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Sample records for ghrelin receptor family

  1. Common structural basis for constitutive activity of the ghrelin receptor family

    DEFF Research Database (Denmark)

    Holst, Birgitte; Holliday, Nicholas D; Bach, Anders

    2004-01-01

    Three members of the ghrelin receptor family were characterized in parallel: the ghrelin receptor, the neurotensin receptor 2 and the orphan receptor GPR39. In transiently transfected COS-7 and human embryonic kidney 293 cells, all three receptors displayed a high degree of ligand......-independent signaling activity. The structurally homologous motilin receptor served as a constitutively silent control; upon agonist stimulation, however, it signaled with a similar efficacy to the three related receptors. The constitutive activity of the ghrelin receptor and of neurotensin receptor 2 through the G...... demonstrated that the epitope-tagged ghrelin receptor was constitutively internalized but could be trapped at the cell surface by an inverse agonist, whereas GPR39 remained at the cell surface. Mutational analysis showed that the constitutive activity of both the ghrelin receptor and GPR39 could systematically...

  2. Thermogenic characterization of ghrelin receptor null mice

    Science.gov (United States)

    Ghrelin is the only known circulating orexigenic hormone that increases food intake and promotes adiposity, and these physiological functions of ghrelin are mediated through its receptor growth hormone secretagogue receptor (GHS-R). Ghrelin/GHS-R signaling plays a crucial role in energy homeostasis....

  3. Physiological roles revealed by ghrelin and ghrelin receptor deficient mice

    Science.gov (United States)

    Ghrelin is a hormone made in the stomach and known primarily for its growth hormone releasing and orexigenic properties. Nevertheless, ghrelin through its receptor, the GHS-R1a, has been shown to exert many roles including regulation of glucose homeostasis, memory & learning, food addiction and neur...

  4. Associations between ghrelin and ghrelin receptor polymorphisms and cancer in Caucasian populations: a meta-analysis

    OpenAIRE

    Pabalan, Noel A; Seim, Inge; Jarjanazi, Hamdi; Chopin, Lisa K

    2014-01-01

    Background There is growing evidence that the ghrelin axis, including ghrelin (GHRL) and its receptor, the growth hormone secretagogue receptor (GHSR), play a role in cancer progression. Ghrelin gene and ghrelin receptor gene polymorphisms have been reported to have a range of effects in cancer, from increased risk, to protection from cancer, or having no association. In this study we aimed to clarify the role of ghrelin and ghrelin receptor polymorphisms in cancer by performing a meta-analys...

  5. Ghrelin receptor controls obesity by fat burning

    Science.gov (United States)

    Emerging evidence show that brown fat in the body produces heat to burn energy, thus prompting weight loss. Ghrelin is the only known hormone which increases appetite and promotes weight gain. We have reported that mice that lack the receptor which mediates the functions of ghrelin are lean. Our fu...

  6. Hepatic changes in metabolic gene expression in old ghrelin and ghrelin receptor knockout mice

    Science.gov (United States)

    Ghrelin knockout (GKO) and ghrelin receptor (growth hormone secretagogue receptor) knockout (GHSRKO) mice exhibit enhanced insulin sensitivity, but the mechanism is unclear. Insulin sensitivity declines with age and is inversely associated with accumulation of lipid in liver, a key glucoregulatory ...

  7. Ghrelin and Ghrelin Receptor Modulation of Psychostimulant Action

    Directory of Open Access Journals (Sweden)

    Paul Jeff Wellman

    2013-09-01

    Full Text Available Ghrelin (GHR is an orexigenic gut peptide that modulates multiple homeostatic functions including gastric emptying, anxiety, stress, memory, feeding and reinforcement. GHR is known to bind and activate growth-hormone secretagogue receptors (termed GHR-Rs. Of interest to our laboratory has been the assessment of the impact of GHR modulation of the locomotor activation and reward/reinforcement properties of psychostimulants such as cocaine and nicotine. Systemic GHR infusions augment cocaine stimulated locomotion and conditioned place preference (CPP in rats, as does food restriction which elevates plasma ghrelin levels. Ghrelin enhancement of psychostimulant function may occur owing to a direct action on mesolimbic dopamine function or may reflect an indirect action of ghrelin on glucocorticoid pathways. Genomic or pharmacological ablation of GHR-Rs attenuates the acute locomotor-enhancing effects of nicotine, cocaine, amphetamine and alcohol and blunts the CPP induced by food, alcohol, amphetamine and cocaine in mice. The stimulant nicotine can induce CPP and like amphetamine and cocaine, repeated administration of nicotine induces locomotor sensitization in rats. Inactivation of ghrelin circuit function in rats by injection of a ghrelin receptor antagonist (e.g. JMV 2959 diminishes the development of nicotine-induced locomotor sensitization. These results suggest a key permissive role for GHR-R activity for the induction of locomotor sensitization to nicotine. Our finding that GHR-R null rats exhibit diminished patterns of responding for intracranial self-stimulation complements an emerging literature implicating central GHR circuits in drug reward/reinforcement. Finally, antagonism of GHR-Rs may represent a smoking cessation modality that not only blocks nicotine-induced reward but that also may limit weight gain after smoking cessation.

