic Male Sterility in Wheat.

    Science.gov (United States)

    Geng, Xingxia; Ye, Jiali; Yang, Xuetong; Li, Sha; Zhang, Lingli; Song, Xiyue

    2018-01-23

    Cytoplasmic male sterility (CMS) where no functional pollen is produced has important roles in wheat breeding. The anther is a unique organ for male gametogenesis and its abnormal development can cause male sterility. However, the mechanisms and regulatory networks related to plant male sterility are poorly understood. In this study, we conducted comparative analyses using isobaric tags for relative and absolute quantification (iTRAQ) of the pollen proteins in a CMS line and its wheat maintainer. Differentially abundant proteins (DAPs) were analyzed based on Gene Ontology classifications, metabolic pathways and transcriptional regulation networks using Blast2GO. We identified 5570 proteins based on 23,277 peptides, which matched with 73,688 spectra, including proteins in key pathways such as glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase and 6-phosphofructokinase 1 in the glycolysis pathway, isocitrate dehydrogenase and citrate synthase in the tricarboxylic acid cycle and nicotinamide adenine dinucleotide (NADH)-dehydrogenase and adenosine-triphosphate (ATP) synthases in the oxidative phosphorylation pathway. These proteins may comprise a network that regulates male sterility in wheat. Quantitative real time polymerase chain reaction (qRT-PCR) analysis, ATP assays and total sugar assays validated the iTRAQ results. These DAPs could be associated with abnormal pollen grain formation and male sterility. Our findings provide insights into the molecular mechanism related to male sterility in wheat.

  8. Evidence of circadian rhythm, oxygen regulation capacity, metabolic repeatability and positive correlations between forced and spontaneous maximal metabolic rates in lake sturgeon Acipenser fulvescens.

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    Jon C Svendsen

    Full Text Available Animal metabolic rate is variable and may be affected by endogenous and exogenous factors, but such relationships remain poorly understood in many primitive fishes, including members of the family Acipenseridae (sturgeons. Using juvenile lake sturgeon (Acipenser fulvescens, the objective of this study was to test four hypotheses: 1 A. fulvescens exhibits a circadian rhythm influencing metabolic rate and behaviour; 2 A. fulvescens has the capacity to regulate metabolic rate when exposed to environmental hypoxia; 3 measurements of forced maximum metabolic rate (MMR(F are repeatable in individual fish; and 4 MMR(F correlates positively with spontaneous maximum metabolic rate (MMR(S. Metabolic rates were measured using intermittent flow respirometry, and a standard chase protocol was employed to elicit MMR(F. Trials lasting 24 h were used to measure standard metabolic rate (SMR and MMR(S. Repeatability and correlations between MMR(F and MMR(S were analyzed using residual body mass corrected values. Results revealed that A. fulvescens exhibit a circadian rhythm in metabolic rate, with metabolism peaking at dawn. SMR was unaffected by hypoxia (30% air saturation (O(2sat, demonstrating oxygen regulation. In contrast, MMR(F was affected by hypoxia and decreased across the range from 100% O(2sat to 70% O(2sat. MMR(F was repeatable in individual fish, and MMR(F correlated positively with MMR(S, but the relationships between MMR(F and MMR(S were only revealed in fish exposed to hypoxia or 24 h constant light (i.e. environmental stressor. Our study provides evidence that the physiology of A. fulvescens is influenced by a circadian rhythm and suggests that A. fulvescens is an oxygen regulator, like most teleost fish. Finally, metabolic repeatability and positive correlations between MMR(F and MMR(S support the conjecture that MMR(F represents a measure of organism performance that could be a target of natural selection.

  9. A Flexible Binding Site Architecture Provides New Insights into CcpA Global Regulation in Gram-Positive Bacteria.

    Science.gov (United States)

    Yang, Yunpeng; Zhang, Lu; Huang, He; Yang, Chen; Yang, Sheng; Gu, Yang; Jiang, Weihong

    2017-01-24

    Catabolite control protein A (CcpA) is the master regulator in Gram-positive bacteria that mediates carbon catabolite repression (CCR) and carbon catabolite activation (CCA), two fundamental regulatory mechanisms that enable competitive advantages in carbon catabolism. It is generally regarded that CcpA exerts its regulatory role by binding to a typical 14- to 16-nucleotide (nt) consensus site that is called a catabolite response element (cre) within the target regions. However, here we report a previously unknown noncanonical flexible architecture of the CcpA-binding site in solventogenic clostridia, providing new mechanistic insights into catabolite regulation. This novel CcpA-binding site, named cre var , has a unique architecture that consists of two inverted repeats and an intervening spacer, all of which are variable in nucleotide composition and length, except for a 6-bp core palindromic sequence (TGTAAA/TTTACA). It was found that the length of the intervening spacer of cre var can affect CcpA binding affinity, and moreover, the core palindromic sequence of cre var is the key structure for regulation. Such a variable architecture of cre var shows potential importance for CcpA's diverse and fine regulation. A total of 103 potential cre var sites were discovered in solventogenic Clostridium acetobutylicum, of which 42 sites were picked out for electrophoretic mobility shift assays (EMSAs), and 30 sites were confirmed to be bound by CcpA. These 30 cre var sites are associated with 27 genes involved in many important pathways. Also of significance, the cre var sites are found to be widespread and function in a great number of taxonomically different Gram-positive bacteria, including pathogens, suggesting their global role in Gram-positive bacteria. In Gram-positive bacteria, the global regulator CcpA controls a large number of important physiological and metabolic processes. Although a typical consensus CcpA-binding site, cre, has been identified, it remains

  10. Metabolism

    Science.gov (United States)

    ... Are More Common in People With Type 1 Diabetes Metabolic Syndrome Your Child's Weight Healthy Eating Endocrine System Blood Test: Basic Metabolic Panel (BMP) Activity: Endocrine System Growth Disorders Diabetes Center Thyroid Disorders Your Endocrine System Movie: Endocrine ...

  11. Glucose metabolic alterations in hippocampus of diabetes mellitus rats and the regulation of aerobic exercise.

    Science.gov (United States)

    Li, Jingjing; Liu, Beibei; Cai, Ming; Lin, Xiaojing; Lou, Shujie

    2017-11-04

    Diabetes could negatively affect the structures and functions of the brain, especially could cause the hippocampal dysfunction, however, the potential metabolic mechanism is unclear. The aim of this study was to investigate the changes of glucose metabolism in hippocampus of diabetes mellitus rats and the regulation of aerobic exercise, and to analyze the possible mechanisms. A rat model of type 2 diabetes mellitus was established by high-fat diet feeding in combination with STZ intraperitoneal injection, then 4 weeks of aerobic exercise was conducted. The glucose metabolites and key enzymes involved in glucose metabolism in hippocampus were respectively detected by GC/MS based metabolomics and western blot. Metabolomics results showed that compared with control rats, the level of citric acid was significantly decreased, while the levels of lactic acid, ribose 5-phosphate, xylulose 5-phosphate and glucitol were significantly increased in the diabetic rat. Compared with diabetic rats, the level of citric acid was significantly increased, while the lactic acid, ribose 5-phosphate and xylulose 5-phosphate were significantly decreased in the diabetic exercise rats. Western blot results showed that lower level of citrate synthase and oxoglutarate dehydrogenase, higher level of aldose reductase and glucose 6-phosphatedehydrogenase were found in the diabetic rats when compared to control rats. After 4 weeks of aerobic exercise, citrate synthase was upregulated and glucose 6-phosphatedehydrogenase was downregulated in the diabetic rats. These results suggest that diabetes could cause abnormal glucose metabolism, and aerobic exercise plays an important role in regulating diabetes-induced disorder of glucose metabolism in the hippocampus. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Regulation of homocysteine metabolism and methylation in human and mouse tissues

    Science.gov (United States)

    Chen, Natalie C.; Yang, Fan; Capecci, Louis M.; Gu, Ziyu; Schafer, Andrew I.; Durante, William; Yang, Xiao-Feng; Wang, Hong

    2010-01-01

    Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Homocysteine (Hcy) metabolism involves multiple enzymes; however, tissue Hcy metabolism and its relevance to methylation remain unknown. Here, we established gene expression profiles of 8 Hcy metabolic and 12 methylation enzymes in 20 human and 19 mouse tissues through bioinformatic analysis using expression sequence tag clone counts in tissue cDNA libraries. We analyzed correlations between gene expression, Hcy, S-adenosylhomocysteine (SAH), and S-adenosylmethionine (SAM) levels, and SAM/SAH ratios in mouse tissues. Hcy metabolic and methylation enzymes were classified into two types. The expression of Type 1 enzymes positively correlated with tissue Hcy and SAH levels. These include cystathionine β-synthase, cystathionine-γ-lyase, paraxonase 1, 5,10-methylenetetrahydrofolate reductase, betaine:homocysteine methyltransferase, methionine adenosyltransferase, phosphatidylethanolamine N-methyltransferases and glycine N-methyltransferase. Type 2 enzyme expressions correlate with neither tissue Hcy nor SAH levels. These include SAH hydrolase, methionyl-tRNA synthase, 5-methyltetrahydrofolate:Hcy methyltransferase, S-adenosylmethionine decarboxylase, DNA methyltransferase 1/3a, isoprenylcysteine carboxyl methyltransferases, and histone-lysine N-methyltransferase. SAH is the only Hcy metabolite significantly correlated with Hcy levels and methylation enzyme expression. We established equations expressing combined effects of methylation enzymes on tissue SAH, SAM, and SAM/SAH ratios. Our study is the first to provide panoramic tissue gene expression profiles and mathematical models of tissue methylation regulation.—Chen, N. C., Yang, F., Capecci, L. M., Gu, Z., Schafer, A. I., Durante, W., Yang, X.-F., Wang, H. Regulation of homocysteine metabolism and methylation in human and mouse tissues. PMID:20305127

  13. Cyclin G Functions as a Positive Regulator of Growth and Metabolism in Drosophila.

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    Patrick Fischer

    2015-08-01

    Full Text Available In multicellular organisms, growth and proliferation is adjusted to nutritional conditions by a complex signaling network. The Insulin receptor/target of rapamycin (InR/TOR signaling cascade plays a pivotal role in nutrient dependent growth regulation in Drosophila and mammals alike. Here we identify Cyclin G (CycG as a regulator of growth and metabolism in Drosophila. CycG mutants have a reduced body size and weight and show signs of starvation accompanied by a disturbed fat metabolism. InR/TOR signaling activity is impaired in cycG mutants, combined with a reduced phosphorylation status of the kinase Akt1 and the downstream factors S6-kinase and eukaryotic translation initiation factor 4E binding protein (4E-BP. Moreover, the expression and accumulation of Drosophila insulin like peptides (dILPs is disturbed in cycG mutant brains. Using a reporter assay, we show that the activity of one of the first effectors of InR signaling, Phosphoinositide 3-kinase (PI3K92E, is unaffected in cycG mutants. However, the metabolic defects and weight loss in cycG mutants were rescued by overexpression of Akt1 specifically in the fat body and by mutants in widerborst (wdb, the B'-subunit of the phosphatase PP2A, known to downregulate Akt1 by dephosphorylation. Together, our data suggest that CycG acts at the level of Akt1 to regulate growth and metabolism via PP2A in Drosophila.

  14. Globalization of health insecurity: the World Health Organization and the new International Health Regulations.

    Science.gov (United States)

    Aginam, Obijiofor

    2006-12-01

    The transnational spread of communicable and non-communicable diseases has opened new vistas in the discourse of global health security. Emerging and re-emerging pathogens, according to exponents of globalization of public health, disrespect the geo-political boundaries of nation-states. Despite the global ramifications of health insecurity in a globalizing world, contemporary international law still operates as a classic inter-state law within an international system exclusively founded on a coalition of nation-states. This article argues that the dynamic process of globalization has created an opportunity for the World Health Organization to develop effective synergy with a multiplicity of actors in the exercise of its legal powers. WHO's legal and regulatory strategies must transform from traditional international legal approaches to disease governance to a "post-Westphalian public health governance": the use of formal and informal sources from state and non-state actors, hard law (treaties and regulations) and soft law (recommendations and travel advisories) in global health governance. This article assesses the potential promise and problems of WHO's new International Health Regulations (IHR) as a regulatory strategy for global health governance and global health security.

  15. Effects of physical characteristics of carbon black on metabolic regulation in mice

    International Nuclear Information System (INIS)

    Chuang, Hsiao-Chi; Hsiao, Ta-Chih; Lee, Chii-Hong; Chun-Te Lin, Justin; Chuang, Kai-Jen; Feng, Po-Hao; Cheng, Tsun-Jen

    2018-01-01

    Potential adverse effects of human exposure to carbon black (CB) have been reported, but limited knowledge regarding CB-regulated metabolism is currently available. To evaluate how physical parameters of CB influence metabolism, we investigated CB and diesel exhaust particles (DEPs) and attempted to relate various physical parameters, including the hydrodynamic diameter, zeta potential, and particle number concentrations, to lung energy metabolism in female BALB/c mice. A body weight increase was arrested by 3 months of exposure to CB of smaller-size fractions, which was negatively correlated with pyruvate in plasma. There were no significant differences in cytotoxic lactate dehydrogenase (LDH) or total protein in bronchoalveolar lavage fluid (BALF) after 3 months of CB exposure. However, we observed alterations in acetyl CoA and the NADP/NADPH ratio in lung tissues with CB exposure. Additionally, the NADP/NADPH ratio was associated with the zeta potential of CB. Mild peribronchiovascular and interstitial inflammation and multinucleated giant cells (macrophages) with a transparent and rhomboid appearance and containing foreign bodies were observed in lung sections. We suggest that physical characteristics of CB, such as the zeta potential, may disrupt metabolism after pulmonary exposure. These results, therefore, provide the first evidence of a link between pulmonary exposure to CB and metabolism. - Highlights: • We evaluated how physical parameters of CB influence metabolism in mice lungs. • Body weight was arrested by exposure to CB in mice. • CB-induced peribronchiovascular and interstitial inflammation in the lungs. • Disruption in functions of acetyl CoA and NADP/NADPH was observed in lungs. • NADP/NADPH ratio was associated with the zeta potentials of CB.

  16. Plasticity in habitat use determines metabolic response of fish to global warming in stratified lakes.

    Science.gov (United States)

    Busch, Susan; Kirillin, Georgiy; Mehner, Thomas

    2012-09-01

    We used a coupled lake physics and bioenergetics-based foraging model to evaluate how the plasticity in habitat use modifies the seasonal metabolic response of two sympatric cold-water fishes (vendace and Fontane cisco, Coregonus spp.) under a global warming scenario for the year 2100. In different simulations, the vertically migrating species performed either a plastic strategy (behavioral thermoregulation) by shifting their population depth at night to maintain the temperatures occupied at current in-situ observations, or a fixed strategy (no thermoregulation) by keeping their occupied depths at night but facing modified temperatures. The lake physics model predicted higher temperatures above 20 m and lower temperatures below 20 m in response to warming. Using temperature-zooplankton relationships, the density of zooplankton prey was predicted to increase at the surface, but to decrease in hypolimnetic waters. Simulating the fixed strategy, growth was enhanced only for the deeper-living cisco due to the shift in thermal regime at about 20 m. In contrast, simulating the plastic strategy, individual growth of cisco and young vendace was predicted to increase compared to growth currently observed in the lake. Only growth rates of older vendace are reduced under future global warming scenarios irrespective of the behavioral strategy. However, performing behavioral thermoregulation would drive both species into the same depth layers, and hence will erode vertical microhabitat segregation and intensify inter-specific competition between the coexisting coregonids.

  17. Uncovering transcriptional regulation of glycerol metabolism in Aspergilli through genome-wide gene expression data anlysis

    DEFF Research Database (Denmark)

    Salazar, Margarita Pena; Vongsangnak, Wanwipa; Panagiotou, Gianni

    2009-01-01

    Glycerol is catabolized by a wide range of microorganisms including Aspergillus species. To identify the transcriptional regulation of glycerol metabolism in Aspergillus, we analyzed data from triplicate batch fermentations of three different Aspergilli (Aspergillus nidulans, Aspergillus oryzae...... and Aspergillus niger) with glucose and glycerol as carbon sources. Protein comparisons and cross-analysis with gene expression data of all three species resulted in the identification of 88 genes having a conserved response across the three Aspergilli. A promoter analysis of the up-regulated genes led...... to the identification of a conserved binding site for a putative regulator to be 5′-TGCGGGGA-3′, a binding site that is similar to the binding site for Adr1 in yeast and humans. We show that this Adr1 consensus binding sequence was over-represented on promoter regions of several genes in A. nidulans, A. oryzae and A...

  18. Genetic variants of methyl metabolizing enzymes and epigenetic regulators: Associations with promoter CpG island hypermethylation in colorectal cancer

    NARCIS (Netherlands)

    Vogel, S. de; Wouters, K.A.D.; Gottschalk, R.W.H.; Schooten, F.J. van; Goeij, A.F.P.M. de; Bruïne, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den; Weijenberg, M.P.; Engeland, M. van

    2009-01-01

    Aberrant DNA methylation affects carcinogenesis of colorectal cancer. Folate metabolizing enzymes may influence the bioavailability of methyl groups, whereas DNA and histone methyltransferases are involved in epigenetic regulation of gene expression. We studied associations of genetic variants of

  19. Kinetic analysis of zinc metabolism and its regulation in normal humans

    International Nuclear Information System (INIS)

    Wastney, M.E.; Aamodt, R.L.; Rumble, W.F.; Henkin, R.I.

    1986-01-01

    Zinc metabolism was studied in 32 normal volunteers after oral or intravenous administration of 65 Zn. Data were collected from the blood, urine, feces, whole body, and over the liver and thigh regions for 9 mo while the subjects consumed their regular diets (containing 10 mg Zn ion/day) and for an additional 9 mo while the subjects received an exogenous oral supplement of 100 mg Zn ion/day. Data from each subject were fitted by a compartmental model for zinc metabolism that was developed previously for patients with taste and smell dysfunction. These data from normal subjects were used to determine the absorption, distribution, and excretion of zinc and the mass of zinc in erythrocytes, liver, thigh, and whole body. By use of additional data obtained from the present study, the model was refined further such that a large compartment, which was previously determined to contain 90% of the body zinc, was subdivided into two compartments to represent zinc in muscle and bone. When oral zinc intake was increased 11-fold three new sites of regulation of zinc metabolism were identified in addition to the two sites previously defined in patients with taste and smell dysfunction (absorption of zinc from gut and excretion of zinc in urine). The three new sites are exchange of zinc with erythrocytes, release of zinc by muscle, and secretion of zinc into gut. Regulation at these five sites appears to maintain some tissue concentrations of zinc when dietary zinc increases

  20. FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1.

    Directory of Open Access Journals (Sweden)

    Carsten C Scholz

    2016-01-01

    Full Text Available The asparagine hydroxylase, factor inhibiting HIF (FIH, confers oxygen-dependence upon the hypoxia-inducible factor (HIF, a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1 is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit.

  1. Hydrological pulse regulating the bacterial heterotrophic metabolism between Amazonian mainstems and floodplain lakes

    Directory of Open Access Journals (Sweden)

    Luciana Oliveira Vidal

    2015-09-01

    Full Text Available We evaluated in situ rates of bacterial carbon processing in Amazonian floodplain lakes and mainstems, during both high and low water phases (p < 0.05. Our results showed that Bacterial Production (BP was lower and more variable than Bacterial Respiration (BR, determined as total respiration. Bacterial Carbon Demand (BCD was mostly accounted by BR and presented the same pattern that BR in both water phases. Bacterial growth efficiency showed a wide range (0.2–23% and low mean value of 3 and 6 %, (in high and low water respectively suggesting that dissolved organic carbon (DOC was mostly allocated to catabolic metabolism. However, BGE was regulated by BP in low water phase. Consequently, changes in BGE showed the same pattern that BP. In addition, the hydrological pulse effects on mainstems and floodplains lakes connectivity were found for BP and BGE in low water. Multiple correlation analyses revealed that indexes of organic matter quality (chlorophyll-a, N stable isotopes and C/N ratios were the strongest seasonal drivers of bacterial carbon metabolism. Our work indicated that: (1 the bacterial metabolism was mostly driven by respiration in Amazonian aquatic ecosystems resulting in low BGE in either high and low water phase; (2 the hydrological pulse regulated

  2. DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance.

    Science.gov (United States)

    Caron, Alexandre; Labbé, Sébastien M; Mouchiroud, Mathilde; Huard, Renaud; Lanfray, Damien; Richard, Denis; Laplante, Mathieu

    2016-06-01

    We have recently demonstrated that specific overexpression of DEP-domain containing mTOR-interacting protein (DEPTOR) in the mediobasal hypothalamus (MBH) protects mice against high-fat diet-induced obesity, revealing DEPTOR as a significant contributor to energy balance regulation. On the basis of evidence that DEPTOR is expressed in the proopiomelanocortin (POMC) neurons of the MBH, the present study aimed to investigate whether these neurons mediate the metabolic effects of DEPTOR. Here, we report that specific DEPTOR overexpression in POMC neurons does not recapitulate any of the phenotypes observed when the protein was overexpressed in the MBH. Unlike the previous model, mice overexpressing DEPTOR only in POMC neurons 1) did not show differences in feeding behavior, 2) did not exhibit changes in locomotion activity and oxygen consumption, 3) did not show an improvement in systemic glucose metabolism, and 4) were not resistant to high-fat diet-induced obesity. These results support the idea that other neuronal populations are responsible for these phenotypes. Nonetheless, we observed a mild elevation in fasting blood glucose, insulin resistance, and alterations in liver glucose and lipid homeostasis in mice overexpressing DEPTOR in POMC neurons. Taken together, these results show that DEPTOR overexpression in POMC neurons does not affect energy balance regulation but could modulate metabolism through a brain-liver connection. Copyright © 2016 the American Physiological Society.

  3. Regulation of the yeast metabolic cycle by transcription factors with periodic activities

    Directory of Open Access Journals (Sweden)

    Pellegrini Matteo

    2011-10-01

    Full Text Available Abstract Background When growing budding yeast under continuous, nutrient-limited conditions, over half of yeast genes exhibit periodic expression patterns. Periodicity can also be observed in respiration, in the timing of cell division, as well as in various metabolite levels. Knowing the transcription factors involved in the yeast metabolic cycle is helpful for determining the cascade of regulatory events that cause these patterns. Results Transcription factor activities were estimated by linear regression using time series and genome-wide transcription factor binding data. Time-translation matrices were estimated using least squares and were used to model the interactions between the most significant transcription factors. The top transcription factors have functions involving respiration, cell cycle events, amino acid metabolism and glycolysis. Key regulators of transitions between phases of the yeast metabolic cycle appear to be Hap1, Hap4, Gcn4, Msn4, Swi6 and Adr1. Conclusions Analysis of the phases at which transcription factor activities peak supports previous findings suggesting that the various cellular functions occur during specific phases of the yeast metabolic cycle.

  4. p38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage

    DEFF Research Database (Denmark)

    Borisova, Marina E; Voigt, Andrea; Tollenaere, Maxim A X

    2018-01-01

    quantitative phosphoproteomics and protein kinase inhibition to provide a systems view on protein phosphorylation patterns induced by UV light and uncover the dependencies of phosphorylation events on the canonical DNA damage signaling by ATM/ATR and the p38 MAP kinase pathway. We identify RNA-binding proteins......Ultraviolet (UV) light radiation induces the formation of bulky photoproducts in the DNA that globally affect transcription and splicing. However, the signaling pathways and mechanisms that link UV-light-induced DNA damage to changes in RNA metabolism remain poorly understood. Here we employ...

  5. Effect of Diet, Insulin and Exercise on the Regulation of Carbohydrate Metabolism in Health and Type 1 Diabetes

    OpenAIRE

    Chokkalingam, Kamalakkannan

    2007-01-01

    The objective of this thesis was to further the understanding of the effect of diet, insulin and exercise on the regulation of carbohydrate metabolism in health and type 1 diabetes. Three studies were undertaken in both non-diabetic healthy volunteers and patients with type 1 diabetes. The first study determined the influence of high fat diet on biochemical and molecular regulators of whole body and muscle metabolism in healthy volunteers. The second study examined the influence of insulin on...

  6. Proteomics Reveals Global Regulation of Protein SUMOylation by ATM and ATR Kinases during Replication Stress

    DEFF Research Database (Denmark)

    Munk, Stephanie; Sigurðsson, Jón Otti; Xiao, Zhenyu

    2017-01-01

    The mechanisms that protect eukaryotic DNA during the cumbersome task of replication depend on the precise coordination of several post-translational modification (PTM)-based signaling networks. Phosphorylation is a well-known regulator of the replication stress response, and recently an essentia....... They analyze changes in the SUMO and phosphoproteome after MMC and hydroxyurea treatments and find that the DNA damage response kinases ATR and ATM globally regulate SUMOylation upon replication stress and fork breakage....

  7. The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism

    DEFF Research Database (Denmark)

    Szekeres, Ferenc; Chadt, Alexandra; Tom, Robby Z

    2012-01-01

    The Rab-GTPase-activating protein TBC1D1 has emerged as a novel candidate involved in metabolic regulation. Our aim was to determine whether TBC1D1 is involved in insulin as well as energy-sensing signals controlling skeletal muscle metabolism. TBC1D1-deficient congenic B6.SJL-Nob1.10 (Nob1.10(SJL...... be explained partly by a 50% reduction in GLUT4 protein, since proximal signaling at the level of Akt, AMPK, and acetyl-CoA carboxylase (ACC) was unaltered. Paradoxically, in vivo insulin-stimulated 2-deoxyglucose uptake was increased in EDL and tibialis anterior muscle from TBC1D1-deficient mice......)) and wild-type littermates were studied. Glucose and insulin tolerance, glucose utilization, hepatic glucose production, and tissue-specific insulin-mediated glucose uptake were determined. The effect of insulin, AICAR, or contraction on glucose transport was studied in isolated skeletal muscle. Glucose...

  8. Substrate availability and transcriptional regulation of metabolic genes in human skeletal muscle during recovery from exercise

    DEFF Research Database (Denmark)

    Pilegaard, Henriette; Osada, Takuya; Andersen, Lisbeth Tingsted

    2005-01-01

    before exercise and 2, 5, 8, and 24 hours after exercise. Muscle glycogen was restored to near resting levels within 5 hours in the HC trial, but remained depressed through 24 hours in the LC trial. During the 2- to 8-hour recovery period, leg glucose uptake was 5- to 15-fold higher with HC ingestion......In skeletal muscle of humans, transcription of several metabolic genes is transiently induced during recovery from exercise when no food is consumed. To determine the potential influence of substrate availability on the transcriptional regulation of metabolic genes during recovery from exercise, 9...... male subjects (aged 22-27) completed 75 minutes of cycling exercise at 75% V¿o2max on 2 occasions, consuming either a high-carbohydrate (HC) or low-carbohydrate (LC) diet during the subsequent 24 hours of recovery. Nuclei were isolated and tissue frozen from vastus lateralis muscle biopsies obtained...

  9. Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease

    DEFF Research Database (Denmark)

    Nielsen, Thomas Svava; Jessen, Niels; Jørgensen, Jens Otto Lunde

    2014-01-01

    is tightly regulated by hormonal and nutritional factors. Under conditions of negative energy balance such as fasting and exercise, stimulation of lipolysis results in a profound increase in FFA release from adipose tissue. This response is crucial in order to provide the organism with a sufficient supply......Lipolysis is the process by which triglycerides are hydrolyzed to free fatty acids (FFA) and glycerol. In adipocytes, this is achieved by the sequential action of Adipose Triglyceride Lipase (ATGL), Hormone Sensitive Lipase (HSL) and Monoglyceride Lipase (MGL). The activity in the lipolytic pathway...... of substrate for oxidative metabolism. However, failure to efficiently suppress lipolysis when FFA demands are low can have serious metabolic consequences and is believed to be a key mechanism in the development of type 2 diabetes in obesity. Since the discovery of ATGL in 2004, substantial progress has been...

  10. Pathogenicity of Mycobacterium tuberculosis is expressed by regulating metabolic thresholds of the host macrophage.

    Directory of Open Access Journals (Sweden)

    Parul Mehrotra

    2014-07-01

    Full Text Available The success of Mycobacterium tuberculosis as a pathogen derives from its facile adaptation to the intracellular milieu of human macrophages. To explore this process, we asked whether adaptation also required interference with the metabolic machinery of the host cell. Temporal profiling of the metabolic flux, in cells infected with differently virulent mycobacterial strains, confirmed that this was indeed the case. Subsequent analysis identified the core subset of host reactions that were targeted. It also elucidated that the goal of regulation was to integrate pathways facilitating macrophage survival, with those promoting mycobacterial sustenance. Intriguingly, this synthesis then provided an axis where both host- and pathogen-derived factors converged to define determinants of pathogenicity. Consequently, whereas the requirement for macrophage survival sensitized TB susceptibility to the glycemic status of the individual, mediation by pathogen ensured that the virulence properties of the infecting strain also contributed towards the resulting pathology.

  11. Modeling the role of negative cooperativity in metabolic regulation and homeostasis.

    Directory of Open Access Journals (Sweden)

    Eliot C Bush

    Full Text Available A significant proportion of enzymes display cooperativity in binding ligand molecules, and such effects have an important impact on metabolic regulation. This is easiest to understand in the case of positive cooperativity. Sharp responses to changes in metabolite concentrations can allow organisms to better respond to environmental changes and maintain metabolic homeostasis. However, despite the fact that negative cooperativity is almost as common as positive, it has been harder to imagine what advantages it provides. Here we use computational models to explore the utility of negative cooperativity in one particular context: that of an inhibitor binding to an enzyme. We identify several factors which may contribute, and show that acting together they can make negative cooperativity advantageous.

  12. Aflatoxin regulations and global pistachio trade: insights from social network analysis.

    Science.gov (United States)

    Bui-Klimke, Travis R; Guclu, Hasan; Kensler, Thomas W; Yuan, Jian-Min; Wu, Felicia

    2014-01-01

    Aflatoxins, carcinogenic toxins produced by Aspergillus fungi, contaminate maize, peanuts, and tree nuts in many regions of the world. Pistachios are the main source of human dietary aflatoxins from tree nuts worldwide. Over 120 countries have regulations for maximum allowable aflatoxin levels in food commodities. We developed social network models to analyze the association between nations' aflatoxin regulations and global trade patterns of pistachios from 1996-2010. The main pistachio producing countries are Iran and the United States (US), which together contribute to nearly 75% of the total global pistachio market. Over this time period, during which many nations developed or changed their aflatoxin regulations in pistachios, global pistachio trade patterns changed; with the US increasingly exporting to countries with stricter aflatoxin standards. The US pistachio crop has had consistently lower levels of aflatoxin than the Iranian crop over this same time period. As similar trading patterns have also been documented in maize, public health may be affected if countries without aflatoxin regulations, or with more relaxed regulations, continually import crops with higher aflatoxin contamination. Unlike the previous studies on maize, this analysis includes a dynamic element, examining how trade patterns change over time with introduction or adjustment of aflatoxin regulations.

  13. Brassinosteroid Regulates Cell Elongation by Modulating Gibberellin Metabolism in Rice[C][W][OPEN

    Science.gov (United States)

    Tong, Hongning; Xiao, Yunhua; Liu, Dapu; Gao, Shaopei; Liu, Linchuan; Yin, Yanhai; Jin, Yun; Qian, Qian; Chu, Chengcai

    2014-01-01

    Brassinosteroid (BR) and gibberellin (GA) are two predominant hormones regulating plant cell elongation. A defect in either of these leads to reduced plant growth and dwarfism. However, their relationship remains unknown in rice (Oryza sativa). Here, we demonstrated that BR regulates cell elongation by modulating GA metabolism in rice. Under physiological conditions, BR promotes GA accumulation by regulating the expression of GA metabolic genes to stimulate cell elongation. BR greatly induces the expression of D18/GA3ox-2, one of the GA biosynthetic genes, leading to increased GA1 levels, the bioactive GA in rice seedlings. Consequently, both d18 and loss-of-function GA-signaling mutants have decreased BR sensitivity. When excessive active BR is applied, the hormone mostly induces GA inactivation through upregulation of the GA inactivation gene GA2ox-3 and also represses BR biosynthesis, resulting in decreased hormone levels and growth inhibition. As a feedback mechanism, GA extensively inhibits BR biosynthesis and the BR response. GA treatment decreases the enlarged leaf angles in plants with enhanced BR biosynthesis or signaling. Our results revealed a previously unknown mechanism underlying BR and GA crosstalk depending on tissues and hormone levels, which greatly advances our understanding of hormone actions in crop plants and appears much different from that in Arabidopsis thaliana. PMID:25371548

  14. New avenues for regulation of lipid metabolism by thyroid hormones and analogs.

    Science.gov (United States)

    Senese, Rosalba; Lasala, Pasquale; Leanza, Cristina; de Lange, Pieter

    2014-01-01

    Weight loss due to negative energy balance is a goal in counteracting obesity and type 2 diabetes mellitus. The thyroid is known to be an important regulator of energy metabolism through the action of thyroid hormones (THs). The classic, active TH, 3,5,3'-triiodo-L-thyronine (T3) acts predominantly by binding to nuclear receptors termed TH receptors (TRs), that recognize TH response elements (TREs) on the DNA, and so regulate transcription. T3 also acts through "non-genomic" pathways that do not necessarily involve TRs. Lipid-lowering therapies have been suggested to have potential benefits, however, the establishment of comprehensive therapeutic strategies is still awaited. One drawback of using T3 in counteracting obesity has been the occurrence of heart rhythm disturbances. These are mediated through one TR, termed TRα. The end of the previous century saw the exploration of TH mimetics that specifically bind to TR beta in order to prevent cardiac disturbances, and TH derivatives such as 3,5-diiodo-L-thyronine (T2), that possess interesting biological activities. Several TH derivatives and functional analogs have low affinity for the TRs, and are suggested to act predominantly through non-genomic pathways. All this has opened new perspectives in thyroid physiology and TH derivative usage as anti-obesity therapies. This review addresses the pros and cons of these compounds, in light of their effects on energy balance regulation and on lipid/cholesterol metabolism.

  15. New Avenues for Regulation of Lipid Metabolism by Thyroid Hormones and Analogs

    Directory of Open Access Journals (Sweden)

    Rosalba eSenese

    2014-12-01

    Full Text Available Weight loss due to negative energy balance is a goal in counteracting obesity and type 2 diabetes mellitus. The thyroid is known to be an important regulator of energy metabolism through the action of thyroid hormones (THs. The classic, active TH, 3,5,3’-triiodo-L-thyronine (T3 acts predominantly by binding to nuclear receptors termed TH receptors (TRs, that recognize TH response elements (TREs on the DNA, and so regulate transcription. T3 also acts through non-genomic pathways that do not necessarily involve TRs. Lipid-lowering therapies have been suggested to have potential benefits, however, the establishment of comprehensive therapeutic strategies is still awaited. One drawback of using T3 in counteracting obesity has been the occurrence of heart rhythm disturbances. These are mediated through one TR, termed TR alpha. The end of the previous century saw the exploration of TH mimetics that specifically bind to TR beta in order to prevent cardiac disturbances, and TH derivatives such as 3,5-diiodo-L-thyronine (T2, that possess interesting biological activities. Several TH derivatives and functional analogs have low affinity for the TRs, and are suggested to act predominantly through non-genomic pathways. All this has opened new perspectives in thyroid physiology and TH derivative usage as anti-obesity therapies. This review addresses the pros and cons of these compounds, in light of their effects on energy balance regulation and on lipid/cholesterol metabolism.

  16. Effect of growth regulators on 'Brookfield' apple gas diffusion and metabolism under controlled atmosphere storage

    Directory of Open Access Journals (Sweden)

    Auri Brackmann

    2014-05-01

    Full Text Available The objective of this work was to evaluate the effect of growth regulators on gas diffusion and on metabolism of 'Brookfield' apple, and to determine their correlation with quality characteristics of fruit stored in controlled atmosphere. A completely randomized design was used with four replicates. After eight months of storage, the effects of water (control, aminoethoxyvinylglycine (AVG, AVG + ethephon, AVG + naphthaleneacetic acid (NAA, ethephon + NAA, sole NAA, 1-MCP, ethylene absorption by potassium permanganate (ABS, AVG + ABS, and of AVG + 1-MCP - applied at different rates and periods - were evaluated on: gas diffusion rate, ethylene production, respiratory rate, internal ethylene concentration, internal CO2 content, mealiness, and intercellular space. Fruit from the control and sole NAA treatments had the highest mealiness occurrence. Growth regulators significantly changed the gaseous diffusion through the pulp of 'Brookfield' apple, mainly in the treatment AVG + ABS, which kept the highest gas diffusion rate. NAA spraying in the field, with or without another growth regulator, increased ripening metabolism by rising ethylene production and respiration rate, and reduced gas diffusion during shelf life. AVG spraying cannot avoid the ethephon effect during the ripening process, and reduces both the internal space and mealiness incidence, but it is not able to induce ethylene production or to increase respiration rates.

  17. MicroRNA-211 Regulates Oxidative Phosphorylation and Energy Metabolism in Human Vitiligo.

    Science.gov (United States)

    Sahoo, Anupama; Lee, Bongyong; Boniface, Katia; Seneschal, Julien; Sahoo, Sanjaya K; Seki, Tatsuya; Wang, Chunyan; Das, Soumen; Han, Xianlin; Steppie, Michael; Seal, Sudipta; Taieb, Alain; Perera, Ranjan J

    2017-09-01

    Vitiligo is a common chronic skin disorder characterized by loss of epidermal melanocytes and progressive depigmentation. Vitiligo has complex immune, genetic, environmental, and biochemical causes, but the exact molecular mechanisms of vitiligo development and progression, particularly those related to metabolic control, are poorly understood. In this study we characterized the human vitiligo cell line PIG3V and the normal human melanocyte line HEM-l by RNA sequencing, targeted metabolomics, and shotgun lipidomics. Melanocyte-enriched microRNA-211, a known metabolic switch in nonpigmented melanoma cells, was severely down-regulated in vitiligo cell line PIG3V and skin biopsy samples from vitiligo patients, whereas its predicted targets PPARGC1A, RRM2, and TAOK1 were reciprocally up-regulated. microRNA-211 binds to PGC1-α 3' untranslated region locus and represses it. Although mitochondrial numbers were constant, mitochondrial complexes I, II, and IV and respiratory responses were defective in vitiligo cells. Nanoparticle-coated microRNA-211 partially augmented the oxygen consumption rate in PIG3V cells. The lower oxygen consumption rate, changes in lipid and metabolite profiles, and increased reactive oxygen species production observed in vitiligo cells appear to be partly due to abnormal regulation of microRNA-211 and its target genes. These genes represent potential biomarkers and therapeutic targets in human vitiligo. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Concurrent and robust regulation of feeding behaviors and metabolism by orexin neurons.

    Science.gov (United States)

    Inutsuka, Ayumu; Inui, Azusa; Tabuchi, Sawako; Tsunematsu, Tomomi; Lazarus, Michael; Yamanaka, Akihiro

    2014-10-01

    Orexin neurons in the hypothalamus regulate energy homeostasis by coordinating various physiological responses. Past studies have shown the role of the orexin peptide itself; however, orexin neurons contain not only orexin but also other neurotransmitters such as glutamate and dynorphin. In this study, we examined the physiological role of orexin neurons in feeding behavior and metabolism by pharmacogenetic activation and chronic ablation. We generated novel orexin-Cre mice and utilized Cre-dependent adeno-associated virus vectors to express Gq-coupled modified GPCR, hM3Dq or diphtheria toxin fragment A in orexin neurons. By intraperitoneal injection of clozapine-N oxide in orexin-Cre mice expressing hM3Dq in orexin neurons, we could selectively manipulate the activity of orexin neurons. Pharmacogenetic stimulation of orexin neurons simultaneously increased locomotive activity, food intake, water intake and the respiratory exchange ratio (RER). Elevation of blood glucose levels and RER persisted even after locomotion and feeding behaviors returned to basal levels. Accordantly, 83% ablation of orexin neurons resulted in decreased food and water intake, while 70% ablation had almost no effect on these parameters. Our results indicate that orexin neurons play an integral role in regulation of both feeding behavior and metabolism. This regulation is so robust that greater than 80% of orexin neurons were ablated before significant changes in feeding behavior emerged. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. The nutritional status of Methanosarcina acetivorans regulates glycogen metabolism and gluconeogenesis and glycolysis fluxes.

    Science.gov (United States)

    Santiago-Martínez, Michel Geovanni; Encalada, Rusely; Lira-Silva, Elizabeth; Pineda, Erika; Gallardo-Pérez, Juan Carlos; Reyes-García, Marco Antonio; Saavedra, Emma; Moreno-Sánchez, Rafael; Marín-Hernández, Alvaro; Jasso-Chávez, Ricardo

    2016-05-01

    Gluconeogenesis is an essential pathway in methanogens because they are unable to use exogenous hexoses as carbon source for cell growth. With the aim of understanding the regulatory mechanisms of central carbon metabolism in Methanosarcina acetivorans, the present study investigated gene expression, the activities and metabolic regulation of key enzymes, metabolite contents and fluxes of gluconeogenesis, as well as glycolysis and glycogen synthesis/degradation pathways. Cells were grown with methanol as a carbon source. Key enzymes were kinetically characterized at physiological pH/temperature. Active consumption of methanol during exponential cell growth correlated with significant methanogenesis, gluconeogenic flux and steady glycogen synthesis. After methanol exhaustion, cells reached the stationary growth phase, which correlated with the rise in glycogen consumption and glycolytic flux, decreased methanogenesis, negligible acetate production and an absence of gluconeogenesis. Elevated activities of carbon monoxide dehydrogenase/acetyl-CoA synthetase complex and pyruvate: ferredoxin oxidoreductase suggested the generation of acetyl-CoA and pyruvate for glycogen synthesis. In the early stationary growth phase, the transcript contents and activities of pyruvate phosphate dikinase, fructose 1,6-bisphosphatase and glycogen synthase decreased, whereas those of glycogen phosphorylase, ADP-phosphofructokinase and pyruvate kinase increased. Therefore, glycogen and gluconeogenic metabolites were synthesized when an external carbon source was provided. Once such a carbon source became depleted, glycolysis and methanogenesis fed by glycogen degradation provided the ATP supply. Weak inhibition of key enzymes by metabolites suggested that the pathways evaluated were mainly transcriptionally regulated. Because glycogen metabolism and glycolysis/gluconeogenesis are not present in all methanogens, the overall data suggest that glycogen storage might represent an environmental

  20. Environmental oxygen tension regulates the energy metabolism and self-renewal of human embryonic stem cells.

    Science.gov (United States)

    Forristal, Catherine E; Christensen, David R; Chinnery, Fay E; Petruzzelli, Raffaella; Parry, Kate L; Sanchez-Elsner, Tilman; Houghton, Franchesca D

    2013-01-01

    Energy metabolism is intrinsic to cell viability but surprisingly has been little studied in human embryonic stem cells (hESCs). The current study aims to investigate the effect of environmental O2 tension on carbohydrate utilisation of hESCs. Highly pluripotent hESCs cultured at 5% O2 consumed significantly more glucose, less pyruvate and produced more lactate compared to those maintained at 20% O2. Moreover, hESCs cultured at atmospheric O2 levels expressed significantly less OCT4, SOX2 and NANOG than those maintained at 5% O2. To determine whether this difference in metabolism was a reflection of the pluripotent state, hESCs were cultured at 5% O2 in the absence of FGF2 for 16 hours leading to a significant reduction in the expression of SOX2. In addition, these cells consumed less glucose and produced significantly less lactate compared to those cultured in the presence of FGF2. hESCs maintained at 5% O2 were found to consume significantly less O2 than those cultured in the absence of FGF2, or at 20% O2. GLUT1 expression correlated with glucose consumption and using siRNA and chromatin immunoprecipitation was found to be directly regulated by hypoxia inducible factor (HIF)-2α at 5% O2. In conclusion, highly pluripotent cells associated with hypoxic culture consume low levels of O2, high levels of glucose and produce large amounts of lactate, while at atmospheric conditions glucose consumption and lactate production are reduced and there is an increase in oxidative metabolism. These data suggest that environmental O2 regulates energy metabolism and is intrinsic to the self-renewal of hESCs.

  1. Impact of hypothalamic reactive oxygen species in the regulation of energy metabolism and food intake.

    Science.gov (United States)

    Drougard, Anne; Fournel, Audren; Valet, Philippe; Knauf, Claude

    2015-01-01

    Hypothalamus is a key area involved in the control of metabolism and food intake via the integrations of numerous signals (hormones, neurotransmitters, metabolites) from various origins. These factors modify hypothalamic neurons activity and generate adequate molecular and behavioral responses to control energy balance. In this complex integrative system, a new concept has been developed in recent years, that includes reactive oxygen species (ROS) as a critical player in energy balance. ROS are known to act in many signaling pathways in different peripheral organs, but also in hypothalamus where they regulate food intake and metabolism by acting on different types of neurons, including proopiomelanocortin (POMC) and agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons. Hypothalamic ROS release is under the influence of different factors such as pancreatic and gut hormones, adipokines (leptin, apelin,…), neurotransmitters and nutrients (glucose, lipids,…). The sources of ROS production are multiple including NADPH oxidase, but also the mitochondria which is considered as the main ROS producer in the brain. ROS are considered as signaling molecules, but conversely impairment of this neuronal signaling ROS pathway contributes to alterations of autonomic nervous system and neuroendocrine function, leading to metabolic diseases such as obesity and type 2 diabetes. In this review we focus our attention on factors that are able to modulate hypothalamic ROS release in order to control food intake and energy metabolism, and whose deregulations could participate to the development of pathological conditions. This novel insight reveals an original mechanism in the hypothalamus that controls energy balance and identify hypothalamic ROS signaling as a potential therapeutic strategy to treat metabolic disorders.

  2. Genetic regulation of bone metabolism in the chicken: similarities and differences to Mammalian systems.

    Directory of Open Access Journals (Sweden)

    Martin Johnsson

    2015-05-01

    Full Text Available Birds have a unique bone physiology, due to the demands placed on them through egg production. In particular their medullary bone serves as a source of calcium for eggshell production during lay and undergoes continuous and rapid remodelling. We take advantage of the fact that bone traits have diverged massively during chicken domestication to map the genetic basis of bone metabolism in the chicken. We performed a quantitative trait locus (QTL and expression QTL (eQTL mapping study in an advanced intercross based on Red Junglefowl (the wild progenitor of the modern domestic chicken and White Leghorn chickens. We measured femoral bone traits in 456 chickens by peripheral computerised tomography and femoral gene expression in a subset of 125 females from the cross with microarrays. This resulted in 25 loci for female bone traits, 26 loci for male bone traits and 6318 local eQTL loci. We then overlapped bone and gene expression loci, before checking for an association between gene expression and trait values to identify candidate quantitative trait genes for bone traits. A handful of our candidates have been previously associated with bone traits in mice, but our results also implicate unexpected and largely unknown genes in bone metabolism. In summary, by utilising the unique bone metabolism of an avian species, we have identified a number of candidate genes affecting bone allocation and metabolism. These findings can have ramifications not only for the understanding of bone metabolism genetics in general, but could also be used as a potential model for osteoporosis as well as revealing new aspects of vertebrate bone regulation or features that distinguish avian and mammalian bone.

  3. Ptpmt1 induced by HIF-2α regulates the proliferation and glucose metabolism in erythroleukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Qin-Qin [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining, 810001 (China); Qinghai Provincial People' s Hospital, Xining (China); Xiao, Feng-Jun; Sun, Hui-Yan [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850 (China); Shi, Xue-Feng [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining, 810001 (China); Qinghai Provincial People' s Hospital, Xining (China); Wang, Hua; Yang, Yue-Feng; Li, Yu-Xiang [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850 (China); Wang, Li-Sheng, E-mail: wangls@bmi.ac.cn [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, 100850 (China); Ge, Ri-Li, E-mail: geriligao@hotmail.com [High Altitude Medicine of Ministry of Chinese Education and Research Center for High Altitude Medicine, Qinghai University, Xining, 810001 (China)

    2016-03-18

    Hypoxia provokes metabolism misbalance, mitochondrial dysfunction and oxidative stress in both human and animal cells. However, the mechanisms which hypoxia causes mitochondrial dysfunction and energy metabolism misbalance still remain unclear. In this study, we presented evidence that mitochondrial phosphatase Ptpmt1 is a hypoxia response molecule that regulates cell proliferation, survival and glucose metabolism in human erythroleukemia TF-1 cells. Exposure to hypoxia or DFO treatment results in upregulation of HIF1-α, HIF-2α and Ptpmt1. Only inhibition of HIF-2α by shRNA transduction reduces Ptpmt1 expression in TF-1 cells under hypoxia. Ptpmt1 inhibitor suppresses the growth and induces apoptosis of TF-1 cells. Furthermore, we demonstrated that Ptpmt1 inhibition reduces the Glut1 and Glut3 expression and decreases the glucose consumption in TF-1 cells. In additional, Ptpmt1 knockdown also results in the mitochondrial dysfunction determined by JC1 staining. These results delineate a key role for HIF-2α-induced Ptpmt1 upregulation in proliferation, survival and glucose metabolism of erythroleukemia cells. It is indicated that Ptpmt1 plays important roles in hypoxia-induced cell metabolism and mitochondrial dysfunction. - Highlights: • Hypoxia induces upregulation of HIF-1α, HIF-2α and Ptpmt1; HIF-2a induces Ptpmt1 upregulation in TF-1 cells. • PTPMT-1 inhibition reduces growth and induces apoptosis of TF-1 cells. • PTPMT1 inhibition downregulates Glut-1, Glut-3 expression and reduces glucose consumption.