  8. Evidence that central pathways that mediate defecation utilize ghrelin receptors but do not require endogenous ghrelin.

    Science.gov (United States)

    Pustovit, Ruslan V; Callaghan, Brid; Ringuet, Mitchell T; Kerr, Nicole F; Hunne, Billie; Smyth, Ian M; Pietra, Claudio; Furness, John B

    2017-08-01

    In laboratory animals and in human, centrally penetrant ghrelin receptor agonists, given systemically or orally, cause defecation. Animal studies show that the effect is due to activation of ghrelin receptors in the spinal lumbosacral defecation centers. However, it is not known whether there is a physiological role of ghrelin or the ghrelin receptor in the control of defecation. Using immunohistochemistry and immunoassay, we detected and measured ghrelin in the stomach, but were unable to detect ghrelin by either method in the lumbosacral spinal cord, or other regions of the CNS In rats in which the thoracic spinal cord was transected 5 weeks before, the effects of a ghrelin agonist on colorectal propulsion were significantly enhanced, but defecation caused by water avoidance stress (WAS) was reduced. In knockout rats that expressed no ghrelin and in wild-type rats, WAS-induced defecation was reduced by a ghrelin receptor antagonist, to similar extents. We conclude that the ghrelin receptors of the lumbosacral defecation centers have a physiological role in the control of defecation, but that their role is not dependent on ghrelin. This implies that a transmitter other than ghrelin engages the ghrelin receptor or a ghrelin receptor complex. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  9. Hindbrain ghrelin receptor signaling is sufficient to maintain fasting glucose.

    Directory of Open Access Journals (Sweden)

    Michael M Scott

    Full Text Available The neuronal coordination of metabolic homeostasis requires the integration of hormonal signals with multiple interrelated central neuronal circuits to produce appropriate levels of food intake, energy expenditure and fuel availability. Ghrelin, a peripherally produced peptide hormone, circulates at high concentrations during nutrient scarcity. Ghrelin promotes food intake, an action lost in ghrelin receptor null mice and also helps maintain fasting blood glucose levels, ensuring an adequate supply of nutrients to the central nervous system. To better understand mechanisms of ghrelin action, we have examined the roles of ghrelin receptor (GHSR expression in the mouse hindbrain. Notably, selective hindbrain ghrelin receptor expression was not sufficient to restore ghrelin-stimulated food intake. In contrast, the lowered fasting blood glucose levels observed in ghrelin receptor-deficient mice were returned to wild-type levels by selective re-expression of the ghrelin receptor in the hindbrain. Our results demonstrate the distributed nature of the neurons mediating ghrelin action.

  10. Association studies on ghrelin and ghrelin receptor gene polymorphisms with obesity.

    Science.gov (United States)

    Gueorguiev, Maria; Lecoeur, Cécile; Meyre, David; Benzinou, Michael; Mein, Charles A; Hinney, Anke; Vatin, Vincent; Weill, Jacques; Heude, Barbara; Hebebrand, Johannes; Grossman, Ashley B; Korbonits, Márta; Froguel, Philippe

    2009-04-01

    Ghrelin exerts a stimulatory effect on appetite and regulates energy homeostasis. Ghrelin gene variants have been shown to be associated with metabolic traits, although there is evidence suggesting linkage and association with obesity and the ghrelin receptor (GHSR). We hypothesized that these genes are good candidates for susceptibility to obesity. Direct sequencing identified 12 ghrelin single-nucleotide polymorphisms (SNPs) and 8 GHSR SNPs. The 10 common SNPs were genotyped in 1,275 obese subjects and in 1,059 subjects from a general population cohort of European origin. In the obesity case-control study, the GHSR SNP rs572169 was found to be associated with obesity (P = 0.007 in additive model, P = 0.001 in dominant model, odds ratio (OR) 1.73, 95% confidence interval (1.23-2.44)). The ghrelin variant, g.A265T (rs4684677), showed an association with obesity (P = 0.009, BMI adjusted for age and sex) in obese families. The ghrelin variant, g.A-604G (rs27647), showed an association with insulin levels at 2-h post-oral glucose tolerance test (OGTT) (P = 0.009) in obese families. We found an association between the eating behavior "overeating" and the GHSR SNP rs2232169 (P = 0.02) in obese subjects. However, none of these associations remained significant when corrected for multiple comparisons. Replication of the nominal associations with obesity could not be confirmed in a German genome-wide association (GWA) study for rs4684677 and rs572169 polymorphisms. Our data suggest that common polymorphisms in ghrelin and its receptor genes are not major contributors to the development of polygenic obesity, although common variants may alter body weight and eating behavior and contribute to insulin resistance, in particular in the context of early-onset obesity.