  4. Analysis of clock-regulated genes in Neurospora reveals widespread posttranscriptional control of metabolic potential

    Science.gov (United States)

    Hurley, Jennifer M.; Dasgupta, Arko; Emerson, Jillian M.; Zhou, Xiaoying; Ringelberg, Carol S.; Knabe, Nicole; Lipzen, Anna M.; Lindquist, Erika A.; Daum, Christopher G.; Barry, Kerrie W.; Grigoriev, Igor V.; Smith, Kristina M.; Galagan, James E.; Bell-Pedersen, Deborah; Freitag, Michael; Cheng, Chao; Loros, Jennifer J.; Dunlap, Jay C.

    2014-01-01

    Neurospora crassa has been for decades a principal model for filamentous fungal genetics and physiology as well as for understanding the mechanism of circadian clocks. Eukaryotic fungal and animal clocks comprise transcription-translation–based feedback loops that control rhythmic transcription of a substantial fraction of these transcriptomes, yielding the changes in protein abundance that mediate circadian regulation of physiology and metabolism: Understanding circadian control of gene expression is key to understanding eukaryotic, including fungal, physiology. Indeed, the isolation of clock-controlled genes (ccgs) was pioneered in Neurospora where circadian output begins with binding of the core circadian transcription factor WCC to a subset of ccg promoters, including those of many transcription factors. High temporal resolution (2-h) sampling over 48 h using RNA sequencing (RNA-Seq) identified circadianly expressed genes in Neurospora, revealing that from ∼10% to as much 40% of the transcriptome can be expressed under circadian control. Functional classifications of these genes revealed strong enrichment in pathways involving metabolism, protein synthesis, and stress responses; in broad terms, daytime metabolic potential favors catabolism, energy production, and precursor assembly, whereas night activities favor biosynthesis of cellular components and growth. Discriminative regular expression motif elicitation (DREME) identified key promoter motifs highly correlated with the temporal regulation of ccgs. Correlations between ccg abundance from RNA-Seq, the degree of ccg-promoter activation as reported by ccg-promoter–luciferase fusions, and binding of WCC as measured by ChIP-Seq, are not strong. Therefore, although circadian activation is critical to ccg rhythmicity, posttranscriptional regulation plays a major role in determining rhythmicity at the mRNA level. PMID:25362047

  5. PPARγ regulates the expression of cholesterol metabolism genes in alveolar macrophages

    International Nuclear Information System (INIS)

    Baker, Anna D.; Malur, Anagha; Barna, Barbara P.; Kavuru, Mani S.; Malur, Achut G.; Thomassen, Mary Jane

    2010-01-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear transcription factor involved in lipid metabolism that is constitutively expressed in the alveolar macrophages of healthy individuals. PPARγ has recently been implicated in the catabolism of surfactant by alveolar macrophages, specifically the cholesterol component of surfactant while the mechanism remains unclear. Studies from other tissue macrophages have shown that PPARγ regulates cholesterol influx, efflux, and metabolism. PPARγ promotes cholesterol efflux through the liver X receptor-alpha (LXRα) and ATP-binding cassette G1 (ABCG1). We have recently shown that macrophage-specific PPARγ knockout (PPARγ KO) mice accumulate cholesterol-laden alveolar macrophages that exhibit decreased expression of LXRα and ABCG1 and reduced cholesterol efflux. We hypothesized that in addition to the dysregulation of these cholesterol efflux genes, the expression of genes involved in cholesterol synthesis and influx was also dysregulated and that replacement of PPARγ would restore regulation of these genes. To investigate this hypothesis, we have utilized a Lentivirus expression system (Lenti-PPARγ) to restore PPARγ expression in the alveolar macrophages of PPARγ KO mice. Our results show that the alveolar macrophages of PPARγ KO mice have decreased expression of key cholesterol synthesis genes and increased expression of cholesterol receptors CD36 and scavenger receptor A-I (SRA-I). The replacement of PPARγ (1) induced transcription of LXRα and ABCG1; (2) corrected suppressed expression of cholesterol synthesis genes; and (3) enhanced the expression of scavenger receptors CD36. These results suggest that PPARγ regulates cholesterol metabolism in alveolar macrophages.

  6. PPAR{gamma} regulates the expression of cholesterol metabolism genes in alveolar macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Baker, Anna D.; Malur, Anagha; Barna, Barbara P.; Kavuru, Mani S. [Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, East Carolina University (United States); Malur, Achut G. [Department of Microbiology and Immunology, East Carolina University (United States); Thomassen, Mary Jane, E-mail: thomassenm@ecu.edu [Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, East Carolina University (United States); Department of Microbiology and Immunology, East Carolina University (United States)

    2010-03-19

    Peroxisome proliferator-activated receptor-gamma (PPAR{gamma}) is a nuclear transcription factor involved in lipid metabolism that is constitutively expressed in the alveolar macrophages of healthy individuals. PPAR{gamma} has recently been implicated in the catabolism of surfactant by alveolar macrophages, specifically the cholesterol component of surfactant while the mechanism remains unclear. Studies from other tissue macrophages have shown that PPAR{gamma} regulates cholesterol influx, efflux, and metabolism. PPAR{gamma} promotes cholesterol efflux through the liver X receptor-alpha (LXR{alpha}) and ATP-binding cassette G1 (ABCG1). We have recently shown that macrophage-specific PPAR{gamma} knockout (PPAR{gamma} KO) mice accumulate cholesterol-laden alveolar macrophages that exhibit decreased expression of LXR{alpha} and ABCG1 and reduced cholesterol efflux. We hypothesized that in addition to the dysregulation of these cholesterol efflux genes, the expression of genes involved in cholesterol synthesis and influx was also dysregulated and that replacement of PPAR{gamma} would restore regulation of these genes. To investigate this hypothesis, we have utilized a Lentivirus expression system (Lenti-PPAR{gamma}) to restore PPAR{gamma} expression in the alveolar macrophages of PPAR{gamma} KO mice. Our results show that the alveolar macrophages of PPAR{gamma} KO mice have decreased expression of key cholesterol synthesis genes and increased expression of cholesterol receptors CD36 and scavenger receptor A-I (SRA-I). The replacement of PPAR{gamma} (1) induced transcription of LXR{alpha} and ABCG1; (2) corrected suppressed expression of cholesterol synthesis genes; and (3) enhanced the expression of scavenger receptors CD36. These results suggest that PPAR{gamma} regulates cholesterol metabolism in alveolar macrophages.

  7. Matrix rigidity regulates cancer cell growth by modulating cellular metabolism and protein synthesis.

    Directory of Open Access Journals (Sweden)

    Robert W Tilghman

    Full Text Available Tumor cells in vivo encounter diverse types of microenvironments both at the site of the primary tumor and at sites of distant metastases. Understanding how the various mechanical properties of these microenvironments affect the biology of tumor cells during disease progression is critical in identifying molecular targets for cancer therapy.This study uses flexible polyacrylamide gels as substrates for cell growth in conjunction with a novel proteomic approach to identify the properties of rigidity-dependent cancer cell lines that contribute to their differential growth on soft and rigid substrates. Compared to cells growing on more rigid/stiff substrates (>10,000 Pa, cells on soft substrates (150-300 Pa exhibited a longer cell cycle, due predominantly to an extension of the G1 phase of the cell cycle, and were metabolically less active, showing decreased levels of intracellular ATP and a marked reduction in protein synthesis. Using stable isotope labeling of amino acids in culture (SILAC and mass spectrometry, we measured the rates of protein synthesis of over 1200 cellular proteins under growth conditions on soft and rigid/stiff substrates. We identified cellular proteins whose syntheses were either preferentially inhibited or preserved on soft matrices. The former category included proteins that regulate cytoskeletal structures (e.g., tubulins and glycolysis (e.g., phosphofructokinase-1, whereas the latter category included proteins that regulate key metabolic pathways required for survival, e.g., nicotinamide phosphoribosyltransferase, a regulator of the NAD salvage pathway.The cellular properties of rigidity-dependent cancer cells growing on soft matrices are reminiscent of the properties of dormant cancer cells, e.g., slow growth rate and reduced metabolism. We suggest that the use of relatively soft gels as cell culture substrates would allow molecular pathways to be studied under conditions that reflect the different mechanical

  8. MicroRNA-mediated regulation of glutathione and methionine metabolism and its relevance for liver disease.

    Science.gov (United States)

    Lu, Shelly C; Mato, José M; Espinosa-Diez, Cristina; Lamas, Santiago

    2016-11-01

    The discovery of the microRNA (miRNA) family of small RNAs as fundamental regulators of post-transcriptional gene expression has fostered research on their importance in every area of biology and clinical medicine. In the particular area of liver metabolism and disease, miRNAs are gaining increasing importance. By focusing on two fundamental hepatic biosynthetic pathways, glutathione and methionine, we review recent advances on the comprehension of the role of miRNAs in liver pathophysiology and more specifically of models of hepatic cholestasis/fibrosis and hepatocellular carcinoma. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism.

    Science.gov (United States)

    Dienel, Gerald A; Cruz, Nancy F

    2016-07-01

    Aerobic glycolysis occurs during brain activation and is characterized by preferential up-regulation of glucose utilization compared with oxygen consumption even though oxygen level and delivery are adequate. Aerobic glycolysis is a widespread phenomenon that underlies energetics of diverse brain activities, such as alerting, sensory processing, cognition, memory, and pathophysiological conditions, but specific cellular functions fulfilled by aerobic glycolysis are poorly understood. Evaluation of evidence derived from different disciplines reveals that aerobic glycolysis is a complex, regulated phenomenon that is prevented by propranolol, a non-specific β-adrenoceptor antagonist. The metabolic pathways that contribute to excess utilization of glucose compared with oxygen include glycolysis, the pentose phosphate shunt pathway, the malate-aspartate shuttle, and astrocytic glycogen turnover. Increased lactate production by unidentified cells, and lactate dispersal from activated cells and lactate release from the brain, both facilitated by astrocytes, are major factors underlying aerobic glycolysis in subjects with low blood lactate levels. Astrocyte-neuron lactate shuttling with local oxidation is minor. Blockade of aerobic glycolysis by propranolol implicates adrenergic regulatory processes including adrenal release of epinephrine, signaling to brain via the vagus nerve, and increased norepinephrine release from the locus coeruleus. Norepinephrine has a powerful influence on astrocytic metabolism and glycogen turnover that can stimulate carbohydrate utilization more than oxygen consumption, whereas β-receptor blockade 're-balances' the stoichiometry of oxygen-glucose or -carbohydrate metabolism by suppressing glucose and glycogen utilization more than oxygen consumption. This conceptual framework may be helpful for design of future studies to elucidate functional roles of preferential non-oxidative glucose utilization and glycogen turnover during brain

  10. Building Responsive and Responsible Financial Regulators in the Aftermath of the Global Financial Crisis

    NARCIS (Netherlands)

    Iglesias Rodriguez, P.

    2015-01-01

    The global financial crisis that started in 2007 sparked several academic debates about the role that financial sector regulators played in the crisis and prompted policy reforms in the financial supervision architectures of several countries. This book focuses on the question of what

  11. More to NAD+ than meets the eye: A regulator of metabolic pools and gene expression in Arabidopsis.

    Science.gov (United States)

    Gakière, Bertrand; Fernie, Alisdair R; Pétriacq, Pierre

    2018-01-05

    Since its discovery more than a century ago, nicotinamide adenine dinucleotide (NAD + ) is recognised as a fascinating cornerstone of cellular metabolism. This ubiquitous energy cofactor plays vital roles in metabolic pathways and regulatory processes, a fact emphasised by the essentiality of a balanced NAD + metabolism for normal plant growth and development. Research on the role of NAD in plants has been predominantly carried out in the model plant Arabidopsis thaliana (Arabidopsis) with emphasis on the redox properties and cellular signalling functions of the metabolite. This review examines the current state of knowledge concerning how NAD can regulate both metabolic pools and gene expression in Arabidopsis. Particular focus is placed on recent studies highlighting the complexity of metabolic regulations involving NAD, more particularly in the mitochondrial compartment, and of signalling roles with respect to interactions with environmental fluctuations most specifically those involving plant immunity. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Global Metabolic Stress of Isoeffort Continuous and High Intensity Interval Aerobic Exercise: A Comparative 1H NMR Metabonomic Study.

    Science.gov (United States)

    Zafeiridis, Andreas; Chatziioannou, Anastasia Chrysovalantou; Sarivasiliou, Haralambos; Kyparos, Antonios; Nikolaidis, Michalis G; Vrabas, Ioannis S; Pechlivanis, Alexandros; Zoumpoulakis, Panagiotis; Baskakis, Constantinos; Dipla, Konstantina; Theodoridis, Georgios A

    2016-12-02

    The overall metabolic/energetic stress that occurs during an acute bout of exercise is proposed to be the main driving force for long-term training adaptations. Continuous and high-intensity interval exercise protocols (HIIE) are currently prescribed to acquire the muscular and metabolic benefits of aerobic training. We applied 1 H NMR-based metabonomics to compare the overall metabolic perturbation and activation of individual bioenergetic pathways of three popular aerobic exercises matched for effort/strain. Nine men performed continuous, long-interval (3 min), and short-interval (30 s) bouts of exercise under isoeffort conditions. Blood was collected before and after exercise. The multivariate PCA and OPLS-DA models showed a distinct separation of pre- and postexercise samples in three protocols. The two models did not discriminate the postexercise overall metabolic profiles of the three exercise types. Analysis focused on muscle bioenergetic pathways revealed an extensive upregulation of carbohydrate-lipid metabolism and the TCA cycle in all three protocols; there were only a few differences among protocols in the postexercise abundance of molecules when long-interval bouts were performed. In conclusion, continuous and HIIE exercise protocols, when performed with similar effort/strain, induce comparable global metabolic response/stress despite their marked differences in work-bout intensities. This study highlights the importance of NMR metabonomics in comprehensive monitoring of metabolic consequences of exercise training in the blood of athletes and exercising individuals.

  13. Fairness through regulation? Reflections on a cosmopolitan approach to global finance

    Directory of Open Access Journals (Sweden)

    Marta Božina Beroš

    2013-11-01

    Full Text Available In the aftermath of the last financial crisis a strong message prevails that ‘something’ has to be changed in the manner global finance is governed. What exactly this ‘something’ entails and what could constitute the ‘common ground’ of anticipated change is more difficult to determine. Many envisage future improvements of global financial governance by evoking deliberative democracy, political equality and cosmopolitanism. As financial regulation is the main instrument through which global finance is shaped and governed nowadays, these principles should then be transmitted to regulatory arrangements. This paper focuses on a new conceptual approach to regulatory and governance issues in global finance, by employing the philosophical idea of cosmopolitanism. It argues that although as a concept, cosmopolitanism cannot mitigate all the flaws attributed to contemporary finance, its development and extension to international financial regulation that is promulgated by institutions of the global financial system, would represent a worthwhile endeavour in making global finance more accountable and just in the eyes of many.

  14. A Natural Light/Dark Cycle Regulation of Carbon-Nitrogen Metabolism and Gene Expression in Rice Shoots.

    Science.gov (United States)

    Li, Haixing; Liang, Zhijun; Ding, Guangda; Shi, Lei; Xu, Fangsen; Cai, Hongmei

    2016-01-01

    Light and temperature are two particularly important environmental cues for plant survival. Carbon and nitrogen are two essential macronutrients required for plant growth and development, and cellular carbon and nitrogen metabolism must be tightly coordinated. In order to understand how the natural light/dark cycle regulates carbon and nitrogen metabolism in rice plants, we analyzed the photosynthesis, key carbon-nitrogen metabolites, and enzyme activities, and differentially expressed genes and miRNAs involved in the carbon and nitrogen metabolic pathway in rice shoots at the following times: 2:00, 6:00, 10:00, 14:00, 18:00, and 22:00. Our results indicated that more CO2 was fixed into carbohydrates by a high net photosynthetic rate, respiratory rate, and stomatal conductance in the daytime. Although high levels of the nitrate reductase activity, free ammonium and carbohydrates were exhibited in the daytime, the protein synthesis was not significantly facilitated by the light and temperature. In mRNA sequencing, the carbon and nitrogen metabolism-related differentially expressed genes were obtained, which could be divided into eight groups: photosynthesis, TCA cycle, sugar transport, sugar metabolism, nitrogen transport, nitrogen reduction, amino acid metabolism, and nitrogen regulation. Additionally, a total of 78,306 alternative splicing events have been identified, which primarily belong to alternative 5' donor sites, alternative 3' acceptor sites, intron retention, and exon skipping. In sRNA sequencing, four carbon and nitrogen metabolism-related miRNAs (osa-miR1440b, osa-miR2876-5p, osa-miR1877 and osa-miR5799) were determined to be regulated by natural light/dark cycle. The expression level analysis showed that the four carbon and nitrogen metabolism-related miRNAs negatively regulated their target genes. These results may provide a good strategy to study how natural light/dark cycle regulates carbon and nitrogen metabolism to ensure plant growth and

  15. Skeletal muscle interleukin-6 regulates metabolic factors in iWAT during HFD and exercise training

    DEFF Research Database (Denmark)

    Knudsen, Jakob Grunnet; Bertholdt, Lærke; Joensen, Ella

    2015-01-01

    in combination with exercise training (HFD ExTr) for 16 weeks. RESULTS: Total fat mass increased (P mass than HFD Floxed mice. Accordingly, iWAT glucose transporter 4 (GLUT4) protein content, 5'AMP......OBJECTIVE: To investigate the role of skeletal muscle (SkM) interleukin (IL)-6 in the regulation of adipose tissue metabolism. METHODS: Muscle-specific IL-6 knockout (IL-6 MKO) and IL-6(loxP/loxP) (Floxed) mice were subjected to standard rodent diet (Chow), high-fat diet (HFD), or HFD.......05) in HFD IL-6 MKO than HFD Floxed mice, and pyruvate dehydrogenase E1α (PDH-E1α) protein content was higher (P mass through regulation of glucose uptake capacity as well as lipogenic...

  16. Metabolism

    Science.gov (United States)

    ... lin), which signals cells to increase their anabolic activities. Metabolism is a complicated chemical process, so it's not ... how those enzymes or hormones work. When the metabolism of body chemicals is ... Hyperthyroidism (pronounced: hi-per-THIGH-roy-dih-zum). Hyperthyroidism ...

  17. Globalization of the energy sector - a U.S. regulator`s perspective

    Energy Technology Data Exchange (ETDEWEB)

    Kallaur, Carolita [Offshore Minerals Management, U.S. Department of the Interior (United States)

    1998-12-01

    This publication relates to globalization of the energy sector addressing issues of significant importance to the United States. The author touches upon a number of activities MMS (Mineral Management Service) is involved in with a focus on a joint project being engaged in with NPD (Norwegian Petroleum Directorate) to help the Russian Federation develop a safety and environment regime for its offshore. The aim of the project are national standards that set requirements for local and regional governments, safety and environment requirements that conform to international standards, apply to both Russian and foreign firms, and sharing of best practices between NPD, MMS and Russian authorities

  18. Fungal Morphology, Iron Homeostasis, and Lipid Metabolism Regulated by a GATA Transcription Factor in Blastomyces dermatitidis.

    Directory of Open Access Journals (Sweden)

    Amber J Marty

    2015-06-01

    Full Text Available In response to temperature, Blastomyces dermatitidis converts between yeast and mold forms. Knowledge of the mechanism(s underlying this response to temperature remains limited. In B. dermatitidis, we identified a GATA transcription factor, SREB, important for the transition to mold. Null mutants (SREBΔ fail to fully complete the conversion to mold and cannot properly regulate siderophore biosynthesis. To capture the transcriptional response regulated by SREB early in the phase transition (0-48 hours, gene expression microarrays were used to compare SREB∆ to an isogenic wild type isolate. Analysis of the time course microarray data demonstrated SREB functioned as a transcriptional regulator at 37°C and 22°C. Bioinformatic and biochemical analyses indicated SREB was involved in diverse biological processes including iron homeostasis, biosynthesis of triacylglycerol and ergosterol, and lipid droplet formation. Integration of microarray data, bioinformatics, and chromatin immunoprecipitation identified a subset of genes directly bound and regulated by SREB in vivo in yeast (37°C and during the phase transition to mold (22°C. This included genes involved with siderophore biosynthesis and uptake, iron homeostasis, and genes unrelated to iron assimilation. Functional analysis suggested that lipid droplets were actively metabolized during the phase transition and lipid metabolism may contribute to filamentous growth at 22°C. Chromatin immunoprecipitation, RNA interference, and overexpression analyses suggested that SREB was in a negative regulatory circuit with the bZIP transcription factor encoded by HAPX. Both SREB and HAPX affected morphogenesis at 22°C; however, large changes in transcript abundance by gene deletion for SREB or strong overexpression for HAPX were required to alter the phase transition.

  19. Transcriptome analysis of temporal regulation of carbon metabolism by CcpA in Bacillus subtilis reveals additional target genes

    NARCIS (Netherlands)

    Lulko, Andrzej T.; Buist, Girbe; Kok, Jan; Kuipers, Oscar P.

    2007-01-01

    The pleiotropic regulator of carbon metabolism in Grampositive bacteria, CcpA, regulates gene expression by binding to so-called cre elements, which are located either upstream or in promoter regions, or in open-reading frames. In this study we compared the transcriptomes of Bacillus subtilis 168

  20. Hormonal regulation of lipid metabolism in developing coho salmon, Oncorhynchus kisutch

    International Nuclear Information System (INIS)

    Sheridan, M.A.

    1985-01-01

    Lipid metabolism in juvenile coho salmon is characterized, and adaptive changes in lipid mobilization are described in relation to development and hormonal influences. The rates of lipogenesis and lipolysis were determined in selected tissues of juvenile salmon during the period of seawater preadaptive development (smoltification). Neutral lipid (sterol) and fatty acid synthesis in the liver and mesenteric fat was measured by tritium incorporation. Fatty acid synthesis in the liver and mesenteric fat decreased by 88% and 81%, respectively, between late February (parr) and early June (smolt). To assess the role of hormones in smoltification-associated lipid depletion, growth hormone, prolactin, thyroxin and cortisol were administered in vivo early in development (parr) to determine if any of these factors could initiate the metabolic responses normally seen later in development (smolt). Growth hormone stimulated lipid mobilization from coho salmon parr. Prolactin strongly stimulated lipid mobilization in coho parr. Thyroxin and cortisol also stimulated lipid mobilization for coho salmon parr. The direct effect of hormones was studied by in vitro pH-stat incubation of liver slices. These data suggest that norepinephrine stimulates fatty acid release via β-adrenergic pathways. Somatostatin and its partial analogue from the fish caudal neurosecretory system, urotensin II, also affect lipid mobilization. These results establish the presence of hormone-sensitive lipase in salmon liver and suggest that the regulation of lipid metabolism in salmon involves both long-acting and short-acting hormonal agents

  1. Pre- and post-natal nutritional factors in the metabolic regulation of obesity

    Directory of Open Access Journals (Sweden)

    E. Villanueva-Ortega

    2017-04-01

    Full Text Available In recent decades there has been a very significant increase in obesity in most developing countries. In addition to environmental, genetic and hormonal factors, nutritional and maternal environment factors influencing critical periods of foetal development have acquired increasing significance since the thrifty phenotype theory was described by Harles and Barker and epidemiological studies demonstrated that perinatal conditions may modify individuals’ future metabolic responses via genomic reprogramming. Perinatal programming corresponds to a critical and accelerated period of developmental plasticity from preconception through early postnatal life. This characteristic may also have a long-term influence on metabolic health and obesity. Epigenetic modifications favour the survival of the individual in critical periods when nutritional restriction is established, but exerts long-term risks, as metabolic programming tracks into infancy and adulthood and induces fat mass accumulation, particularly if energy consumption is exceeded. Although the mechanisms are not yet fully understood, it is evident that hormonal factors such as insulin and leptin may influence the programming of hypothalamic circuits for energy balance regulation. Nutritional interventions in animal models at critical stages of development have demonstrated that microenvironmental modifications might induce a permanent modulation of the progeny genome expression via epigenetic mechanisms. A transgenerational transmission of obesity has been proposed.

  2. Endocrine regulation of fetal skeletal muscle growth: impact on future metabolic health

    Science.gov (United States)

    Brown, Laura D.

    2014-01-01

    Establishing sufficient skeletal muscle mass is essential for lifelong metabolic health. The intrauterine environment is a major determinant of the muscle mass that is present for the life course of an individual, because muscle fiber number is set at the time of birth. Thus, a compromised intrauterine environment from maternal nutrient restriction or placental insufficiency that restricts development of muscle fiber number can have permanent effects on the amount of muscle an individual will live with. Reduced muscle mass due to fewer muscle fibers persists even after compensatory or “catch up” postnatal growth occurs. Furthermore, muscle hypertrophy can only partially compensate for this limitation in fiber number. Compelling associations link low birth weight and decreased muscle mass to future insulin resistance, which can drive the development of the metabolic syndrome and type 2 diabetes, and risk for cardiovascular events later in life. There are gaps in knowledge about the origins of reduced muscle growth at the cellular level and how these patterns are set during fetal development. By understanding the nutrient and endocrine regulation of fetal skeletal muscle growth and development, we can direct research efforts towards improving muscle growth early in life in order to prevent the development of chronic metabolic disease later in life. PMID:24532817

  3. Regulation of neurotrophic factors and energy metabolism by antidepressants in astrocytes

    KAUST Repository

    Martin, Jean Luc; Magistretti, Pierre J.; Allaman, Igor

    2013-01-01

    There is growing evidence that astrocytes are involved in the neuropathology of major depression. In particular, decreases in glial cell density observed in the cerebral cortex of individuals with major depressive disorder are accompanied by a reduction of several astrocytic markers suggesting that astrocyte dysfunction may contribute to the pathophysiology of major depression. In rodents, glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors and antidepressant treatment prevents the stress-induced reduction of astrocyte number in the hippocampus. Collectively, these data support the existence of a link between astrocyte loss or dysfunction, depressive-like behavior and antidepressant treatment. Astrocytes are increasingly recognized to play important roles in neuronal development, neurotransmission, synaptic plasticity and maintenance of brain homeostasis. It is also well established that astrocytes provide trophic, structural, and metabolic support to neurons. In this article, we review evidence that antidepressants regulate energy metabolism and neurotrophic factor expression with particular emphasis on studies in astrocytes. These observations support a role for astrocytes as new targets for antidepressants. The contribution of changes in astrocyte glucose metabolism and neurotrophic factor expression to the therapeutic effects of antidepressants remains to be established. © 2013 Bentham Science Publishers.

  4. Transcriptional Regulation and the Diversification of Metabolism in Wine Yeast Strains

    Science.gov (United States)

    Rossouw, Debra; Jacobson, Dan; Bauer, Florian F.

    2012-01-01

    Transcription factors and their binding sites have been proposed as primary targets of evolutionary adaptation because changes to single transcription factors can lead to far-reaching changes in gene expression patterns. Nevertheless, there is very little concrete evidence for such evolutionary changes. Industrial wine yeast strains, of the species Saccharomyces cerevisiae, are a geno- and phenotypically diverse group of organisms that have adapted to the ecological niches of industrial winemaking environments and have been selected to produce specific styles of wine. Variation in transcriptional regulation among wine yeast strains may be responsible for many of the observed differences and specific adaptations to different fermentative conditions in the context of commercial winemaking. We analyzed gene expression profiles of wine yeast strains to assess the impact of transcription factor expression on metabolic networks. The data provide new insights into the molecular basis of variations in gene expression in industrial strains and their consequent effects on metabolic networks important to wine fermentation. We show that the metabolic phenotype of a strain can be shifted in a relatively predictable manner by changing expression levels of individual transcription factors, opening opportunities to modify transcription networks to achieve desirable outcomes. PMID:22042577

  5. Adiponectin activates the AMPK signaling pathway to regulate lipid metabolism in bovine hepatocytes.

    Science.gov (United States)

    Chen, Hui; Zhang, Liang; Li, Xinwei; Li, Xiaobing; Sun, Guoquan; Yuan, Xue; Lei, Liancheng; Liu, Juxiong; Yin, Liheng; Deng, Qinghua; Wang, Jianguo; Liu, Zhaoxi; Yang, Wentao; Wang, Zhe; Zhang, Hui; Liu, Guowen

    2013-11-01

    Adiponectin (Ad) plays a crucial role in hepatic lipid metabolism. However, the regulating mechanism of hepatic lipid metabolism by Ad in dairy cows is unclear. Hepatocytes from a newborn female calf were cultured in vitro and treated with different concentrations of Ad and BML-275 (an AMPKα inhibitor). The results showed that Ad significantly increased the expression of two Ad receptors. Furthermore, the phosphorylation and activity of AMPKα, as well as the expression levels and transcriptional activity of peroxisome proliferator activated receptor-α (PPARα) and its target genes involved in lipid oxidation, showed a corresponding trend of upregulation. However, the expression levels and transcriptional activity of sterol regulatory element binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP) decreased in a similar manner. When BML-275 was added, the p-AMPKα level as well as the expression and activity of PPARα and its target genes were significantly decreased. However, the expression levels of SREBP-1c, ChREBP and their target genes showed a trend of upregulation. Furthermore, the triglyceride (TG) content was significantly decreased in the Ad-treated groups. These results indicate that Ad activates the AMPK signaling pathway and mediates lipid metabolism in bovine hepatocytes cultured in vitro by promoting lipid oxidation, suppressing lipid synthesis and reducing hepatic lipid accumulation. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Role of the Irr protein in the regulation of iron metabolism in Rhodobacter sphaeroides.

    Directory of Open Access Journals (Sweden)

    Verena Peuser

    Full Text Available In Rhizobia the Irr protein is an important regulator for iron-dependent gene expression. We studied the role of the Irr homolog RSP_3179 in the photosynthetic alpha-proteobacterium Rhodobacter sphaeroides. While Irr had little effect on growth under iron-limiting or non-limiting conditions its deletion resulted in increased resistance to hydrogen peroxide and singlet oxygen. This correlates with an elevated expression of katE for catalase in the Irr mutant compared to the wild type under non-stress conditions. Transcriptome studies revealed that Irr affects the expression of genes for iron metabolism, but also has some influence on genes involved in stress response, citric acid cycle, oxidative phosphorylation, transport, and photosynthesis. Most genes showed higher expression levels in the wild type than in the mutant under normal growth conditions indicating an activator function of Irr. Irr was however not required to activate genes of the iron metabolism in response to iron limitation, which showed even stronger induction in the absence of Irr. This was also true for genes mbfA and ccpA, which were verified as direct targets for Irr. Our results suggest that in R. sphaeroides Irr diminishes the strong induction of genes for iron metabolism under iron starvation.

  7. Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels

    Science.gov (United States)

    Liu, Jinfeng; Dong, Huansheng; Zhang, Yong; Cao, Mingjun; Song, Lili; Pan, Qingjie; Bulmer, Andrew; Adams, David B.; Dong, Xiao; Wang, Hongjun

    2015-01-01

    Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice. PMID:26017184

  8. The metabolic sensors FXRα, PGC-1α, and SIRT1 cooperatively regulate hepatitis B virus transcription.

    Science.gov (United States)

    Curtil, Claire; Enache, Liviu S; Radreau, Pauline; Dron, Anne-Gaëlle; Scholtès, Caroline; Deloire, Alexandre; Roche, Didier; Lotteau, Vincent; André, Patrice; Ramière, Christophe

    2014-03-01

    Hepatitis B virus (HBV) genome transcription is highly dependent on liver-enriched, metabolic nuclear receptors (NRs). Among others, NR farnesoid X receptor α (FXRα) enhances HBV core promoter activity and pregenomic RNA synthesis. Interestingly, two food-withdrawal-induced FXRα modulators, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and deacetylase SIRT1, have been found to be associated with HBV genomes ex vivo. Whereas PGC-1α induction was shown to increase HBV replication, the effect of SIRT1 on HBV transcription remains unknown. Here, we showed that, in hepatocarcinoma-derived Huh-7 cells, combined activation of FXRα by GW4064 and SIRT1 by activator 3 increased HBV core promoter-controlled luciferase expression by 25-fold, compared with a 10-fold increase with GW4064 alone. Using cell lines differentially expressing FXRα in overexpression and silencing experiments, we demonstrated that SIRT1 activated the core promoter in an FXRα- and PGC-1α-dependent manner. Maximal activation (>150-fold) was observed in FXRα- and PGC-1α-overexpressing Huh-7 cells treated with FXRα and SIRT1 activators. Similarly, in cells transfected with full-length HBV genomes, maximal induction (3.5-fold) of core promoter-controlled synthesis of 3.5-kb RNA was observed in the same conditions of transfection and treatments. Thus, we identified a subnetwork of metabolic factors regulating HBV replication, strengthening the hypothesis that transcription of HBV and metabolic genes is similarly controlled.

  9. Regulation of neurotrophic factors and energy metabolism by antidepressants in astrocytes

    KAUST Repository

    Martin, Jean Luc

    2013-09-01

    There is growing evidence that astrocytes are involved in the neuropathology of major depression. In particular, decreases in glial cell density observed in the cerebral cortex of individuals with major depressive disorder are accompanied by a reduction of several astrocytic markers suggesting that astrocyte dysfunction may contribute to the pathophysiology of major depression. In rodents, glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors and antidepressant treatment prevents the stress-induced reduction of astrocyte number in the hippocampus. Collectively, these data support the existence of a link between astrocyte loss or dysfunction, depressive-like behavior and antidepressant treatment. Astrocytes are increasingly recognized to play important roles in neuronal development, neurotransmission, synaptic plasticity and maintenance of brain homeostasis. It is also well established that astrocytes provide trophic, structural, and metabolic support to neurons. In this article, we review evidence that antidepressants regulate energy metabolism and neurotrophic factor expression with particular emphasis on studies in astrocytes. These observations support a role for astrocytes as new targets for antidepressants. The contribution of changes in astrocyte glucose metabolism and neurotrophic factor expression to the therapeutic effects of antidepressants remains to be established. © 2013 Bentham Science Publishers.

  10. Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.

    Science.gov (United States)

    Guitart, Amelie V; Panagopoulou, Theano I; Villacreces, Arnaud; Vukovic, Milica; Sepulveda, Catarina; Allen, Lewis; Carter, Roderick N; van de Lagemaat, Louie N; Morgan, Marcos; Giles, Peter; Sas, Zuzanna; Gonzalez, Marta Vila; Lawson, Hannah; Paris, Jasmin; Edwards-Hicks, Joy; Schaak, Katrin; Subramani, Chithra; Gezer, Deniz; Armesilla-Diaz, Alejandro; Wills, Jimi; Easterbrook, Aaron; Coman, David; So, Chi Wai Eric; O'Carroll, Donal; Vernimmen, Douglas; Rodrigues, Neil P; Pollard, Patrick J; Morton, Nicholas M; Finch, Andrew; Kranc, Kamil R

    2017-03-06

    Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specific Fh1 deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure. Reexpression of extramitochondrial Fh1 (which normalized fumarate levels but not maximal mitochondrial respiration) rescued these phenotypes, indicating the causal role of cellular fumarate accumulation. However, HSCs lacking mitochondrial Fh1 (which had normal fumarate levels but defective maximal mitochondrial respiration) failed to self-renew and displayed lymphoid differentiation defects. In contrast, leukemia-initiating cells lacking mitochondrial Fh1 efficiently propagated Meis1 / Hoxa9 -driven leukemia. Thus, we identify novel roles for fumarate metabolism in HSC maintenance and hematopoietic differentiation and reveal a differential requirement for mitochondrial Fh1 in normal hematopoiesis and leukemia propagation. © 2017 Guitart et al.

  11. Expansion of plants with Crassulacean Acid Metabolism under global environment change

    Science.gov (United States)

    Yu, K.; D'Odorico, P.; Collins, S. L.; Carr, D.

    2016-12-01

    The abundance of plants with Crassulacean Acid Metabolism (CAM) has increased in many drylands worldwide. This is hypothesized to occur because CAM plants store water, take up CO2 at night, exhibit photosynthetic plasticity, and have high water use efficiency. The increased dominance of CAM plants, however, also depends on their competitive relationship with other functional groups, an aspect of CAM plant sensitivity to global environmental change that has remained largely understudied. Here, we investigated the response of CAM plants and their competitive relationships with C3 and C4 plants under global environmental change. We focused on two pairs of CAM and non-CAM species, namely Cylindropuntia imbricata (a constitutive CAM species) and Bouteloua eriopoda (C4 grass), which co-occur in desert grasslands in northern Mexico, and invasive Mesembryanthemum crystallinum (a facultative CAM species) and Bromus mollis (a C3 invasive grass), which coexist in California's coastal grasslands. A set of growth chamber experiments under altered CO2 and water conditions show that C. imbricata outcompeted B. eriopoda under drought conditions, while in well-watered conditions B. eriopoda was a stronger competitor for soil water than C. imbricata. Under drought conditions a more positive response to CO2 enrichment by C. imbricata indirectly disfavored B. eriopoda, which suggests that interspecific competition can outweigh the favorable direct effect of CO2 enrichment on plant growth. A set of greenhouse experiments under water, N, and soil salinity manipulations showed that drought, N deposition, and/or increased soil salinity served as important drivers for success of M. crystallinum invasion, while B. mollis exerted strong competitive effects on M. crystallinum for light and soil nutrients in well-watered conditions. M. crystallinum switched from C3 photosynthesis to CAM photosynthesis as an adaptive strategy in response to moderate intensity of competition from B. mollis, in

  12. Regulation of neuron-astrocyte metabolic coupling across the sleep-wake cycle.

    Science.gov (United States)

    Petit, J-M; Magistretti, P J

    2016-05-26

    Over the last thirty years, a growing number of studies showed that astrocytes play a pivotal role in the energy support to synapses. More precisely, astrocytes adjust energy production to neuronal energy needs through different mechanisms grouped under the term "neurometabolic coupling" (NMC). In this review we describe these mechanisms of coupling and how they involve astrocytes. From a physiological point of view, these mechanisms of coupling are particularly important to ensure normal synaptic functioning when neurons undergo rapid and repetitive changes in the firing rate such as during the sleep/wake transitions. Investigations into brain energy metabolism during the sleep/wake cycle have been mainly focused on glucose (Gluc) consumption and on glycogen metabolism. However, the recent development of substrate-specific biosensors allowed measurements of the variation in extracellular levels of glutamate, Gluc and lactate (Lac) with a time resolution compatible with sleep stage duration. Together with gene expression data these experiments allowed to better define the variations of energy metabolite regulation across the sleep/wake cycle. The aim of this review is to bring into perspective the role of astrocytes and NMC in the regulation of the sleep/wake cycle. The data reviewed also suggest an important role of the astrocytic network. In addition, the role of astrocytes in NMC mechanisms is consistent with the "local and use dependent" sleep hypothesis. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. On the developmental and environmental regulation of secondary metabolism in Vaccinium spp. berries

    Directory of Open Access Journals (Sweden)

    Katja eKarppinen

    2016-05-01

    Full Text Available Secondary metabolites have important defense and signaling roles, and they contribute to the overall quality of developing and ripening fruits. Blueberries, bilberries, cranberries and other Vaccinium berries are fleshy berry fruits recognized for the high levels of bioactive compounds, especially anthocyanin pigments. Besides anthocyanins and other products of the phenylpropanoid and flavonoid pathways, these berries also contain other metabolites of interest, such as carotenoid derivatives, vitamins and flavor compounds. Recently, new information has been achieved on the mechanisms related with developmental, environmental and genetic factors involved in the regulation of secondary metabolism in Vaccinium fruits. Especially light conditions and temperature are demonstrated to have a prominent role on the composition of phenolic compounds. The present review focuses on the studies on mechanisms associated with the regulation of key secondary metabolites, mainly phenolic compounds, in Vaccinium berries. The advances in the research concerning biosynthesis of phenolic compounds in Vaccinium species, including specific studies with mutant genotypes in addition to controlled and field experiments on the genotype x environment (GxE interaction, are discussed. The recently published Vaccinium transcriptome and genome databases provide new tools for the studies on the metabolic routes.

  14. BIOCHEMICAL MARKERS OF BONE RESORPTION AND HORMONAL REGULATION OF BONE METABOLISM FOLLOWING LIVER TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    V. P. Buzulina

    2013-01-01

    Full Text Available Aim. Comparative evaluation of two biochemical markers of bone resorption and hormonal regulation of bone metabolism in liver recipients. Methods and results. Bоne densitometry of L2–L4 and neck of femur, serum level of some hormones (PTH, vitamin D3, estradiol, testosterone regulating osteoclastogenesis as well as com- parative analyses of two bone resorption markers β-crosslaps and tartrate-resistant acid phosphatase type 5b (TRAP-5b were fulfilled in patients after orthotopic liver transplantation (OLT. In 1 month after OLT bone density reduction of L2–L4 and neck of femur; decrease of vitamin D3, estradiol in women, testosterone in men and increase levels of bone resorption markers were observed. In 1 and 2 years after OLT the rise of bone density, increased levels of PTH, estradiol, testosterone and decreased β-crosslaps levels were revealed, while vitamin D3 and TRAP-5b levels remained stable. Conclusion. TRAP-5b was found to be a more speciffic marker of bone resorption, independent from collagen metabolism in liver. Osteoporosis defined in long-term period after OLT was associated with higher TRAP-5b and revialed in women with low estradiol level. 

  15. Concentrating carbohydrates before sleep improves feeding regulation and metabolic and inflammatory parameters in mice.

    Science.gov (United States)

    Sofer, Sigal; Eliraz, Abraham; Madar, Zecharia; Froy, Oren

    2015-10-15

    New evidance highlights the importance of food timing. Recently, we showed that a low-calorie diet with carbohydrates eaten mostly at dinner changed diurnal hormone secretion and led to greater weight loss and improved metabolic status in obese people. Herein, we set out to test whether concentrated-carbohydrates diet (CCD), in which carbohydrates are fed only before sleep, leads to an improved metabolic status in mouse hypothalamus and peripheral tissues. Diet-induced obese mice were given concentrated or distributed carbohydrate diet for 6 weeks. Obese mice fed CCD ate 8.3% less, were 9.3% leaner and had 39.7% less fat mass. Leptin, ghrelin and adiponectin displayed altered secretion. In addition, these mice exhibited an improved biochemical and inflammatory status. In the hypothalamus, anorexigenic signals were up-regulated and orexigenic signals were down-regulated. In peripheral tissues, CCD promoted adiponectin signaling, repressed gluconeogenesis, enhanced lipid oxidation and lowered inflammation, thus ameliorating the major risk factors of obesity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis.

    Science.gov (United States)

    Glover, Louise E; Bowers, Brittelle E; Saeedi, Bejan; Ehrentraut, Stefan F; Campbell, Eric L; Bayless, Amanda J; Dobrinskikh, Evgenia; Kendrick, Agnieszka A; Kelly, Caleb J; Burgess, Adrianne; Miller, Lauren; Kominsky, Douglas J; Jedlicka, Paul; Colgan, Sean P

    2013-12-03

    Mucosal surfaces of the lower gastrointestinal tract are subject to frequent, pronounced fluctuations in oxygen tension, particularly during inflammation. Adaptive responses to hypoxia are orchestrated largely by the hypoxia-inducible transcription factors (HIFs). As HIF-1α and HIF-2α are coexpressed in mucosal epithelia that constitute the barrier between the lumen and the underlying immune milieu, we sought to define the discrete contribution of HIF-1 and HIF-2 transactivation pathways to intestinal epithelial cell homeostasis. The present study identifies creatine kinases (CKs), key metabolic enzymes for rapid ATP generation via the phosphocreatine-creatine kinase (PCr/CK) system, as a unique gene family that is coordinately regulated by HIF. Cytosolic CKs are expressed in a HIF-2-dependent manner in vitro and localize to apical intestinal epithelial cell adherens junctions, where they are critical for junction assembly and epithelial integrity. Supplementation with dietary creatine markedly ameliorated both disease severity and inflammatory responses in colitis models. Further, enzymes of the PCr/CK metabolic shuttle demonstrate dysregulated mucosal expression in a subset of ulcerative colitis and Crohn disease patients. These findings establish a role for HIF-regulated CK in epithelial homeostasis and reveal a fundamental link between cellular bioenergetics and mucosal barrier.

  17. Regulation of metabolic health and adipose tissue function by group 2 innate lymphoid cells.

    Science.gov (United States)

    Cautivo, Kelly M; Molofsky, Ari B

    2016-06-01

    Adipose tissue (AT) is home to an abundance of immune cells. With chronic obesity, inflammatory immune cells accumulate and promote insulin resistance and the progression to type 2 diabetes mellitus. In contrast, recent studies have highlighted the regulation and function of immune cells in lean, healthy AT, including those associated with type 2 or "allergic" immunity. Although traditionally activated by infection with multicellular helminthes, AT type 2 immunity is active independently of infection, and promotes tissue homeostasis, AT "browning," and systemic insulin sensitivity, protecting against obesity-induced metabolic dysfunction and type 2 diabetes mellitus. In particular, group 2 innate lymphoid cells (ILC2s) are integral regulators of AT type 2 immunity, producing the cytokines interleukin-5 and IL-13, promoting eosinophils and alternatively activated macrophages, and cooperating with and promoting AT regulatory T (Treg) cells. In this review, we focus on the recent developments in our understanding of group 2 innate lymphoid cell cells and type 2 immunity in AT metabolism and homeostasis. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Role of sleep duration in the regulation of glucose metabolism and appetite.

    Science.gov (United States)

    Morselli, Lisa; Leproult, Rachel; Balbo, Marcella; Spiegel, Karine

    2010-10-01

    Sleep curtailment has become a common behavior in modern society. This review summarizes the current laboratory evidence indicating that sleep loss may contribute to the pathophysiology of diabetes mellitus and obesity. Experimentally induced sleep loss in healthy volunteers decreases insulin sensitivity without adequate compensation in beta-cell function, resulting in impaired glucose tolerance and increased diabetes risk. Lack of sleep also down-regulates the satiety hormone leptin, up-regulates the appetite-stimulating hormone ghrelin, and increases hunger and food intake. Taken together with the epidemiologic evidence for an association between short sleep and the prevalence or incidence of diabetes mellitus and/or obesity, these results support a role for reduced sleep duration in the current epidemic of these metabolic disorders. Screening for habitual sleep patterns in patients with "diabesity" is therefore of great importance. Studies are warranted to investigate the putative therapeutic impact of extending sleep in habitual short sleepers with metabolic disorders. Copyright © 2010 Elsevier Ltd. All rights reserved.

  19. Integrated proteomics and metabolomics suggests symbiotic metabolism and multimodal regulation in a fungal-endobacterial system.

    Science.gov (United States)

    Li, Zhou; Yao, Qiuming; Dearth, Stephen P; Entler, Matthew R; Castro Gonzalez, Hector F; Uehling, Jessie K; Vilgalys, Rytas J; Hurst, Gregory B; Campagna, Shawn R; Labbé, Jessy L; Pan, Chongle

    2017-03-01

    Many plant-associated fungi host endosymbiotic endobacteria with reduced genomes. While endobacteria play important roles in these tri-partite plant-fungal-endobacterial systems, the active physiology of fungal endobacteria has not been characterized extensively by systems biology approaches. Here, we use integrated proteomics and metabolomics to characterize the relationship between the endobacterium Mycoavidus sp. and the root-associated fungus Mortierella elongata. In nitrogen-poor media, M. elongata had decreased growth but hosted a large and growing endobacterial population. The active endobacterium likely extracted malate from the fungal host as the primary carbon substrate for energy production and biosynthesis of phospho-sugars, nucleobases, peptidoglycan and some amino acids. The endobacterium obtained nitrogen by importing a variety of nitrogen-containing compounds. Further, nitrogen limitation significantly perturbed the carbon and nitrogen flows in the fungal metabolic network. M. elongata regulated many pathways by concordant changes on enzyme abundances, post-translational modifications, reactant concentrations and allosteric effectors. Such multimodal regulations may be a general mechanism for metabolic modulation. © 2016 Society for Applied Microbiology and John Wiley & Sons Ltd.