  11. Ghrelin receptor mutations--too little height and too much hunger

    DEFF Research Database (Denmark)

    Holst, Birgitte; Schwartz, Thue W

    2006-01-01

    The ghrelin receptor is known from in vitro studies to signal in the absence of the hormone ghrelin at almost 50% of its maximal capacity. But, as for many other 7-transmembrane receptors, the in vivo importance of this ligand-independent signaling has remained unclear. In this issue of the JCI......, Pantel et al. find that a natural mutation in the ghrelin receptor, Ala204Glu, which is associated with a selective loss of constitutive activity without affecting ghrelin affinity, potency, or efficacy, segregates in 2 families with the development of short stature (see the related article beginning...... on page 760). By combination of the observations from this study with those related to the phenotype of subjects carrying another natural ghrelin receptor mutation, Phe279Leu, having identical molecular-pharmacological properties, it is proposed that selective lack of ghrelin receptor constitutive...

  12. Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance

    Science.gov (United States)

    Ghrelin and the ghrelin receptor (GH secretagogue receptor, GHS-R) are believed to have important roles in energy homeostasis. We describe results from the first studies to be conducted in congenic (N10) adult ghrelin(-/-) and Ghsr(-/-) mice under conditions of both positive (high-fat diet) and nega...

  13. Family and population-based studies of variation within the ghrelin receptor locus in relation to measures of obesity

    DEFF Research Database (Denmark)

    Gjesing, Anette P.; Larsen, Lesli Hingstrup; Torekov, Signe Sørensen

    2010-01-01

    -carriers (mean BMI: 28+/-5 kg/m(2)) (p>0.05) could be shown. CONCLUSIONS/SIGNIFICANCE: In a population-based study sample of 15,854 Danes no association between GHSR genotypes and measures of obesity and overweight was found. Also, analyses of GHSR haplotypes lack consistent associations with obesity related......BACKGROUND: The growth hormone secretagogue receptor (GHSR) is mediating hunger sensation when stimulated by its natural ligand ghrelin. In the present study, we tested the hypothesis that common and rare variation in the GHSR locus are related to increased prevalence of obesity and overweight...... among Whites. METHODOLOGY/PRINCIPAL FINDINGS: In a population-based study sample of 15,854 unrelated, middle-aged Danes, seven variants were genotyped to capture common variation in an 11 kbp region including GHSR. These were investigated for their individual and haplotypic association with obesity...

  14. Ghrelin

    DEFF Research Database (Denmark)

    Mueller, T. D.; Nogueiras, R.; Andermann, M. L.

    2015-01-01

    Background The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. Scope...... of review In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. Major conclusions In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct...

  15. Ghrelin

    NARCIS (Netherlands)

    T.D. Müller; R. Nogueiras; M.L. Andermann; Z.B. Andrews; S.D. Anker (Stefan); J. Argente; R.L. Batterham; S.C. Benoit; C.Y. Bowers; F. Broglio (Fabio); F.F. Casanueva; D. D'Alessio; I. Depoortere; A. Geliebter; E. Ghigo (Ezio); P.A. Cole; M. Cowley; D.E. Cummings; A. Dagher (Alain); S. Diano; S.L. Dickson; C. Dieguez (Carlos); R. Granata (Riccarda); H.J. Grill; K. Grove; K.M. Habegger; K. Heppner; M.L. Heiman; L. Holsen; B. Holst; A. Inui; J.O. Jansson; H. Kirchner; M. Korbonits; B. Laferrère; C.W. LeRoux; M. Lopez; S. Morin; M. Nakazato; R. Nass; D. Perez-Tilve; P.T. Pfluger; T.W. Schwartz; R.J. Seeley; M. Sleeman; Y. Sun (Yuxiang); L. Sussel; J. Tong; M.O. Thorner; A-J. van der Lely (Aart-Jan); L.H.T. van der Ploeg; J.M. Zigman; M. Kojima; K. Kangawa; R.G. Smith (Roy); T. Horvath; M. Tschop (Matthias)