  20. Regulation of Neuron-Astrocyte Metabolic Coupling across the Sleep-Wake Cycle

    KAUST Repository

    Petit, Jean-Marie

    2015-12-17

    Over the last thirty years, a growing number of studies showed that astrocytes play a pivotal role in the energy support to synapses. More precisely, astrocytes adjust the energy production to the neuronal energy needs through different mechanisms grouped under the term “neurometabolic coupling” (NMC). In this review we describe these mechanisms of coupling and how they involve astrocytes. From a physiological point of view, these mechanisms of coupling are particularly important to ensure normal synaptic functioning when neurons undergo rapid and repetitive changes in firing rate such as during the sleep/wake transitions. Investigations on brain energy metabolism during the sleep/wake cycle have been mainly focused on glucose consumption and on glycogen metabolism. However, the recent development of substrate-specific biosensors allowed measurements of the variation in extracellular levels of glutamate, glucose and lactate with a time resolution compatible with sleep stage duration. Together with gene expression data these experiments allowed to better define the variations of energy metabolites regulation across the sleep/wake cycle. The aim of this review is to bring into perspective the role of astrocytes and neurometabolic coupling in the regulation of the sleep/wake cycle. The data reviewed also suggest an important role of the astrocytic network. In addition, the role of astrocytes in NMC mechanisms is consistent with the “local and use dependent” sleep hypothesis.

  1. Selected regulation of gastrointestinal acid-base secretion and tissue metabolism for the diamondback water snake and Burmese python.

    Science.gov (United States)

    Secor, Stephen M; Taylor, Josi R; Grosell, Martin

    2012-01-01

    Snakes exhibit an apparent dichotomy in the regulation of gastrointestinal (GI) performance with feeding and fasting; frequently feeding species modestly regulate intestinal function whereas infrequently feeding species rapidly upregulate and downregulate intestinal function with the start and completion of each meal, respectively. The downregulatory response with fasting for infrequently feeding snakes is hypothesized to be a selective attribute that reduces energy expenditure between meals. To ascertain the links between feeding habit, whole-animal metabolism, and GI function and metabolism, we measured preprandial and postprandial metabolic rates and gastric and intestinal acid-base secretion, epithelial conductance and oxygen consumption for the frequently feeding diamondback water snake (Nerodia rhombifer) and the infrequently feeding Burmese python (Python molurus). Independent of body mass, Burmese pythons possess a significantly lower standard metabolic rate and respond to feeding with a much larger metabolic response compared with water snakes. While fasting, pythons cease gastric acid and intestinal base secretion, both of which are stimulated with feeding. In contrast, fasted water snakes secreted gastric acid and intestinal base at rates similar to those of digesting snakes. We observed no difference between fasted and fed individuals for either species in gastric or intestinal transepithelial potential and conductance, with the exception of a significantly greater gastric transepithelial potential for fed pythons at the start of titration. Water snakes experienced no significant change in gastric or intestinal metabolism with feeding. Fed pythons, in contrast, experienced a near-doubling of gastric metabolism and a tripling of intestinal metabolic rate. For fasted individuals, the metabolic rate of the stomach and small intestine was significantly lower for pythons than for water snakes. The fasting downregulation of digestive function for pythons is

  2. A Meta-Analysis of the Metabolic Syndrome Prevalence in the Global HIV-Infected Population.

    Directory of Open Access Journals (Sweden)

    Kim A Nguyen

    Full Text Available Cardio-metabolic risk factors are of increasing concern in HIV-infected individuals, particularly with the advent of antiretroviral therapy (ART and the subsequent rise in longevity. However, the prevalence of cardio-metabolic abnormalities in this population and the differential contribution, if any, of HIV specific factors to their distribution, are poorly understood. Therefore, we conducted a systematic review and meta-analysis to estimate the global prevalence of metabolic syndrome (MS in HIV-infected populations, its variation by the different diagnostic criteria, severity of HIV infection, ART used and other major predictive characteristics.We performed a comprehensive search on major databases for original research articles published between 1998 and 2015. The pooled overall prevalence as well as by specific groups and subgroups were computed using random effects models.A total of 65 studies across five continents comprising 55094 HIV-infected participants aged 17-73 years (median age 41 years were included in the final meta-analysis. The overall prevalence of MS according to the following criteria were: ATPIII-2001:16.7% (95%CI: 14.6-18.8, IDF-2005: 18% (95%CI: 14.0-22.4, ATPIII-2004-2005: 24.6% (95%CI: 20.6-28.8, Modified ATPIII-2005: 27.9% (95%CI: 6.7-56.5, JIS-2009: 29.6% (95%CI: 22.9-36.8, and EGIR: 31.3% (95%CI: 26.8-36.0. By some MS criteria, the prevalence was significantly higher in women than in men (IDF-2005: 23.2% vs. 13.4, p = 0.030, in ART compared to non-ART users (ATPIII-2001: 18.4% vs. 11.8%, p = 0.001, and varied significantly by participant age, duration of HIV diagnosis, severity of infection, non-nucleoside reverse transcriptase inhibitors (NNRTIs use and date of study publication. Across criteria, there were significant differences in MS prevalence by sub-groups such as in men, the Americas, older publications, regional studies, younger adults, smokers, ART-naïve participants, NNRTIs users, participants with shorter

  3. Effect of diosgenin on metabolic dysfunction: Role of ERβ in the regulation of PPARγ

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xin, E-mail: xinwang@fmmu.edu.cn [Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi' an 710032 (China); Liu, Jun [Department of Orthopedics, Lanzhou General Hospital of PLA, South Binhe Road, No. 333, Lanzhou 730050 (China); Long, Zi; Sun, Quangui [The First Student Brigade, Fourth Military Medical University, Xi' an, Shaanxi, 710032 (China); Liu, Ying; Wang, Lele; Zhang, Xiaodi [Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi' an 710032 (China); Hai, Chunxu, E-mail: cx-hai@fmmu.edu.cn [Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi' an 710032 (China)

    2015-12-01

    The present study was designed to investigate the effect of diosgenin (DSG) on metabolic dysfunction and to elucidate the possible molecular mechanisms. High fat (HF) diet-fed mice and 3T3-L1 preadipocytes was used to evaluate the effect of DSG. We showed that DSG attenuated metabolic dysfunction in HF diet-fed mice, as evidenced by reduction of blood glucose level and improvement of glucose and insulin intolerance. DSG ameliorated oxidative stress, reduced body weight, fat pads, and systematic lipid profiles and attenuated lipid accumulation. DSG inhibited 3T3-L1 adipocyte differentiation and reduced adipocyte size through regulating key factors. DSG inhibited PPARγ and its target gene expression both in differentiated 3T3-L1 adipocytes and fat tissues in HF diet-fed mice. Overexpression of PPARγ suppressed DSG-inhibited adipocyte differentiation. DSG significantly increased nuclear expression of ERβ. Inhibition of ERβ significantly suppressed DSG-exerted suppression of adipocyte differentiation and PPARγ expression. In response to DSG stimulation, ERβ bound with RXRα and dissociated RXRα from PPARγ, leading to the reduction of transcriptional activity of PPARγ. These data provide new insight into the mechanisms underlying the inhibitory effect of DSG on adipocyte differentiation and demonstrate that ERβ-exerted regulation of PPARγ expression and activity is critical for DSG-inhibited adipocyte differentiation. - Highlights: • Diosgenin (DSG) attenuated metabolic dysfunction in high fat (HF) diet-fed mice. • DSG reduced oxidative stress and lipid accumulation in HF diet-fed mice. • DSG inhibited 3T3-L1 adipocyte differentiation and reduced adipocyte size. • DSG induced the binding of ERβ with RXRα. • DSG-induced activation of ERβ dissociated RXRα from PPARγ and reduced PPARγ activity.

  4. Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models.

    Science.gov (United States)

    Bunik, Victoria I; Tylicki, Adam; Lukashev, Nikolay V

    2013-12-01

    Bringing a knowledge of enzymology into research in vivo and in situ is of great importance in understanding systems biology and metabolic regulation. The central metabolic significance of thiamin (vitamin B1 ) and its diphosphorylated derivative (thiamin diphosphate; ThDP), and the fundamental differences in the ThDP-dependent enzymes of metabolic networks in mammals versus plants, fungi and bacteria, or in health versus disease, suggest that these enzymes are promising targets for biotechnological and medical applications. Here, the in vivo action of known regulators of ThDP-dependent enzymes, such as synthetic structural analogs of the enzyme substrates and thiamin, is analyzed in light of the enzymological data accumulated during half a century of research. Mimicking the enzyme-specific catalytic intermediates, the phosphonate analogs of 2-oxo acids selectively inhibit particular ThDP-dependent enzymes. Because of their selectivity, use of these compounds in cellular and animal models of ThDP-dependent enzyme malfunctions improves the validity of the model and its predictive power when compared with the nonselective and enzymatically less characterized oxythiamin and pyrithiamin. In vitro studies of the interaction of thiamin analogs and their biological derivatives with potential in vivo targets are necessary to identify and attenuate the analog selectivity. For both the substrate and thiamin synthetic analogs, in vitro reactivities with potential targets are highly relevant in vivo. However, effective concentrations in vivo are often higher than in vitro studies would suggest. The significance of specific inihibition of the ThDP-dependent enzymes for the development of herbicides, antibiotics, anticancer and neuroprotective strategies is discussed. © 2013 FEBS.

  5. Effect of diosgenin on metabolic dysfunction: Role of ERβ in the regulation of PPARγ

    International Nuclear Information System (INIS)

    Wang, Xin; Liu, Jun; Long, Zi; Sun, Quangui; Liu, Ying; Wang, Lele; Zhang, Xiaodi; Hai, Chunxu

    2015-01-01

    The present study was designed to investigate the effect of diosgenin (DSG) on metabolic dysfunction and to elucidate the possible molecular mechanisms. High fat (HF) diet-fed mice and 3T3-L1 preadipocytes was used to evaluate the effect of DSG. We showed that DSG attenuated metabolic dysfunction in HF diet-fed mice, as evidenced by reduction of blood glucose level and improvement of glucose and insulin intolerance. DSG ameliorated oxidative stress, reduced body weight, fat pads, and systematic lipid profiles and attenuated lipid accumulation. DSG inhibited 3T3-L1 adipocyte differentiation and reduced adipocyte size through regulating key factors. DSG inhibited PPARγ and its target gene expression both in differentiated 3T3-L1 adipocytes and fat tissues in HF diet-fed mice. Overexpression of PPARγ suppressed DSG-inhibited adipocyte differentiation. DSG significantly increased nuclear expression of ERβ. Inhibition of ERβ significantly suppressed DSG-exerted suppression of adipocyte differentiation and PPARγ expression. In response to DSG stimulation, ERβ bound with RXRα and dissociated RXRα from PPARγ, leading to the reduction of transcriptional activity of PPARγ. These data provide new insight into the mechanisms underlying the inhibitory effect of DSG on adipocyte differentiation and demonstrate that ERβ-exerted regulation of PPARγ expression and activity is critical for DSG-inhibited adipocyte differentiation. - Highlights: • Diosgenin (DSG) attenuated metabolic dysfunction in high fat (HF) diet-fed mice. • DSG reduced oxidative stress and lipid accumulation in HF diet-fed mice. • DSG inhibited 3T3-L1 adipocyte differentiation and reduced adipocyte size. • DSG induced the binding of ERβ with RXRα. • DSG-induced activation of ERβ dissociated RXRα from PPARγ and reduced PPARγ activity.

  6. Global changes in transcription orchestrate metabolic differentiation during symbiotic nitrogen fixation in Lotus japonicus

    DEFF Research Database (Denmark)

    Colebatch, Gillian; Desbrosses, Guilhem; Ott, Thomas

    2004-01-01

    Research on legume nodule metabolism has contributed greatly to our knowledge of primary carbon and nitrogen metabolism in plants in general, and in symbiotic nitrogen fixation in particular. However, most previous studies focused on one or a few genes/enzymes involved in selected metabolic...

  7. A role for PPARα in the regulation of arginine metabolism and nitric oxide synthesis.

    Science.gov (United States)

    Guelzim, Najoua; Mariotti, François; Martin, Pascal G P; Lasserre, Frédéric; Pineau, Thierry; Hermier, Dominique

    2011-10-01

    The pleiotropic effects of PPARα may include the regulation of amino acid metabolism. Nitric oxide (NO) is a key player in vascular homeostasis. NO synthesis may be jeopardized by a differential channeling of arginine toward urea (via arginase) versus NO (via NO synthase, NOS). This was studied in wild-type (WT) and PPARα-null (KO) mice fed diets containing either saturated fatty acids (COCO diet) or 18:3 n-3 (LIN diet). Metabolic markers of arginine metabolism were assayed in urine and plasma. mRNA levels of arginases and NOS were determined in liver. Whole-body NO synthesis and the conversion of systemic arginine into urea were assessed by using (15)N(2)-guanido-arginine and measuring urinary (15)NO(3) and [(15)N]-urea. PPARα deficiency resulted in a markedly lower whole-body NO synthesis, whereas the conversion of systemic arginine into urea remained unaffected. PPARα deficiency also increased plasma arginine and decreased citrulline concentration in plasma. These changes could not be ascribed to a direct effect on hepatic target genes, since NOS mRNA levels were unaffected, and arginase mRNA levels decreased in KO mice. Despite the low level in the diet, the nature of the fatty acids modulated some effects of PPARα deficiency, including plasma arginine and urea, which increased more in KO mice fed the LIN diet than in those fed the COCO diet. In conclusion, PPARα is largely involved in normal whole-body NO synthesis. This warrants further study on the potential of PPARα activation to maintain NO synthesis in the initiation of the metabolic syndrome.

  8. Neuronal LRP1 regulates glucose metabolism and insulin signaling in the brain.

    Science.gov (United States)

    Liu, Chia-Chen; Hu, Jin; Tsai, Chih-Wei; Yue, Mei; Melrose, Heather L; Kanekiyo, Takahisa; Bu, Guojun

    2015-04-08

    Alzheimer's disease (AD) is a neurological disorder characterized by profound memory loss and progressive dementia. Accumulating evidence suggests that Type 2 diabetes mellitus, a metabolic disorder characterized by insulin resistance and glucose intolerance, significantly increases the risk for developing AD. Whereas amyloid-β (Aβ) deposition and neurofibrillary tangles are major histological hallmarks of AD, impairment of cerebral glucose metabolism precedes these pathological changes during the early stage of AD and likely triggers or exacerbates AD pathology. However, the mechanisms linking disturbed insulin signaling/glucose metabolism and AD pathogenesis remain unclear. The low-density lipoprotein receptor-related protein 1 (LRP1), a major apolipoprotein E receptor, plays critical roles in lipoprotein metabolism, synaptic maintenance, and clearance of Aβ in the brain. Here, we demonstrate that LRP1 interacts with the insulin receptor β in the brain and regulates insulin signaling and glucose uptake. LRP1 deficiency in neurons leads to impaired insulin signaling as well as reduced levels of glucose transporters GLUT3 and GLUT4. Consequently, glucose uptake is reduced. By using an in vivo microdialysis technique sampling brain glucose concentration in freely moving mice, we further show that LRP1 deficiency in conditional knock-out mice resulted in glucose intolerance in the brain. We also found that hyperglycemia suppresses LRP1 expression, which further exacerbates insulin resistance, glucose intolerance, and AD pathology. As loss of LRP1 expression is seen in AD brains, our study provides novel insights into insulin resistance in AD. Our work also establishes new targets that can be explored for AD prevention or therapy. Copyright © 2015 the authors 0270-6474/15/355851-09$15.00/0.

  9. A conserved role for syndecan family members in the regulation of whole-body energy metabolism.

    Directory of Open Access Journals (Sweden)

    Maria De Luca

    2010-06-01

    syndecan family members play a key role in the regulation of body metabolism.

  10. PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism.

    Directory of Open Access Journals (Sweden)

    Sri Devi Narasimhan

    2011-04-01

    Full Text Available The insulin/IGF-1 signaling (IIS pathway is a conserved regulator of longevity, development, and metabolism. In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase, AGE-1 (PI 3-kinase, and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16. Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinase activity. However, few phosphatases have been identified that negatively regulate the IIS pathway. Here we identify and characterize pdp-1 as a novel negative modulator of the IIS pathway. We show that PDP-1 regulates multiple outputs of IIS such as longevity, fat storage, and dauer diapause. In addition, PDP-1 promotes DAF-16 nuclear localization and transcriptional activity. Interestingly, genetic epistasis analyses place PDP-1 in the DAF-7/TGF-β signaling pathway, at the level of the R-SMAD proteins DAF-14 and DAF-8. Further investigation into how a component of TGF-β signaling affects multiple outputs of IIS/DAF-16, revealed extensive crosstalk between these two well-conserved signaling pathways. We find that PDP-1 modulates the expression of several insulin genes that are likely to feed into the IIS pathway to regulate DAF-16 activity. Importantly, dysregulation of IIS and TGF-β signaling has been implicated in diseases such as Type 2 Diabetes, obesity, and cancer. Our results may provide a new perspective in understanding of the regulation of these pathways under normal conditions and in the context of disease.

  11. Regulation of the csgD promoter by global regulators HN-S, IHF, and RpoS in E. coli O157:H7 isolates

    Science.gov (United States)

    Introduction: Curli production is essential for the biofilm formation in E. coli and Salmonella. The control of expression of CsgD, the key regulator of the curli operon, is very complex, and has been shown to be regulated by several global regulators and is influenced by various growth and stress...

  12. Autism and increased paternal age related changes in global levels of gene expression regulation.

    Directory of Open Access Journals (Sweden)

    Mark D Alter

    2011-02-01

    Full Text Available A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus. We hypothesized that a similar change in variance might be found in children with autism. Gene expression microarrays covering greater than 47,000 unique RNA transcripts were done on RNA from peripheral blood lymphocytes (PBL of children with autism (n = 82 and controls (n = 64. Variance in the distribution of gene expression levels from each microarray was compared between groups of children. Also tested was whether a risk factor for autism, increased paternal age, was associated with variance. A decrease in the variance in the distribution of gene expression levels in PBL was associated with the diagnosis of autism and a risk factor for autism, increased paternal age. Traditional approaches to microarray analysis of gene expression suggested a possible mechanism for decreased variance in gene expression. Gene expression pathways involved in transcriptional regulation were down-regulated in the blood of children with autism and children of older fathers. Thus, results from global and gene specific approaches to studying microarray data were complimentary and supported the hypothesis that alterations at the global level of gene expression regulation are related to autism and increased paternal age. Global regulation of transcription, thus, represents a possible point of convergence for multiple etiologies of autism and other

  13. The metabolic regulator CodY links L. monocytogenes metabolism to virulence by directly activating the virulence regulatory gene, prfA

    Science.gov (United States)

    Lobel, Lior; Sigal, Nadejda; Borovok, Ilya; Belitsky, Boris R.; Sonenshein, Abraham L.; Herskovits, Anat A.

    2015-01-01

    Summary Metabolic adaptations are critical to the ability of bacterial pathogens to grow within host cells and are normally preceded by sensing of host-specific metabolic signals, which in turn can influence the pathogen's virulence state. Previously, we reported that the intracellular bacterial pathogen Listeria monocytogenes responds to low availability of branched-chain amino acids (BCAA) within mammalian cells by up-regulating both BCAA biosynthesis and virulence genes. The induction of virulence genes required the BCAA-responsive transcription regulator, CodY, but the molecular mechanism governing this mode of regulation was unclear. In this report, we demonstrate that CodY directly binds the coding sequence of the L. monocytogenes master virulence activator gene, prfA, 15 nt downstream of its start codon, and that this binding results in up-regulation of prfA transcription specifically under low concentrations of BCAA. Mutating this site abolished CodY binding and reduced prfA transcription in macrophages, and attenuated bacterial virulence in mice. Notably, the mutated binding site did not alter prfA transcription or PrfA activity under other conditions that are known to activate PrfA, such as during growth in the presence of glucose-1-phosphate. This study highlights the tight crosstalk between L. monocytogenes metabolism and virulence' while revealing novel features of CodY-mediated regulation. PMID:25430920

  14. Induction of the metabolic regulator Txnip in fasting-induced and natural torpor.

    Science.gov (United States)

    Hand, Laura E; Saer, Ben R C; Hui, Simon T; Jinnah, Hyder A; Steinlechner, Stephan; Loudon, Andrew S I; Bechtold, David A

    2013-06-01

    Torpor is a physiological state characterized by controlled lowering of metabolic rate and core body temperature, allowing substantial energy savings during periods of reduced food availability or harsh environmental conditions. The hypothalamus coordinates energy homeostasis and thermoregulation and plays a key role in directing torpor. We recently showed that mice lacking the orphan G protein-coupled receptor Gpr50 readily enter torpor in response to fasting and have now used these mice to conduct a microarray analysis of hypothalamic gene expression changes related to the torpor state. This revealed a strong induction of thioredoxin-interacting protein (Txnip) in the hypothalamus of torpid mice, which was confirmed by quantitative RT-PCR and Western blot analyses. In situ hybridization identified the ependyma lining the third ventricle as the principal site of torpor-related expression of Txnip. To characterize further the relationship between Txnip and torpor, we profiled Txnip expression in mice during prolonged fasting, cold exposure, and 2-deoxyglucose-induced hypometabolism, as well as in naturally occurring torpor bouts in the Siberian hamster. Strikingly, pronounced up-regulation of Txnip expression was only observed in wild-type mice when driven into torpor and during torpor in the Siberian hamster. Increase of Txnip was not limited to the hypothalamus, with exaggerated expression in white adipose tissue, brown adipose tissue, and liver also demonstrated in torpid mice. Given the recent identification of Txnip as a molecular nutrient sensor important in the regulation of energy metabolism, our data suggest that elevated Txnip expression is critical to regulating energy expenditure and fuel use during the extreme hypometabolic state of torpor.

  15. The g0/g1 switch gene 2 is an important regulator of hepatic triglyceride metabolism.

    Science.gov (United States)

    Wang, Yinfang; Zhang, Yahui; Qian, Hang; Lu, Juan; Zhang, Zhifeng; Min, Xinwen; Lang, Mingjian; Yang, Handong; Wang, Nanping; Zhang, Peng

    2013-01-01

    Nonalcoholic fatty liver disease is associated with obesity and insulin resistance. Factors that regulate the disposal of hepatic triglycerides contribute to the development of hepatic steatosis. G0/G1 switch gene 2 (G0S2) is a target of peroxisome proliferator-activated receptors and plays an important role in regulating lipolysis in adipocytes. Therefore, we investigated whether G0S2 plays a role in hepatic lipid metabolism. Adenovirus-mediated expression of G0S2 (Ad-G0S2) potently induced fatty liver in mice. The liver mass of Ad-G0S2-infected mice was markedly increased with excess triglyceride content compared to the control mice. G0S2 did not change cellular cholesterol levels in hepatocytes. G0S2 was found to be co-localized with adipose triglyceride lipase at the surface of lipid droplets. Hepatic G0S2 overexpression resulted in an increase in plasma Low-density lipoprotein (LDL)/Very-Low-density (VLDL) lipoprotein cholesterol level. Plasma High-density lipoprotein (HDL) cholesterol and ketone body levels were slightly decreased in Ad-G0S2 injected mice. G0S2 also increased the accumulation of neutral lipids in cultured HepG2 and L02 cells. However, G0S2 overexpression in the liver significantly improved glucose tolerance in mice. Livers expressing G0S2 exhibited increased 6-(N-(7-nitrobenz-2-oxa-1-3-diazol-4-yl) amino)-6-deoxyglucose uptake compared with livers transfected with control adenovirus. Taken together, our results provide evidence supporting an important role for G0S2 as a regulator of triglyceride content in the liver and suggest that G0S2 may be a molecular target for the treatment of insulin resistance and other obesity-related metabolic disorders.

  16. AMP-Activated Protein Kinase (AMPK) Regulates Energy Metabolism through Modulating Thermogenesis in Adipose Tissue

    Science.gov (United States)

    Wu, Lingyan; Zhang, Lina; Li, Bohan; Jiang, Haowen; Duan, Yanan; Xie, Zhifu; Shuai, Lin; Li, Jia; Li, Jingya

    2018-01-01

    Obesity occurs when excess energy accumulates in white adipose tissue (WAT), whereas brown adipose tissue (BAT), which is specialized in dissipating energy through thermogenesis, potently counteracts obesity. White adipocytes can be converted to thermogenic “brown-like” cells (beige cells; WAT browning) under various stimuli, such as cold exposure. AMP-activated protein kinase (AMPK) is a crucial energy sensor that regulates energy metabolism in multiple tissues. However, the role of AMPK in adipose tissue function, especially in the WAT browning process, is not fully understood. To illuminate the effect of adipocyte AMPK on energy metabolism, we generated Adiponectin-Cre-driven adipose tissue-specific AMPK α1/α2 KO mice (AKO). These AKO mice were cold intolerant and their inguinal WAT displayed impaired mitochondrial integrity and biogenesis, and reduced expression of thermogenic markers upon cold exposure. High-fat-diet (HFD)-fed AKO mice exhibited increased adiposity and exacerbated hepatic steatosis and fibrosis and impaired glucose tolerance and insulin sensitivity. Meanwhile, energy expenditure and oxygen consumption were markedly decreased in the AKO mice both in basal conditions and after stimulation with a β3-adrenergic receptor agonist, CL 316,243. In contrast, we found that in HFD-fed obese mouse model, chronic AMPK activation by A-769662 protected against obesity and related metabolic dysfunction. A-769662 alleviated HFD-induced glucose intolerance and reduced body weight gain and WAT expansion. Notably, A-769662 increased energy expenditure and cold tolerance in HFD-fed mice. A-769662 treatment also induced the browning process in the inguinal fat depot of HFD-fed mice. Likewise, A-769662 enhanced thermogenesis in differentiated inguinal stromal vascular fraction (SVF) cells via AMPK signaling pathway. In summary, a lack of adipocyte AMPKα induced thermogenic impairment and obesity in response to cold and nutrient-overload, respectively

  17. Sugar Allocation to Metabolic Pathways is Tightly Regulated and Affects the Virulence of Streptococcus mutans

    Directory of Open Access Journals (Sweden)

    Miki Kawada-Matsuo

    2016-12-01

    Full Text Available Bacteria take up and metabolize sugar as a carbohydrate source for survival. Most bacteria can utilize many sugars, including glucose, sucrose, and galactose, as well as amino sugars, such as glucosamine and N-acetylglucosamine. After entering the cytoplasm, the sugars are mainly allocated to the glycolysis pathway (energy production and to various bacterial component biosynthesis pathways, including the cell wall, nucleic acids and amino acids. Sugars are also utilized to produce several virulence factors, such as capsule and lipoteichoic acid. Glutamine-fructose-6-phosphate aminotransferase (GlmS and glucosamine-6-phosphate deaminase (NagB have crucial roles in sugar distribution to the glycolysis pathway and to cell wall biosynthesis. In Streptococcus mutans, a cariogenic pathogen, the expression levels of glmS and nagB are coordinately regulated in response to the presence or absence of amino sugars. In addition, the disruption of this regulation affects the virulence of S. mutans. The expression of nagB and glmS is regulated by NagR in S. mutans, but the precise mechanism underlying glmS regulation is not clear. In Staphylococcus aureus and Bacillus subtilis, the mRNA of glmS has ribozyme activity and undergoes self-degradation at the mRNA level. However, there is no ribozyme activity region on glmS mRNA in S. mutans. In this review article, we summarize the sugar distribution, particularly the coordinated regulation of GlmS and NagB expression, and its relationship with the virulence of S. mutans.

  18. Post-Transcriptional Regulation by the Csr Global Regulatory System in Escherichia coli

    OpenAIRE

    Suzuki, Kazushi; 鈴木, 一史

    2007-01-01

    In many species of bacteria, the Csr (carbon storage regulator) global regulatory system coordinates the expression of various genes. In Escherichia coli, the central component of this system, CsrA, is a RNA-binding protein. The CsrA is a homodimer and binds to leader segments of target mRNAs, affecting their translation and stability. CsrA activity is regulated by two small non-coding RNAs, CsrB and CsrC. These RNAs contain multiple CsrA-binding sequences and act by sequestering CsrA. In thi...

  19. The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia

    Directory of Open Access Journals (Sweden)

    Roehl Anna B

    2012-08-01

    Full Text Available Abstract Backround Neuroprotective strategies after cardiopulmonary resuscitation are currently the focus of experimental and clinical research. Levosimendan has been proposed as a promising drug candidate because of its cardioprotective properties, improved haemodynamic effects in vivo and reduced traumatic brain injury in vitro. The effects of levosimendan on brain metabolism during and after ischaemia/hypoxia are unknown. Methods Transient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 μg kg-1 levosimendan followed by a continuous infusion of 0.2 μg kg-1 min-1. The changes in the energy-related metabolites lactate, the lactate/pyruvate ratio, glucose and glutamate were monitored by microdialysis. In addition, the effects on global haemodynamics, cerebral perfusion and autoregulation, oedema and expression of proinflammatory genes in the neocortex were assessed. Results Levosimendan reduced blood pressure during initial reperfusion (72 ± 14 vs. 109 ± 2 mmHg, p = 0.03 and delayed flow maximum by 5 minutes (p = 0.002. Whereas no effects on time course of lactate, glucose, pyruvate and glutamate concentrations in the dialysate could be observed, the lactate/pyruvate ratio during initial reperfusion (144 ± 31 vs. 77 ± 8, p = 0.017 and the glutamate release during 90 minutes of reperfusion (75 ± 19 vs. 24 ± 28 μmol·L-1 were higher in the levosimendan group. The increased expression of IL-6, IL-1ß TNFα and ICAM-1, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan. Conclusion Although levosimendan has neuroprotective actions in vitro and on the spinal cord in vivo and has been shown to cross the blood–brain barrier, the present

  20. Adult onset global loss of the fto gene alters body composition and metabolism in the mouse.

    Directory of Open Access Journals (Sweden)

    Fiona McMurray

    Full Text Available The strongest BMI-associated GWAS locus in humans is the FTO gene. Rodent studies demonstrate a role for FTO in energy homeostasis and body composition. The phenotypes observed in loss of expression studies are complex with perinatal lethality, stunted growth from weaning, and significant alterations in body composition. Thus understanding how and where Fto regulates food intake, energy expenditure, and body composition is a challenge. To address this we generated a series of mice with distinct temporal and spatial loss of Fto expression. Global germline loss of Fto resulted in high perinatal lethality and a reduction in body length, fat mass, and lean mass. When ratio corrected for lean mass, mice had a significant increase in energy expenditure, but more appropriate multiple linear regression normalisation showed no difference in energy expenditure. Global deletion of Fto after the in utero and perinatal period, at 6 weeks of age, removed the high lethality of germline loss. However, there was a reduction in weight by 9 weeks, primarily as loss of lean mass. Over the subsequent 10 weeks, weight converged, driven by an increase in fat mass. There was a switch to a lower RER with no overall change in food intake or energy expenditure. To test if the phenotype can be explained by loss of Fto in the mediobasal hypothalamus, we sterotactically injected adeno-associated viral vectors encoding Cre recombinase to cause regional deletion. We observed a small reduction in food intake and weight gain with no effect on energy expenditure or body composition. Thus, although hypothalamic Fto can impact feeding, the effect of loss of Fto on body composition is brought about by its actions at sites elsewhere. Our data suggest that Fto may have a critical role in the control of lean mass, independent of its effect on food intake.

  1. A new fluorescence-based method identifies protein phosphatases regulating lipid droplet metabolism.

    Directory of Open Access Journals (Sweden)

    Bruno L Bozaquel-Morais

    Full Text Available In virtually every cell, neutral lipids are stored in cytoplasmic structures called lipid droplets (LDs and also referred to as lipid bodies or lipid particles. We developed a rapid high-throughput assay based on the recovery of quenched BODIPY-fluorescence that allows to quantify lipid droplets. The method was validated by monitoring lipid droplet turnover during growth of a yeast culture and by screening a group of strains deleted in genes known to be involved in lipid metabolism. In both tests, the fluorimetric assay showed high sensitivity and good agreement with previously reported data using microscopy. We used this method for high-throughput identification of protein phosphatases involved in lipid droplet metabolism. From 65 yeast knockout strains encoding protein phosphatases and its regulatory subunits, 13 strains revealed to have abnormal levels of lipid droplets, 10 of them having high lipid droplet content. Strains deleted for type I protein phosphatases and related regulators (ppz2, gac1, bni4, type 2A phosphatase and its related regulator (pph21 and sap185, type 2C protein phosphatases (ptc1, ptc4, ptc7 and dual phosphatases (pps1, msg5 were catalogued as high-lipid droplet content strains. Only reg1, a targeting subunit of the type 1 phosphatase Glc7p, and members of the nutrient-sensitive TOR pathway (sit4 and the regulatory subunit sap190 were catalogued as low-lipid droplet content strains, which were studied further. We show that Snf1, the homologue of the mammalian AMP-activated kinase, is constitutively phosphorylated (hyperactive in sit4 and sap190 strains leading to a reduction of acetyl-CoA carboxylase activity. In conclusion, our fast and highly sensitive method permitted us to catalogue protein phosphatases involved in the regulation of LD metabolism and present evidence indicating that the TOR pathway and the SNF1/AMPK pathway are connected through the Sit4p-Sap190p pair in the control of lipid droplet biogenesis.

  2. Increased Global Interaction Across Functional Brain Modules During Cognitive Emotion Regulation.

    Science.gov (United States)

    Brandl, Felix; Mulej Bratec, Satja; Xie, Xiyao; Wohlschläger, Afra M; Riedl, Valentin; Meng, Chun; Sorg, Christian

    2017-07-13

    Cognitive emotion regulation (CER) enables humans to flexibly modulate their emotions. While local theories of CER neurobiology suggest interactions between specialized local brain circuits underlying CER, e.g., in subparts of amygdala and medial prefrontal cortices (mPFC), global theories hypothesize global interaction increases among larger functional brain modules comprising local circuits. We tested the global CER hypothesis using graph-based whole-brain network analysis of functional MRI data during aversive emotional processing with and without CER. During CER, global between-module interaction across stable functional network modules increased. Global interaction increase was particularly driven by subregions of amygdala and cuneus-nodes of highest nodal participation-that overlapped with CER-specific local activations, and by mPFC and posterior cingulate as relevant connector hubs. Results provide evidence for the global nature of human CER, complementing functional specialization of embedded local brain circuits during successful CER. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Solar UV light regulates flavonoid metabolism in apple (Malus x domestica).

    Science.gov (United States)

    Henry-Kirk, Rebecca A; Plunkett, Blue; Hall, Miriam; McGhie, Tony; Allan, Andrew C; Wargent, Jason J; Espley, Richard V

    2018-03-01

    Ultraviolet-B light (UV-B) is one environmental signal perceived by plants that affects the flavonoid pathway and influences the levels of anthocyanins, flavonols, and proanthocyanidins. To understand the mechanisms underlying UV exposure, apple trees were grown under spectral filters that altered transmission of solar UV light. Fruit analysis showed that UV induced changes in physiology, metabolism, and gene expression levels during development over a season. These changes were sustained after storage. Under low UV, ripening was delayed, fruit size decreased, and anthocyanin and flavonols were reduced. Expression analysis showed changes in response to UV light levels for genes in the regulation and biosynthesis of anthocyanin and flavonols. Transcription of flavonol synthase (FLS), ELONGATED HYPOCOTYL 5 (HY5), MYB10, and MYB22 were down-regulated throughout fruit development under reduced UV. Functional testing showed that the FLS promoter was activated by HY5, and this response was enhanced by the presence of MYB22. The MYB22 promoter can also be activated by the anthocyanin regulator, MYB10. As ambient levels of UV light vary around the globe, this study has implications for future crop production, the quality of which can be determined by the response to UV. © 2018 John Wiley & Sons Ltd.

  4. TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology

    Science.gov (United States)

    Entwistle, Lewis J.; Khoury, Hania; Papoutsopoulou, Stamatia; Mahmood, Radma; Mansour, Nuha R.; Ching-Cheng Huang, Stanley; Pearce, Edward J.; Pedro S. de Carvalho, Luiz; Ley, Steven C.

    2016-01-01

    Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8 –/–mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8 –/–M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis. PMID:27487182

  5. Policy Approaches for Regulating Alcohol Marketing in a Global Context: A Public Health Perspective.

    Science.gov (United States)

    Esser, Marissa B; Jernigan, David H

    2018-04-01

    Alcohol consumption is responsible for 3.3 million deaths globally or nearly 6% of all deaths. Alcohol use contributes to both communicable and noncommunicable diseases, as well as violence and injuries. The purpose of this review is to discuss, in the context of the expansion of transnational alcohol corporations and harms associated with alcohol use, policy options for regulating exposure to alcohol marketing. We first provide an overview of the public health problem of harmful alcohol consumption and describe the association between exposure to alcohol marketing and alcohol consumption. We then discuss the growth and concentration of global alcohol corporations and their marketing practices in low- and middle-income countries, as well as in higher-income societies. We review the use and effectiveness of various approaches for regulating alcohol marketing in various countries before discussing challenges and opportunities to protect public health.

  6. Spaceflight Alters Bacterial Gene Expression and Virulence and Reveals Role for Global Regulator Hfq

    Science.gov (United States)

    Wilson, J. W.; Ott, C. M.; zuBentrup, K. Honer; Ramamurthy R.; Quick, L.; Porwollik, S.; Cheng, P.; McClellan, M.; Tsaprailis, G.; Radabaugh, T.; hide

    2007-01-01

    A comprehensive analysis of both the molecular genetic and phenotypic responses of any organism to the spaceflight environment has never been accomplished due to significant technological and logistical hurdles. Moreover, the effects of spaceflight on microbial pathogenicity and associated infectious disease risks have not been studied. The bacterial pathogen Salmonella typhimurium was grown aboard Space Shuttle mission STS-115 and compared to identical ground control cultures. Global microarray and proteomic analyses revealed 167 transcripts and 73 proteins changed expression with the conserved RNA-binding protein Hfq identified as a likely global regulator involved in the response to this environment. Hfq involvement was confirmed with a ground based microgravity culture model. Spaceflight samples exhibited enhanced virulence in a murine infection model and extracellular matrix accumulation consistent with a biofilm. Strategies to target Hfq and related regulators could potentially decrease infectious disease risks during spaceflight missions and provide novel therapeutic options on Earth.

  7. The Emerging Role of Skeletal Muscle Metabolism as a Biological Target and Cellular Regulator of Cancer-Induced Muscle Wasting

    Science.gov (United States)

    Carson, James A.; Hardee, Justin P.; VanderVeen, Brandon N.

    2015-01-01

    While skeletal muscle mass is an established primary outcome related to understanding cancer cachexia mechanisms, considerable gaps exist in our understanding of muscle biochemical and functional properties that have recognized roles in systemic health. Skeletal muscle quality is a classification beyond mass, and is aligned with muscle’s metabolic capacity and substrate utilization flexibility. This supplies an additional role for the mitochondria in cancer-induced muscle wasting. While the historical assessment of mitochondria content and function during cancer-induced muscle loss was closely aligned with energy flux and wasting susceptibility, this understanding has expanded to link mitochondria dysfunction to cellular processes regulating myofiber wasting. The primary objective of this article is to highlight muscle mitochondria and oxidative metabolism as a biological target of cancer cachexia and also as a cellular regulator of cancer-induced muscle wasting. Initially, we examine the role of muscle metabolic phenotype and mitochondria content in cancer-induced wasting susceptibility. We then assess the evidence for cancer-induced regulation of skeletal muscle mitochondrial biogenesis, dynamics, mitophagy, and oxidative stress. In addition, we discuss environments associated with cancer cachexia that can impact the regulation of skeletal muscle oxidative metabolism. The article also examines the role of cytokine-mediated regulation of mitochondria function regulation, followed by the potential role of cancer-induced hypogonadism. Lastly, a role for decreased muscle use in cancer-induced mitochondrial dysfunction is reviewed. PMID:26593326

  8. Regulation of amino-acid metabolism controls flux to lipid accumulation in Yarrowia lipolytica

    DEFF Research Database (Denmark)

    Kerkhoven, Eduard J.; Pomraning, Kyle R.; Baker, Scott E.

    2016-01-01

    Yarrowia lipolytica is a promising microbial cell factory for the production of lipids to be used as fuels and chemicals, but there are few studies on regulation of its metabolism. Here we performed the first integrated data analysis of Y. lipolytica grown in carbon and nitrogen limited chemostat...... is similar to the overflow metabolism observed in many other microorganisms, e.g. ethanol production by Sacchromyces cerevisiae at nitrogen limitation....

  9. ER-tethered Transcription Factor CREBH Regulates Hepatic Lipogenesis, Fatty Acid Oxidation, and Lipolysis upon Metabolic Stress

    OpenAIRE

    Zhang, Chunbin; Wang, Guohui; Zheng, Ze; Maddipati, Krishna Rao; Zhang, Xuebao; Dyson, Gregory; Williams, Paul; Duncan, Stephen A.; Kaufman, Randal J.; Zhang, Kezhong

    2012-01-01

    CREBH is a liver-specific transcription factor that is localized in the endoplasmic reticulum (ER) membrane. Our previous work demonstrated that CREBH is activated by ER stress or inflammatory stimuli to induce an acute-phase hepatic inflammation. Here we demonstrate that CREBH is a key metabolic regulator of hepatic lipogenesis, fatty acid (FA) oxidation, and lipolysis under metabolic stress. Saturated FA, insulin signals, or an atherogenic high-fat diet can induce CREBH activation in the li...

  10. The neuropeptide allatostatin A regulates metabolism and feeding decisions in Drosophila

    DEFF Research Database (Denmark)

    Hentze, Julie Lilith; Carlsson, Mikael A.; Kondo, Shu

    2015-01-01

    Coordinating metabolism and feeding is important to avoid obesity and metabolic diseases, yet the underlying mechanisms, balancing nutrient intake and metabolic expenditure, are poorly understood. Several mechanisms controlling these processes are conserved in Drosophila, where homeostasis and en...

  11. The adverse effect of 4-tert-octylphenol on fat metabolism in pregnant rats via regulation of lipogenic proteins.

    Science.gov (United States)

    Kim, Jun; Kang, Eun-Jin; Park, Mee-Na; Kim, Ji-Eun; Kim, Seung-Chul; Jeung, Eui-Bae; Lee, Geun-Shik; Hwang, Dae-Youn; An, Beum-Soo

    2015-07-01

    Alkylphenols such as 4-tert-octylphenol (OP), nonylphenol, and bisphenol A are classified as endocrine-disrupting chemicals (EDCs). Digestion and metabolism of food are controlled by many endocrine factors, including insulin, glucagon, and estrogen. These factors are differentially regulated during pregnancy. The alteration of nutritional intake and fat metabolism may affect the maintenance of pregnancy and supplementation of nutrients to the fetus, and therefore can cause severe metabolic diseases such as ketosis, marasmus and diabetes mellitus in pregnant individuals. In this study, we examined the effects of OP on fat metabolism in pregnant rats. Ethinyl estradiol (EE) was also administered as an estrogenic positive control. In our results, rats treated with OP showed significantly reduced body weights compared to the control group. In addition, histological analysis showed that the amount of fat deposited in adipocytes was reduced by OP treatment. To study the mechanism of action of OP in fat metabolism, we examined the expression levels of fat metabolism-associated genes in rat adipose tissue and liver by real-time PCR. OP and EE negatively regulated the expression of lipogenic enzymes, including FAS (fatty acid synthase), ACC-1 (acetyl-CoA carboxylase-1), and SCD-1 (stearoyl-CoA desaturase-1). The levels of lipogenic enzyme-associated transcription factors such as C/EBP-α (CAAT enhancer binding protein alpha) and SREBP-1c (sterol regulatory element binding protein-1c) were also reduced in both liver and adipose tissue. In summary, these findings suggest that OP has adverse effects on fat metabolism in pregnant rats and inhibits fat deposition via regulating lipogenic genes in the liver and adipose tissue. The altered fat metabolism by OP may affect the nutrition balance during pregnancy and can cause metabolism-related diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. New Regional and Global HFC Projections and Effects of National Regulations and Montreal Protocol Amendment Proposals

    Science.gov (United States)

    Velders, G. J. M.

    2015-12-01

    Hydrofluorocarbons (HFCs) are used as substitutes for ozone-depleting substances that are being phased out globally under Montreal Protocol regulations. New global scenarios of HFC emissions reach 4.0-5.3 GtCO2-eq yr-1 in 2050, which corresponds to a projected growth from 2015 to 2050 which is 9% to 29% of that for CO2 over the same time period. New baseline scenarios are formulated for 10 HFC compounds, 11 geographic regions, and 13 use categories. These projections are the first to comprehensively assess production and consumption of individual HFCs in multiple use sectors and geographic regions with emission estimates constrained by atmospheric observations. In 2050, in percent of global HFC emissions, China (~30%), India and the rest of Asia (~25%), Middle East and northern Africa (~10%), and USA (~10%) are the principal source regions; and refrigeration and stationary air conditioning are the major use sectors. National regulations to limit HFC use have been adopted recently in the European Union, Japan and USA, and four proposals have been submitted in 2015 to amend the Montreal Protocol to substantially reduce growth in HFC use. Calculated baseline emissions are reduced by 90% in 2050 by implementing the North America Montreal Protocol amendment proposal. Global adoption of technologies required to meet national regulations would be sufficient to reduce 2050 baseline HFC consumption by more than 50% of that achieved with the North America proposal for most developed and developing countries. The new HFC scenarios and effects of national regulations and Montreal Protocol amendment proposals will be presented.

  13. Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritis.

    Science.gov (United States)

    Hardy, Rowan; Juarez, Maria; Naylor, Amy; Tu, Jinwen; Rabbitt, Elizabeth H; Filer, Andrew; Stewart, Paul M; Buckley, Christopher D; Raza, Karim; Cooper, Mark S

    2012-10-18

    Inflammatory arthritis is associated with increased bone resorption and suppressed bone formation. The Wnt antagonist dickkopf-1 (DKK1) is secreted by synovial fibroblasts in response to inflammation and this protein has been proposed to be a master regulator of bone remodelling in inflammatory arthritis. Local glucocorticoid production is also significantly increased during joint inflammation. Therefore, we investigated how locally derived glucocorticoids and inflammatory cytokines regulate DKK1 synthesis in synovial fibroblasts during inflammatory arthritis. We examined expression and regulation of DKK1 in primary cultures of human synovial fibroblasts isolated from patients with inflammatory arthritis. The effect of TNFα, IL-1β and glucocorticoids on DKK1 mRNA and protein expression was examined by real-time PCR and ELISA. The ability of inflammatory cytokine-induced expression of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) to sensitise fibroblasts to endogenous glucocorticoids was explored. Global expression of Wnt signalling and target genes in response to TNFα and glucocorticoids was assessed using a custom array. DKK1 expression in human synovial fibroblasts was directly regulated by glucocorticoids but not proinflammatory cytokines. Glucocorticoids, but not TNFα, regulated expression of multiple Wnt agonists and antagonists in favour of inhibition of Wnt signalling. However, TNFα and IL-1β indirectly stimulated DKK1 production through increased expression of 11β-HSD1. These results demonstrate that in rheumatoid arthritis synovial fibroblasts, DKK1 expression is directly regulated by glucocorticoids rather than TNFα. Consequently, the links between synovial inflammation, altered Wnt signalling and bone remodelling are not direct but are dependent on local activation of endogenous glucocorticoids.

  14. Combating global warming. Possible rules, regulations and administrative arrangements for a global market in CO2 emission entitlements

    International Nuclear Information System (INIS)

    1994-12-01

    When in 1991 the UNCTAD secretariat launched its research into the idea of controlling carbon dioxide emissions through a system of 'tradeable permits', there was little support for this approach. Some felt that the idea was premature and should not detract from efforts to introduce more conventional measures, such as environmental taxes and new regulations. However, in a few short years, the idea of using tradeable market-based instruments to combat global warming has gained widespread acceptance. The UNCTAD secretariat's 1992 study on a global system of tradeable carbon emission entitlements (UNCTAD/RDP/DFP/1), was widely regarded as a major breakthrough in this area. This study argued that tradeable permits were both an efficient means of controlling man-made carbon dioxide emissions at minimum cost, and an effective mechanism for transferring resources to developing countries and countries in transition, to help them to contribute to the international effort to abate emissions of greenhouse gases. The study contained a detailed assessment of key technical elements of a tradeable CO 2 entitlements system, including permit allocation techniques, resource transfers, equity/distributional implications, institutional and administrative requirements. The present publication explores the institutional requirements for both policy-making and the organization of a global market in CO 2 emission allowances. It shows that one can start with a simple pilot scheme based on the joint implementation of commitments, which constitutes the cornerstone of the Framework Convention, and evolve gradually to a more complete system on the basis of 'learning by doing'. Since the use of markets can dramatically lower the cost of controlling greenhouse gas emissions, it is clearly in the self-interest of major emitters to act as 'market leaders' willing to pioneer

  15. Protein kinase N2 regulates AMP kinase signaling and insulin responsiveness of glucose metabolism in skeletal muscle.

    Science.gov (United States)

    Ruby, Maxwell A; Riedl, Isabelle; Massart, Julie; Åhlin, Marcus; Zierath, Juleen R

    2017-10-01

    Insulin resistance is central to the development of type 2 diabetes and related metabolic disorders. Because skeletal muscle is responsible for the majority of whole body insulin-stimulated glucose uptake, regulation of glucose metabolism in this tissue is of particular importance. Although Rho GTPases and many of their affecters influence skeletal muscle metabolism, there is a paucity of information on the protein kinase N (PKN) family of serine/threonine protein kinases. We investigated the impact of PKN2 on insulin signaling and glucose metabolism in primary human skeletal muscle cells in vitro and mouse tibialis anterior muscle in vivo. PKN2 knockdown in vitro decreased insulin-stimulated glucose uptake, incorporation into glycogen, and oxidation. PKN2 siRNA increased 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling while stimulating fatty acid oxidation and incorporation into triglycerides and decreasing protein synthesis. At the transcriptional level, PKN2 knockdown increased expression of PGC-1α and SREBP-1c and their target genes. In mature skeletal muscle, in vivo PKN2 knockdown decreased glucose uptake and increased AMPK phosphorylation. Thus, PKN2 alters key signaling pathways and transcriptional networks to regulate glucose and lipid metabolism. Identification of PKN2 as a novel regulator of insulin and AMPK signaling may provide an avenue for manipulation of skeletal muscle metabolism. Copyright © 2017 the American Physiological Society.

  16. Evidence for a role of proline and hypothalamic astrocytes in the regulation of glucose metabolism in rats.

    Science.gov (United States)

    Arrieta-Cruz, Isabel; Su, Ya; Knight, Colette M; Lam, Tony K T; Gutiérrez-Juárez, Roger

    2013-04-01

    The metabolism of lactate to pyruvate in the mediobasal hypothalamus (MBH) regulates hepatic glucose production. Because astrocytes and neurons are functionally linked by metabolic coupling through lactate transfer via the astrocyte-neuron lactate shuttle (ANLS), we reasoned that astrocytes might be involved in the hypothalamic regulation of glucose metabolism. To examine this possibility, we used the gluconeogenic amino acid proline, which is metabolized to pyruvate in astrocytes. Our results showed that increasing the availability of proline in rats either centrally (MBH) or systemically acutely lowered blood glucose. Pancreatic clamp studies revealed that this hypoglycemic effect was due to a decrease of hepatic glucose production secondary to an inhibition of glycogenolysis, gluconeogenesis, and glucose-6-phosphatase flux. The effect of proline was mimicked by glutamate, an intermediary of proline metabolism. Interestingly, proline's action was markedly blunted by pharmacological inhibition of hypothalamic lactate dehydrogenase (LDH) suggesting that metabolic flux through LDH was required. Furthermore, short hairpin RNA-mediated knockdown of hypothalamic LDH-A, an astrocytic component of the ANLS, also blunted the glucoregulatory action of proline. Thus our studies suggest not only a new role for proline in the regulation of hepatic glucose production but also indicate that hypothalamic astrocytes are involved in the regulatory mechanism as well.

  17. Capturing the response of Clostridium acetobutylicum to chemical stressors using a regulated genome-scale metabolic model

    International Nuclear Information System (INIS)

    Dash, Satyakam; Mueller, Thomas J.; Venkataramanan, Keerthi P.; Papoutsakis, Eleftherios T.; Maranas, Costas D.

    2014-01-01

    Clostridia are anaerobic Gram-positive Firmicutes containing broad and flexible systems for substrate utilization, which have been used successfully to produce a range of industrial compounds. Clostridium acetobutylicum has been used to produce butanol on an industrial scale through acetone-butanol-ethanol (ABE) fermentation. A genome-scale metabolic (GSM) model is a powerful tool for understanding the metabolic capacities of an organism and developing metabolic engineering strategies for strain development. The integration of stress related specific transcriptomics information with the GSM model provides opportunities for elucidating the focal points of regulation

  18. TCPTP Regulates Insulin Signalling in AgRP Neurons to Coordinate Glucose Metabolism with Feeding.

    Science.gov (United States)

    Dodd, Garron T; Lee-Young, Robert S; Brüning, Jens C; Tiganis, Tony

    2018-04-30

    Insulin regulates glucose metabolism by eliciting effects on peripheral tissues as well as the brain. Insulin receptor (IR) signalling inhibits AgRP-expressing neurons in the hypothalamus to contribute to the suppression of hepatic glucose production (HGP) by insulin, whereas AgRP neuronal activation attenuates brown adipose tissue (BAT) glucose uptake. The tyrosine phosphatase TCPTP suppresses IR signalling in AgRP neurons. Hypothalamic TCPTP is induced by fasting and degraded after feeding. Here we assessed the influence of TCPTP in AgRP neurons in the control of glucose metabolism. TCPTP deletion in AgRP neurons ( Agrp -Cre; Ptpn2 fl/fl ) enhanced insulin sensitivity as assessed by the increased glucose infusion rates and reduced HGP during hyperinsulinemic-euglycemic clamps, accompanied by increased [ 14 C]-2-deoxy-D-glucose uptake in BAT and browned white adipose tissue. TCPTP deficiency in AgRP neurons promoted the intracerebroventricular insulin-induced repression of hepatic gluconeogenesis in otherwise unresponsive food-restricted mice yet had no effect in fed/satiated mice where hypothalamic TCPTP levels are reduced. The improvement in glucose homeostasis in Agrp -Cre; Ptpn2 fl/fl mice was corrected by IR heterozygosity ( Agrp -Cre; Ptpn2 fl/fl ; Insr fl/+ ), causally linking the effects on glucose metabolism with the IR signalling in AgRP neurons. Our findings demonstrate that TCPTP controls IR signalling in AgRP neurons to coordinate HGP and brown/beige adipocyte glucose uptake in response to feeding/fasting. © 2018 by the American Diabetes Association.

  19. Genetic manipulation of a metabolic enzyme and a transcriptional regulator increasing succinate excretion from unicellular cyanobacterium

    Directory of Open Access Journals (Sweden)

    Takashi eOsanai

    2015-10-01

    Full Text Available Succinate is a building block compound that the U.S. Department of Energy has declared as important in biorefineries, and it is widely used as a commodity chemical. Here, we identified the two genes increasing succinate production of the unicellular cyanobacterium Synechocystis sp. PCC 6803. Succinate was excreted under dark, anaerobic conditions, and its production level increased by knocking out ackA, which encodes an acetate kinase, and by overexpressing sigE, which encodes an RNA polymerase sigma factor. Glycogen catabolism and organic acid biosynthesis were enhanced in the mutant lacking ackA and overexpressing sigE, leading to an increase in succinate production reaching 5 times of the wild-type levels. Our genetic and metabolomic analyses thus demonstrated the effect of genetic manipulation of a metabolic enzyme and a transcriptional regulator on succinate excretion from this cyanobacterium with the data based on metabolomic technique.

  20. Hormonal and metabolic regulation of tomato fruit sink activity and yield under salinity

    DEFF Research Database (Denmark)

    Albacete, Alfonso; Cantero-Navarro, Elena; Balibrea, María E.

    2014-01-01

    Salinization of water and soil has a negative impact on tomato (Solanum lycopersicum L.) productivity by reducing growth of sink organs and by inducing senescence in source leaves. It has been hypothesized that yield stability implies the maintenance or increase of sink activity in the reproductive...... structures, thus contributing to the transport of assimilates from the source leaves through changes in sucrolytic enzymes and their regulation by phytohormones. In this study, classical and functional physiological approaches have been integrated to study the influence of metabolic and hormonal factors...... sucrolytic activities (mainly cwInv and sucrose synthase), sink strength, and fruit weight, whereas the ethylene-releasing compound ethephon had a negative effect in equivalent non-stressed fruits. Fruit yield was increased by both the constitutive expression of CIN1 in the fruits (up to 4-fold) or IPT...

  1. Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism

    DEFF Research Database (Denmark)

    Caesar, Robert; Nygren, Heli; Orešič, Matej

    2016-01-01

    The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene...... of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl...... esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota...

  2. Global regulator SATB1 recruits beta-catenin and regulates T(H2 differentiation in Wnt-dependent manner.

    Directory of Open Access Journals (Sweden)

    Dimple Notani

    2010-01-01

    Full Text Available In vertebrates, the conserved Wnt signalling cascade promotes the stabilization and nuclear accumulation of beta-catenin, which then associates with the lymphoid enhancer factor/T cell factor proteins (LEF/TCFs to activate target genes. Wnt/beta -catenin signalling is essential for T cell development and differentiation. Here we show that special AT-rich binding protein 1 (SATB1, the T lineage-enriched chromatin organizer and global regulator, interacts with beta-catenin and recruits it to SATB1's genomic binding sites. Gene expression profiling revealed that the genes repressed by SATB1 are upregulated upon Wnt signalling. Competition between SATB1 and TCF affects the transcription of TCF-regulated genes upon beta-catenin signalling. GATA-3 is a T helper type 2 (T(H2 specific transcription factor that regulates production of T(H2 cytokines and functions as T(H2 lineage determinant. SATB1 positively regulated GATA-3 and siRNA-mediated knockdown of SATB1 downregulated GATA-3 expression in differentiating human CD4(+ T cells, suggesting that SATB1 influences T(H2 lineage commitment by reprogramming gene expression. In the presence of Dickkopf 1 (Dkk1, an inhibitor of Wnt signalling, GATA-3 is downregulated and the expression of signature T(H2 cytokines such as IL-4, IL-10, and IL-13 is reduced, indicating that Wnt signalling is essential for T(H2 differentiation. Knockdown of beta-catenin also produced similar results, confirming the role of Wnt/beta-catenin signalling in T(H2 differentiation. Furthermore, chromatin immunoprecipitation analysis revealed that SATB1 recruits beta-catenin and p300 acetyltransferase on GATA-3 promoter in differentiating T(H2 cells in a Wnt-dependent manner. SATB1 coordinates T(H2 lineage commitment by reprogramming gene expression. The SATB1:beta-catenin complex activates a number of SATB1 regulated genes, and hence this study has potential to find novel Wnt responsive genes. These results demonstrate that SATB1

  3. Neuronal Calcium Signaling in Metabolic Regulation and Adaptation to Nutrient Stress.

    Science.gov (United States)

    Jayakumar, Siddharth; Hasan, Gaiti

    2018-01-01

    All organisms can respond physiologically and behaviorally to environmental fluxes in nutrient levels. Different nutrient sensing pathways exist for specific metabolites, and their inputs ultimately define appropriate nutrient uptake and metabolic homeostasis. Nutrient sensing mechanisms at the cellular level require pathways such as insulin and target of rapamycin (TOR) signaling that integrates information from different organ systems like the fat body and the gut. Such integration is essential for coordinating growth with development. Here we review the role of a newly identified set of integrative interneurons and the role of intracellular calcium signaling within these neurons, in regulating nutrient sensing under conditions of nutrient stress. A comparison of the identified Drosophila circuit and cellular mechanisms employed in this circuit, with vertebrate systems, suggests that the identified cell signaling mechanisms may be conserved for neural circuit function related to nutrient sensing by central neurons. The ideas proposed are potentially relevant for understanding the molecular basis of metabolic disorders, because these are frequently linked to nutritional stress.

  4. Duodenal Cytochrome b (DCYTB in Iron Metabolism: An Update on Function and Regulation

    Directory of Open Access Journals (Sweden)

    Darius J. R. Lane

    2015-03-01

    Full Text Available Iron and ascorbate are vital cellular constituents in mammalian systems. The bulk-requirement for iron is during erythropoiesis leading to the generation of hemoglobin-containing erythrocytes. Additionally; both iron and ascorbate are required as co-factors in numerous metabolic reactions. Iron homeostasis is controlled at the level of uptake; rather than excretion. Accumulating evidence strongly suggests that in addition to the known ability of dietary ascorbate to enhance non-heme iron absorption in the gut; ascorbate regulates iron homeostasis. The involvement of ascorbate in dietary iron absorption extends beyond the direct chemical reduction of non-heme iron by dietary ascorbate. Among other activities; intra-enterocyte ascorbate appears to be involved in the provision of electrons to a family of trans-membrane redox enzymes; namely those of the cytochrome b561 class. These hemoproteins oxidize a pool of ascorbate on one side of the membrane in order to reduce an electron acceptor (e.g., non-heme iron on the opposite side of the membrane. One member of this family; duodenal cytochrome b (DCYTB; may play an important role in ascorbate-dependent reduction of non-heme iron in the gut prior to uptake by ferrous-iron transporters. This review discusses the emerging relationship between cellular iron homeostasis; the emergent “IRP1-HIF2α axis”; DCYTB and ascorbate in relation to iron metabolism.

  5. The effects of space flight on some rat liver enzymes regulating carbohydrate and lipid metabolism

    Science.gov (United States)

    Abraham, S.; Lin, C. Y.; Klein, H. P.; Volkmann, C.

    1981-01-01

    The effects of space flight conditions on the activities of certain enzymes regulating carbohydrate and lipid metabolism in rat liver are investigated in an attempt to account for the losses in body weight observed during space flight despite preflight caloric consumption. Liver samples were analyzed for the activities of 32 cytosolic and microsomal enzymes as well as hepatic glycogen and individual fatty acid levels for ground control rats and rats flown on board the Cosmos 936 biosatellite under normal space flight conditions and in centrifuges which were sacrificed upon recovery or 25 days after recovery. Significant decreases in the activities of glycogen phosphorylase, alpha-glycerol phosphate acyl transferase, diglyceride acyl transferase, aconitase and 6-phosphogluconate dehydrogenase and an increase in palmitoyl CoA desaturase are found in the flight stationary relative to the flight contrifuged rats upon recovery, with all enzymes showing alterations returning to normal values 25 days postflight. The flight stationary group is also observed to be characterized by more than twice the amount of liver glycogen of the flight centrifuged group as well as a significant increase in the ratio of palmitic to palmitoleic acid. Results thus indicate metabolic changes which may be involved in the mechanism of weight loss during weightlessness, and demonstrate the equivalence of centrifugation during space flight to terrestrial gravity.

  6. Kaempferol ameliorates symptoms of metabolic syndrome by regulating activities of liver X receptor-β.

    Science.gov (United States)

    Hoang, Minh-Hien; Jia, Yaoyao; Mok, Boram; Jun, Hee-jin; Hwang, Kwang-Yeon; Lee, Sung-Joon

    2015-08-01

    Kaempferol is a dietary flavonol previously shown to regulate cellular lipid and glucose metabolism. However, its molecular mechanisms of action and target proteins have remained elusive, probably due to the involvement of multiple proteins. This study investigated the molecular targets of kaempferol. Ligand binding of kaempferol to liver X receptors (LXRs) was quantified by time-resolved fluorescence resonance energy transfer and surface plasmon resonance analyses. Kaempferol directly binds to and induces the transactivation of LXRs, with stronger specificity for the β-subtype (EC50 = 0.33 μM). The oral administration of kaempferol in apolipoprotein-E-deficient mice (150 mg/day/kg body weight) significantly reduced plasma glucose and increased high-density lipoprotein cholesterol levels and insulin sensitivity compared with the vehicle-fed control. Kaempferol also reduced plasma triglyceride concentrations and did not cause liver steatosis, a common side effect of potent LXR activation. In immunoblotting analysis, kaempferol reduced the nuclear accumulation of sterol regulatory element-binding protein-1 (SREBP-1). Our results show that the suppression of SREBP-1 activity and the selectivity for LXR-β over LXR-α by kaempferol contribute to the reductions of plasma and hepatic triglyceride concentrations in mice fed kaempferol. They also suggest that kaempferol activates LXR-β and suppresses SREBP-1 to enhance symptoms in metabolic syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. The Role of Circulating Amino Acids in the Hypothalamic Regulation of Liver Glucose Metabolism.

    Science.gov (United States)

    Arrieta-Cruz, Isabel; Gutiérrez-Juárez, Roger

    2016-07-01

    A pandemic of diabetes and obesity has been developing worldwide in close association with excessive nutrient intake and a sedentary lifestyle. Variations in the protein content of the diet have a direct impact on glucose homeostasis because amino acids (AAs) are powerful modulators of insulin action. In this work we review our recent findings on how elevations in the concentration of the circulating AAs leucine and proline activate a metabolic mechanism located in the mediobasal hypothalamus of the brain that sends a signal to the liver via the vagus nerve, which curtails glucose output. This neurogenic signal is strictly dependent on the metabolism of leucine and proline to acetyl-coenzyme A (CoA) and the subsequent production of malonyl-CoA; the signal also requires functional neuronal ATP-sensitive potassium channels. The liver then responds by lowering the rate of gluconeogenesis and glycogenolysis, ultimately leading to a net decrease in glucose production and in concentrations of circulating glucose. Furthermore, we review here how our work with proline suggests a new role of astrocytes in the central regulation of glycemia. Last, we outline how factors such as the consumption of fat-rich diets can interfere with glucoregulatory mechanisms and, in the long term, may contribute to the development of hyperglycemia, a hallmark of type 2 diabetes. © 2016 American Society for Nutrition.

  8. The Role of Circulating Amino Acids in the Hypothalamic Regulation of Liver Glucose Metabolism123

    Science.gov (United States)

    Arrieta-Cruz, Isabel; Gutiérrez-Juárez, Roger

    2016-01-01

    A pandemic of diabetes and obesity has been developing worldwide in close association with excessive nutrient intake and a sedentary lifestyle. Variations in the protein content of the diet have a direct impact on glucose homeostasis because amino acids (AAs) are powerful modulators of insulin action. In this work we review our recent findings on how elevations in the concentration of the circulating AAs leucine and proline activate a metabolic mechanism located in the mediobasal hypothalamus of the brain that sends a signal to the liver via the vagus nerve, which curtails glucose output. This neurogenic signal is strictly dependent on the metabolism of leucine and proline to acetyl-coenzyme A (CoA) and the subsequent production of malonyl-CoA; the signal also requires functional neuronal ATP-sensitive potassium channels. The liver then responds by lowering the rate of gluconeogenesis and glycogenolysis, ultimately leading to a net decrease in glucose production and in concentrations of circulating glucose. Furthermore, we review here how our work with proline suggests a new role of astrocytes in the central regulation of glycemia. Last, we outline how factors such as the consumption of fat-rich diets can interfere with glucoregulatory mechanisms and, in the long term, may contribute to the development of hyperglycemia, a hallmark of type 2 diabetes. PMID:27422516

  9. [Regulation of terpene metabolism]. Annual progress report, March 15, 1989--March 14, 1990

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1989-11-09

    Terpenoid oils, resins, and waxes from plants are important renewable resources. The objective of this project is to understand the regulation of terpenoid metabolism using the monoterpenes (C{sub 10}) as a model. The pathways of monoterpene biosynthesis and catabolism have been established, and the relevant enzymes characterized. Developmental studies relating enzyme levels to terpene accumulation within the oil gland sites of synthesis, and work with bioregulators, indicate that monoterpene production is controlled by terpene cyclases, the enzymes catalyzing the first step of the monoterpene pathway. As the leaf oil glands mature, cyclase levels decline and monoterpene biosynthesis ceases. Yield then decreases as the monoterpenes undergo catabolism by a process involving conversion to a glycoside and transport from the leaf glands to the root. At this site, the terpenoid is oxidatively degraded to acetate that is recycled into other lipid metabolites. During the transition from terpene biosynthesis to catabolism, the oil glands undergo dramatic ultrastructural modification. Degradation of the producing cells results in mixing of previously compartmentized monoterpenes with the catabolic enzymes, ultimately leading to yield decline. This regulatory model is being applied to the formation of other terpenoid classes (C{sub 15} C{sub 20}, C{sub 30}, C{sub 40}) within the oil glands. Preliminary investigations on the formation of sesquiterpenes (C{sub 15}) suggest that the corresponding cyclases may play a lesser role in determining yield of these products, but that compartmentation effects are important. From these studies, a comprehensive scheme for the regulation of terpene metabolism is being constructed. Results from this project wail have important consequences for the yield and composition of terpenoid natural products that can be made available for industrial exploitation.

  10. Regulation of Cell Wall Plasticity by Nucleotide Metabolism in Lactococcus lactis*

    Science.gov (United States)

    Solopova, Ana; Formosa-Dague, Cécile; Courtin, Pascal; Furlan, Sylviane; Veiga, Patrick; Péchoux, Christine; Armalyte, Julija; Sadauskas, Mikas; Kok, Jan; Hols, Pascal; Dufrêne, Yves F.; Kuipers, Oscar P.; Chapot-Chartier, Marie-Pierre; Kulakauskas, Saulius

    2016-01-01

    To ensure optimal cell growth and separation and to adapt to environmental parameters, bacteria have to maintain a balance between cell wall (CW) rigidity and flexibility. This can be achieved by a concerted action of peptidoglycan (PG) hydrolases and PG-synthesizing/modifying enzymes. In a search for new regulatory mechanisms responsible for the maintenance of this equilibrium in Lactococcus lactis, we isolated mutants that are resistant to the PG hydrolase lysozyme. We found that 14% of the causative mutations were mapped in the guaA gene, the product of which is involved in purine metabolism. Genetic and transcriptional analyses combined with PG structure determination of the guaA mutant enabled us to reveal the pivotal role of the pyrB gene in the regulation of CW rigidity. Our results indicate that conversion of l-aspartate (l-Asp) to N-carbamoyl-l-aspartate by PyrB may reduce the amount of l-Asp available for PG synthesis and thus cause the appearance of Asp/Asn-less stem peptides in PG. Such stem peptides do not form PG cross-bridges, resulting in a decrease in PG cross-linking and, consequently, reduced PG thickness and rigidity. We hypothesize that the concurrent utilization of l-Asp for pyrimidine and PG synthesis may be part of the regulatory scheme, ensuring CW flexibility during exponential growth and rigidity in stationary phase. The fact that l-Asp availability is dependent on nucleotide metabolism, which is tightly regulated in accordance with the growth rate, provides L. lactis cells the means to ensure optimal CW plasticity without the need to control the expression of PG synthesis genes. PMID:27022026

  11. Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies.

    Science.gov (United States)

    Dhamrait, Sukhbir S; Maubaret, Cecilia; Pedersen-Bjergaard, Ulrik; Brull, David J; Gohlke, Peter; Payne, John R; World, Michael; Thorsteinsson, Birger; Humphries, Steve E; Montgomery, Hugh E

    2016-07-01

    Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role. © 2016 The Authors. BioEssays published by WILEY Periodicals, Inc.

  12. Mitochondrial uncoupling proteins regulate angiotensin‐converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies

    Science.gov (United States)

    Maubaret, Cecilia; Pedersen‐Bjergaard, Ulrik; Brull, David J.; Gohlke, Peter; Payne, John R.; World, Michael; Thorsteinsson, Birger; Humphries, Steve E.; Montgomery, Hugh E.

    2015-01-01

    Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin‐converting enzyme (ACE) is the central component of endocrine and local tissue renin–angiotensin systems (RAS), which also regulate diverse aspects of whole‐body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3‐55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role. PMID:27347560

  13. Global metabolic analyses identify key differences in metabolite levels between polymyxin-susceptible and polymyxin-resistant Acinetobacter baumannii.

    Science.gov (United States)

    Maifiah, Mohd Hafidz Mahamad; Cheah, Soon-Ee; Johnson, Matthew D; Han, Mei-Ling; Boyce, John D; Thamlikitkul, Visanu; Forrest, Alan; Kaye, Keith S; Hertzog, Paul; Purcell, Anthony W; Song, Jiangning; Velkov, Tony; Creek, Darren J; Li, Jian

    2016-02-29

    Multidrug-resistant Acinetobacter baumannii presents a global medical crisis and polymyxins are used as the last-line therapy. This study aimed to identify metabolic differences between polymyxin-susceptible and polymyxin-resistant A. baumannii using untargeted metabolomics. The metabolome of each A. baumannii strain was measured using liquid chromatography-mass spectrometry. Multivariate and univariate statistics and pathway analyses were employed to elucidate metabolic differences between the polymyxin-susceptible and -resistant A. baumannii strains. Significant differences were identified between the metabolic profiles of the polymyxin-susceptible and -resistant A. baumannii strains. The lipopolysaccharide (LPS) deficient, polymyxin-resistant 19606R showed perturbation in specific amino acid and carbohydrate metabolites, particularly pentose phosphate pathway (PPP) and tricarboxylic acid (TCA) cycle intermediates. Levels of nucleotides were lower in the LPS-deficient 19606R. Furthermore, 19606R exhibited a shift in its glycerophospholipid profile towards increased abundance of short-chain lipids compared to the parent polymyxin-susceptible ATCC 19606. In contrast, in a pair of clinical isolates 03-149.1 (polymyxin-susceptible) and 03-149.2 (polymyxin-resistant, due to modification of lipid A), minor metabolic differences were identified. Notably, peptidoglycan biosynthesis metabolites were significantly depleted in both of the aforementioned polymyxin-resistant strains. This is the first comparative untargeted metabolomics study to show substantial differences in the metabolic profiles of the polymyxin-susceptible and -resistant A. baumannii.

  14. The challenges for global harmonisation of food safety norms and regulations: issues for India.

    Science.gov (United States)

    Prakash, Jamuna

    2014-08-01

    Safe and adequate food is a human right, safety being a prime quality attribute without which food is unfit for consumption. Food safety regulations are framed to exercise control over all types of food produced, processed and sold so that the customer is assured that the food consumed will not cause any harm. From the Indian perspective, global harmonisation of food regulations is needed to improve food and nutrition security, the food trade and delivery of safe ready-to-eat (RTE) foods at all places and at all times. The Millennium Development Goals (MDGs) put forward to transform developing societies incorporate many food safety issues. The success of the MDGs, including that of poverty reduction, will in part depend on an effective reduction of food-borne diseases, particularly among the vulnerable group, which includes women and children. Food- and water-borne illnesses can be a serious health hazard, being responsible for high incidences of morbidity and mortality across all age groups of people. Global harmonisation of food regulations would assist in facilitating food trade within and outside India through better compliance, ensuring the safety of RTE catered foods, as well as addressing issues related to the environment. At the same time, regulations need to be optimum, as overregulation may have undue negative effects on the food trade. © 2013 Society of Chemical Industry.

  15. Linker Histone Phosphorylation Regulates Global Timing of Replication Origin Firing*S⃞

    Science.gov (United States)

    Thiriet, Christophe; Hayes, Jeffrey J.

    2009-01-01

    Despite the presence of linker histone in all eukaryotes, the primary function(s) of this histone have been difficult to clarify. Knock-out experiments indicate that H1s play a role in regulation of only a small subset of genes but are an essential component in mouse development. Here, we show that linker histone (H1) is involved in the global regulation of DNA replication in Physarum polycephalum. We find that genomic DNA of H1 knock-down cells is more rapidly replicated, an effect due at least in part to disruption of the native timing of replication fork firing. Immunoprecipitation experiments demonstrate that H1 is transiently lost from replicating chromatin via a process facilitated by phosphorylation. Our results suggest that linker histones generate a chromatin environment refractory to replication and that their transient removal via protein phosphorylation during S phase is a critical step in the epigenetic regulation of replication timing. PMID:19015270

  16. Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira

    Science.gov (United States)

    Adhikarla, Haritha; Wunder, Elsio A.; Mechaly, Ariel E.; Mehta, Sameet; Wang, Zheng; Santos, Luciane; Bisht, Vimla; Diggle, Peter; Murray, Gerald; Adler, Ben; Lopez, Francesc; Townsend, Jeffrey P.; Groisman, Eduardo; Picardeau, Mathieu; Buschiazzo, Alejandro; Ko, Albert I.

    2018-01-01

    Leptospirosis is an emerging zoonotic disease with more than 1 million cases annually. Currently there is lack of evidence for signaling pathways involved during the infection process of Leptospira. In our comprehensive genomic analysis of 20 Leptospira spp. we identified seven pathogen-specific Two-Component System (TCS) proteins. Disruption of two these TCS genes in pathogenic Leptospira strain resulted in loss-of-virulence in a hamster model of leptospirosis. Corresponding genes lvrA and lvrB (leptospira virulence regulator) are juxtaposed in an operon and are predicted to encode a hybrid histidine kinase and a hybrid response regulator, respectively. Transcriptome analysis of lvr mutant strains with disruption of one (lvrB) or both genes (lvrA/B) revealed global transcriptional regulation of 850 differentially expressed genes. Phosphotransfer assays demonstrated that LvrA phosphorylates LvrB and predicted further signaling downstream to one or more DNA-binding response regulators, suggesting that it is a branched pathway. Phylogenetic analyses indicated that lvrA and lvrB evolved independently within different ecological lineages in Leptospira via gene duplication. This study uncovers a novel-signaling pathway that regulates virulence in pathogenic Leptospira (Lvr), providing a framework to understand the molecular bases of regulation in this life-threatening bacterium. PMID:29600195

  17. Exenatide Regulates Cerebral Glucose Metabolism in Brain Areas Associated With Glucose Homeostasis and Reward System.

    Science.gov (United States)

    Daniele, Giuseppe; Iozzo, Patricia; Molina-Carrion, Marjorie; Lancaster, Jack; Ciociaro, Demetrio; Cersosimo, Eugenio; Tripathy, Devjit; Triplitt, Curtis; Fox, Peter; Musi, Nicolas; DeFronzo, Ralph; Gastaldelli, Amalia

    2015-10-01

    Glucagon-like peptide 1 receptors (GLP-1Rs) have been found in the brain, but whether GLP-1R agonists (GLP-1RAs) influence brain glucose metabolism is currently unknown. The study aim was to evaluate the effects of a single injection of the GLP-1RA exenatide on cerebral and peripheral glucose metabolism in response to a glucose load. In 15 male subjects with HbA1c of 5.7 ± 0.1%, fasting glucose of 114 ± 3 mg/dL, and 2-h glucose of 177 ± 11 mg/dL, exenatide (5 μg) or placebo was injected in double-blind, randomized fashion subcutaneously 30 min before an oral glucose tolerance test (OGTT). The cerebral glucose metabolic rate (CMRglu) was measured by positron emission tomography after an injection of [(18)F]2-fluoro-2-deoxy-d-glucose before the OGTT, and the rate of glucose absorption (RaO) and disposal was assessed using stable isotope tracers. Exenatide reduced RaO0-60 min (4.6 ± 1.4 vs. 13.1 ± 1.7 μmol/min ⋅ kg) and decreased the rise in mean glucose0-60 min (107 ± 6 vs. 138 ± 8 mg/dL) and insulin0-60 min (17.3 ± 3.1 vs. 24.7 ± 3.8 mU/L). Exenatide increased CMRglu in areas of the brain related to glucose homeostasis, appetite, and food reward, despite lower plasma insulin concentrations, but reduced glucose uptake in the hypothalamus. Decreased RaO0-60 min after exenatide was inversely correlated to CMRglu. In conclusion, these results demonstrate, for the first time in man, a major effect of a GLP-1RA on regulation of brain glucose metabolism in the absorptive state. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  18. Virulence meets metabolism: Cra and KdpE gene regulation in enterohemorrhagic Escherichia coli.

    Science.gov (United States)

    Njoroge, Jacqueline W; Nguyen, Y; Curtis, Meredith M; Moreira, Cristiano G; Sperandio, Vanessa

    2012-10-16

    Gastrointestinal (GI) bacteria sense diverse environmental signals as cues for differential gene regulation and niche adaptation. Pathogens such as enterohemorrhagic Escherichia coli (EHEC), which causes bloody diarrhea, use these signals for the temporal and energy-efficient regulation of their virulence factors. One of the main virulence strategies employed by EHEC is the formation of attaching and effacing (AE) lesions on enterocytes. Most of the genes necessary for the formation of these lesions are grouped within a pathogenicity island, the locus of enterocyte effacement (LEE), whose expression requires the LEE-encoded regulator Ler. Here we show that growth of EHEC in glycolytic environments inhibits the expression of ler and consequently all other LEE genes. Conversely, growth within a gluconeogenic environment activates expression of these genes. This sugar-dependent regulation is achieved through two transcription factors: KdpE and Cra. Both Cra and KdpE directly bind to the ler promoter, and Cra's affinity to this promoter is catabolite dependent. Moreover, we show that the Cra and KdpE proteins interact in vitro and that KdpE's ability to bind DNA is enhanced by the presence of Cra. Cra is important for AE lesion formation, and KdpE contributes to this Cra-dependent regulation. The deletion of cra and kdpE resulted in the ablation of AE lesions. One of the many challenges that bacteria face within the GI tract is to successfully compete for carbon sources. Linking carbon metabolism to the precise coordination of virulence expression is a key step in the adaptation of pathogens to the GI environment. IMPORTANCE An appropriate and prompt response to environmental cues is crucial for bacterial survival. Cra and KdpE are two proteins found in both nonpathogenic and pathogenic bacteria that regulate genes in response to differences in metabolite concentration. In this work, we show that, in the deadly pathogen enterohemorrhagic Escherichia coli (EHEC) O157:H7

  19. Identifying the preferred subset of enzymatic profiles in nonlinear kinetic metabolic models via multiobjective global optimization and Pareto filters.

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    Carlos Pozo

    Full Text Available Optimization models in metabolic engineering and systems biology focus typically on optimizing a unique criterion, usually the synthesis rate of a metabolite of interest or the rate of growth. Connectivity and non-linear regulatory effects, however, make it necessary to consider multiple objectives in order to identify useful strategies that balance out different metabolic issues. This is a fundamental aspect, as optimization of maximum yield in a given condition may involve unrealistic values in other key processes. Due to the difficulties associated with detailed non-linear models, analysis using stoichiometric descriptions and linear optimization methods have become rather popular in systems biology. However, despite being useful, these approaches fail in capturing the intrinsic nonlinear nature of the underlying metabolic systems and the regulatory signals involved. Targeting more complex biological systems requires the application of global optimization methods to non-linear representations. In this work we address the multi-objective global optimization of metabolic networks that are described by a special class of models based on the power-law formalism: the generalized mass action (GMA representation. Our goal is to develop global optimization methods capable of efficiently dealing with several biological criteria simultaneously. In order to overcome the numerical difficulties of dealing with multiple criteria in the optimization, we propose a heuristic approach based on the epsilon constraint method that reduces the computational burden of generating a set of Pareto optimal alternatives, each achieving a unique combination of objectives values. To facilitate the post-optimal analysis of these solutions and narrow down their number prior to being tested in the laboratory, we explore the use of Pareto filters that identify the preferred subset of enzymatic profiles. We demonstrate the usefulness of our approach by means of a case study

  20. Identifying the preferred subset of enzymatic profiles in nonlinear kinetic metabolic models via multiobjective global optimization and Pareto filters.

    Science.gov (United States)

    Pozo, Carlos; Guillén-Gosálbez, Gonzalo; Sorribas, Albert; Jiménez, Laureano

    2012-01-01

    Optimization models in metabolic engineering and systems biology focus typically on optimizing a unique criterion, usually the synthesis rate of a metabolite of interest or the rate of growth. Connectivity and non-linear regulatory effects, however, make it necessary to consider multiple objectives in order to identify useful strategies that balance out different metabolic issues. This is a fundamental aspect, as optimization of maximum yield in a given condition may involve unrealistic values in other key processes. Due to the difficulties associated with detailed non-linear models, analysis using stoichiometric descriptions and linear optimization methods have become rather popular in systems biology. However, despite being useful, these approaches fail in capturing the intrinsic nonlinear nature of the underlying metabolic systems and the regulatory signals involved. Targeting more complex biological systems requires the application of global optimization methods to non-linear representations. In this work we address the multi-objective global optimization of metabolic networks that are described by a special class of models based on the power-law formalism: the generalized mass action (GMA) representation. Our goal is to develop global optimization methods capable of efficiently dealing with several biological criteria simultaneously. In order to overcome the numerical difficulties of dealing with multiple criteria in the optimization, we propose a heuristic approach based on the epsilon constraint method that reduces the computational burden of generating a set of Pareto optimal alternatives, each achieving a unique combination of objectives values. To facilitate the post-optimal analysis of these solutions and narrow down their number prior to being tested in the laboratory, we explore the use of Pareto filters that identify the preferred subset of enzymatic profiles. We demonstrate the usefulness of our approach by means of a case study that optimizes the

  1. Prioritizing Candidate Disease Metabolites Based on Global Functional Relationships between Metabolites in the Context of Metabolic Pathways

    Science.gov (United States)

    Yang, Haixiu; Xu, Yanjun; Han, Junwei; Li, Jing; Su, Fei; Zhang, Yunpeng; Zhang, Chunlong; Li, Dongguo; Li, Xia

    2014-01-01

    Identification of key metabolites for complex diseases is a challenging task in today's medicine and biology. A special disease is usually caused by the alteration of a series of functional related metabolites having a global influence on the metabolic network. Moreover, the metabolites in the same metabolic pathway are often associated with the same or similar disease. Based on these functional relationships between metabolites in the context of metabolic pathways, we here presented a pathway-based random walk method called PROFANCY for prioritization of candidate disease metabolites. Our strategy not only takes advantage of the global functional relationships between metabolites but also sufficiently exploits the functionally modular nature of metabolic networks. Our approach proved successful in prioritizing known metabolites for 71 diseases with an AUC value of 0.895. We also assessed the performance of PROFANCY on 16 disease classes and found that 4 classes achieved an AUC value over 0.95. To investigate the robustness of the PROFANCY, we repeated all the analyses in two metabolic networks and obtained similar results. Then we applied our approach to Alzheimer's disease (AD) and found that a top ranked candidate was potentially related to AD but had not been reported previously. Furthermore, our method was applicable to prioritize the metabolites from metabolomic profiles of prostate cancer. The PROFANCY could identify prostate cancer related-metabolites that are supported by literatures but not considered to be significantly differential by traditional differential analysis. We also developed a freely accessible web-based and R-based tool at http://bioinfo.hrbmu.edu.cn/PROFANCY. PMID:25153931

  2. Two-Component Signal Transduction System SaeRS Positively Regulates Staphylococcus epidermidis Glucose Metabolism

    Directory of Open Access Journals (Sweden)

    Qiang Lou

    2014-01-01

    Full Text Available Staphylococcus epidermidis, which is a causative pathogen of nosocomial infection, expresses its virulent traits such as biofilm and autolysis regulated by two-component signal transduction system SaeRS. In this study, we performed a proteomic analysis of differences in expression between the S. epidermidis 1457 wild-type and saeRS mutant to identify candidates regulated by saeRS using two-dimensional gel electrophoresis (2-DE combined with matrix-assisted laser desorption/lonization mass spectrometry (MALDI-TOF-MS. Of 55 identified proteins that significantly differed in expression between the two strains, 15 were upregulated and 40 were downregulated. The downregulated proteins included enzymes related to glycolysis and TCA cycle, suggesting that glucose is not properly utilized in S. epidermidis when saeRS was deleted. The study will be helpful for treatment of S. epidermidis infection from the viewpoint of metabolic modulation dependent on two-component signal transduction system SaeRS.

  3. Polyunsaturated fatty acid regulation of gene transcription: a molecular mechanism to improve the metabolic syndrome.

    Science.gov (United States)

    Clarke, S D

    2001-04-01

    This review addresses the hypothesis that polyunsaturated fatty acids (PUFA), particularly those of the (n-3) family, play pivotal roles as "fuel partitioners" in that they direct fatty acids away from triglyceride storage and toward oxidation, and that they enhance glucose flux to glycogen. In doing this, PUFA may protect against the adverse symptoms of the metabolic syndrome and reduce the risk of heart disease. PUFA exert their beneficial effects by up-regulating the expression of genes encoding proteins involved in fatty acid oxidation while simultaneously down-regulating genes encoding proteins of lipid synthesis. PUFA govern oxidative gene expression by activating the transcription factor peroxisome proliferator-activated receptor alpha. PUFA suppress lipogenic gene expression by reducing the nuclear abundance and DNA-binding affinity of transcription factors responsible for imparting insulin and carbohydrate control to lipogenic and glycolytic genes. In particular, PUFA suppress the nuclear abundance and expression of sterol regulatory element binding protein-1 and reduce the DNA-binding activities of nuclear factor Y, Sp1 and possibly hepatic nuclear factor-4. Collectively, the studies discussed suggest that the fuel "repartitioning" and gene expression actions of PUFA should be considered among criteria used in defining the dietary needs of (n-6) and (n-3) and in establishing the dietary ratio of (n-6) to (n-3) needed for optimum health benefit.

  4. Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism

    Science.gov (United States)

    Kim, Hyunbae; Mendez, Roberto; Chen, Xuequn; Fang, Deyu

    2015-01-01

    Cyclic AMP-responsive element-binding protein 3-like 3, hepatocyte specific (CREBH), is a hepatic transcription factor that functions as a key regulator of energy homeostasis. Here, we defined a regulatory CREBH posttranslational modification process, namely, lysine-specific acetylation, and its functional involvement in fasting-induced hepatic lipid metabolism. Fasting induces CREBH acetylation in mouse livers in a time-dependent manner, and this event is critical for CREBH transcriptional activity in regulating hepatic lipid homeostasis. The histone acetyltransferase PCAF-mediated acetylation and the deacetylase sirtuin-1-mediated deacetylation coexist to maintain CREBH acetylation states under fasting conditions. Site-directed mutagenesis and functional analyses revealed that the lysine (K) residue at position 294 (K294) within the bZIP domain of the CREBH protein is the site where fasting-induced acetylation/deacetylation occurs. Introduction of the acetylation-deficient (K294R) or acetylation-mimicking (K294Q) mutation inhibited or enhanced CREBH transcriptional activity, respectively. Importantly, CREBH acetylation at lysine 294 was required for the interaction and synergy between CREBH and peroxisome proliferator-activated receptor α (PPARα) in activating their target genes upon fasting or glucagon stimulation. Introduction of the CREBH lysine 294 mutation in the liver leads to hepatic steatosis and hyperlipidemia in animals under prolonged fasting. In summary, our study reveals a molecular mechanism by which fasting or glucagon stimulation modulates lipid homeostasis through acetylation of CREBH. PMID:26438600

  5. [Regulation of terpene metabolism]. Annual progress report, March 15, 1990--March 14, 1991

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1991-12-31

    During the last grant period, we have completed studies on the key pathways of monoterpene biosynthesis and catabolism in sage and peppermint, and have, by several lines of evidence, deciphered the rate-limiting step of each pathway. We have at least partially purified and characterized the relevant enzymes of each pathway. We have made a strong case, based on analytical, in vivo, and in vitro studies, that terpene accumulation depends upon the balance between biosynthesis and catabolism, and provided supporting evidence that these processes are developmentally-regulated and very closely associated with senescence of the oil glands. Oil gland ontogeny has been characterized at the ultrastructural level. We have exploited foliar-applied bioregulators to delay gland senescence, and have developed tissue explant and cell culture systems to study several elusive aspects of catabolism. We have isolated pure gland cell clusters and localized monoterpene biosynthesis and catabolism within these structures, and have used these preparations as starting materials for the purification to homogeneity of target ``regulatory`` enzymes. We have thus developed the necessary background knowledge, based on a firm understanding of enzymology, as well as the necessary experimental tools for studying the regulation of monoterpene metabolism at the molecular level. Furthermore, we are now in a position to extend our systematic approach to other terpenoid classes (C{sub 15}-C{sub 30}) produced by oil glands.

  6. NADPH oxidases differentially regulate ROS metabolism and nutrient uptake under cadmium toxicity.

    Science.gov (United States)

    Gupta, D K; Pena, L B; Romero-Puertas, M C; Hernández, A; Inouhe, M; Sandalio, L M

    2017-04-01

    The role of NADPH oxidases under cadmium (Cd) toxicity was studied using Arabidopsis thaliana mutants AtrbohC, AtrbohD and AtrbohF, which were grown under hydroponic conditions with 25 and 100 μM Cd for 1 and 5 days. Cadmium reduced the growth of leaves in WT, AtrbohC and D, but not in AtrbohF. A time-dependent increase in H 2 O 2 and lipid peroxidation was observed in all genotypes, with AtrbohC showing the smallest increase. An opposite behaviour was observed with NO accumulation. Cadmium increased catalase activity in WT plants and decreased it in Atrboh mutants, while glutathione reductase and glycolate oxidase activities increased in Atrboh mutants, and superoxide dismutases were down-regulated in AtrbohC. The GSH/GSSG and ASA/DHA couples were also affected by the treatment, principally in AtrbohC and AtrbohF, respectively. Cadmium translocation to the leaves was severely reduced in Atrboh mutants after 1 day of treatment and even after 5 days in AtrbohF. Similar results were observed for S, P, Ca, Zn and Fe accumulation, while an opposite trend was observed for K accumulation, except in AtrbohF. Thus, under Cd stress, RBOHs differentially regulate ROS metabolism, redox homeostasis and nutrient balance and could be of potential interest in biotechnology for the phytoremediation of polluted soils. © 2016 John Wiley & Sons Ltd.

  7. A Small Potassium Current in AgRP/NPY Neurons Regulates Feeding Behavior and Energy Metabolism.

    Science.gov (United States)

    He, Yanlin; Shu, Gang; Yang, Yongjie; Xu, Pingwen; Xia, Yan; Wang, Chunmei; Saito, Kenji; Hinton, Antentor; Yan, Xiaofeng; Liu, Chen; Wu, Qi; Tong, Qingchun; Xu, Yong

    2016-11-08

    Neurons that co-express agouti-related peptide (AgRP) and neuropeptide Y (NPY) are indispensable for normal feeding behavior. Firing activities of AgRP/NPY neurons are dynamically regulated by energy status and coordinate appropriate feeding behavior to meet nutritional demands. However, intrinsic mechanisms that regulate AgRP/NPY neural activities during the fed-to-fasted transition are not fully understood. We found that AgRP/NPY neurons in satiated mice express high levels of the small-conductance calcium-activated potassium channel 3 (SK3) and are inhibited by SK3-mediated potassium currents; on the other hand, food deprivation suppresses SK3 expression in AgRP/NPY neurons, and the decreased SK3-mediated currents contribute to fasting-induced activation of these neurons. Genetic mutation of SK3 specifically in AgRP/NPY neurons leads to increased sensitivity to diet-induced obesity, associated with chronic hyperphagia and decreased energy expenditure. Our results identify SK3 as a key intrinsic mediator that coordinates nutritional status with AgRP/NPY neural activities and animals' feeding behavior and energy metabolism. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  8. The lateral hypothalamic area revisited: neuroanatomy, body weight regulation, neuroendocrinology and metabolism.

    Science.gov (United States)

    Bernardis, L L; Bellinger, L L

    1993-01-01

    This article reviews findings that have accumulated since the original description of the syndrome that follows destruction of the lateral hypothalamic area (LHA). These data comprise the areas of neuroanatomy, body weight regulation, neuroendocrinology, neurochemistry, and intermediary metabolism. Neurons in the LHA are the largest in the hypothalamus, and are topographically well organized. The LHA belongs to the parasympathetic area of the hypothalamus, and connects with all major parts of the brain and the major hypothalamic nuclei. Rats with LHA lesions regulate their body weight set point in a primary manner and not because of destruction of a "feeding center". The lower body weight is not due to finickiness. In the early stages of the syndrome, catabolism and running activity are enhanced, and so is the activity of the sympathetic nervous system (SNS) as shown by increased norepinephrine excretion that normalizes one mo later. The LHA plays a role in the feedback control of body weight regulation different from ventromedial (VMN) and dorsomedial (DMN). Tissue preparations from the LHA promote glucose utilization and insulin release. Although it does not belong to the classical hypothysiotropic area of the hypothalamus, the LHA does affect neuroendocrine secretions. No plasma data on growth hormone are available following electrolytic lesions LHA but electrical stimulation fails to elicit GH secretion. Nevertheless, antiserum raised against the 1-37 fragment of human GHRF stains numerous perikarya in the dorsolateral LHA. The plasma circadian corticosterone rhythm is disrupted in LHA lesioned rats, but this is unlikely due to destruction of intrinsic oscillators. Stimulation studies show a profound role of the LHA in glucose metabolism (glycolysis, glycogenesis, gluconeogenesis), this mechanism being cholinergic. Its role in lipolysis appears not to be critical. In general, stimulation of the VMN elicits opposite effects. Lesion studies in rats show altered

  9. MiR130b-Regulation of PPARγ Coactivator- 1α Suppresses Fat Metabolism in Goat Mammary Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Zhi Chen

    Full Text Available Fat metabolism is a complicated process regulated by a series of factors. microRNAs (miRNAs are a class of negative regulator of proteins and play crucial roles in many biological processes; including fat metabolism. Although there have been some researches indicating that miRNAs could influence the milk fat metabolism through targeting some factors, little is known about the effect of miRNAs on goat milk fat metabolism. Here we utilized an improved miRNA detection assay, S-Poly-(T, to profile the expression of miRNAs in the goat mammary gland in different periods, and found that miR-130b was abundantly and differentially expressed in goat mammary gland. Additionally, overexpressing miR-130b impaired adipogenesis while inhibiting miR-130b enhanced adipogenesis in goat mammary epithelial cells. Utilizing 3'-UTR assay and Western Blot analusis, the protein peroxisome proliferator-activated receptor coactivator-1α (PGC1α, a