    2015-01-01

    textabstractThe gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. Scope

  16. Ghrelin

    Science.gov (United States)

    Müller, T.D.; Nogueiras, R.; Andermann, M.L.; Andrews, Z.B.; Anker, S.D.; Argente, J.; Batterham, R.L.; Benoit, S.C.; Bowers, C.Y.; Broglio, F.; Casanueva, F.F.; D'Alessio, D.; Depoortere, I.; Geliebter, A.; Ghigo, E.; Cole, P.A.; Cowley, M.; Cummings, D.E.; Dagher, A.; Diano, S.; Dickson, S.L.; Diéguez, C.; Granata, R.; Grill, H.J.; Grove, K.; Habegger, K.M.; Heppner, K.; Heiman, M.L.; Holsen, L.; Holst, B.; Inui, A.; Jansson, J.O.; Kirchner, H.; Korbonits, M.; Laferrère, B.; LeRoux, C.W.; Lopez, M.; Morin, S.; Nakazato, M.; Nass, R.; Perez-Tilve, D.; Pfluger, P.T.; Schwartz, T.W.; Seeley, R.J.; Sleeman, M.; Sun, Y.; Sussel, L.; Tong, J.; Thorner, M.O.; van der Lely, A.J.; van der Ploeg, L.H.T.; Zigman, J.M.; Kojima, M.; Kangawa, K.; Smith, R.G.; Horvath, T.; Tschöp, M.H.

    2015-01-01

    Background The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. Scope of review In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. Major conclusions In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism. PMID:26042199

  17. Ghrelin receptor regulates adipose tissue inflammation in aging

    Science.gov (United States)

    Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth ho...

  18. Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging

    Science.gov (United States)

    Obesity is a hallmark of aging in many Western societies, and is a precursor to numerous serious age-related diseases. Ghrelin ("Ghrl"), via its receptor (growth hormone secretagogue receptor, GHS-R), is shown to stimulate GH secretion and appetite. Surprisingly, our previous studies showed that "Gh...

  19. Associations between ghrelin and ghrelin receptor polymorphisms and cancer in Caucasian populations: a meta-analysis.

    Science.gov (United States)

    Pabalan, Noel A; Seim, Inge; Jarjanazi, Hamdi; Chopin, Lisa K

    2014-11-07

    There is growing evidence that the ghrelin axis, including ghrelin (GHRL) and its receptor, the growth hormone secretagogue receptor (GHSR), play a role in cancer progression. Ghrelin gene and ghrelin receptor gene polymorphisms have been reported to have a range of effects in cancer, from increased risk, to protection from cancer, or having no association. In this study we aimed to clarify the role of ghrelin and ghrelin receptor polymorphisms in cancer by performing a meta-analysis of published case-control studies. In the overall analysis, homozygous and recessive associations indicated that the minor alleles of rs696217 and rs2075356 GHRL polymorphisms conferred reduced cancer risk (odds ratio [OR] 0.61-0.78). The risk was unchanged for breast cancer patients when analysed separately (OR 0.73-0.83). In contrast, the rs4684677 GHRL and the rs572169 GHSR polymorphisms conferred increased breast cancer risk (OR 1.97-1.98, p = 0.08 and OR 1.42-1.43, p = 0.08, respectively). All dominant and co-dominant effects showed null effects (OR 0.96-1.05), except for the rs572169 co-dominant effect, with borderline increased risk (OR 1.08, p = 0.05). This study suggests that the rs696217 and rs2075356 ghrelin gene (GHRL) polymorphisms may protect carriers against breast cancer, and the rs4684677 GHRL and rs572169 GHSR polymorphisms may increase the risk among carriers. In addition, larger studies are required to confirm these findings.

  20. Ghrelin

    Science.gov (United States)

    The gut hormone ghrelin was discovered in 1999. In the last 15 years, ample data have been generated on ghrelin. Bedsides its hallmark function as an appetite stimulator, ghrelin also has many other important functions. In this review, we discussed ghrelin's functions in learning and memory, gut mov...

  1. Anxiolytic-Like Effects of Increased Ghrelin Receptor Signaling in the Amygdala

    DEFF Research Database (Denmark)

    Jensen, Morten; Ratner, Cecilia; Rudenko, Olga

    2016-01-01

    BACKGROUND: Besides the well-known effects of ghrelin on adiposity and food intake regulation, the ghrelin system has been shown to regulate aspects of behavior including anxiety and stress. However, the effect of virus-mediated overexpression of the ghrelin receptor in the amygdala has...... not previously been addressed directly. METHOD: First, we examined the acute effect of peripheral ghrelin administration on anxiety- and depression-like behavior using the open field, elevated plus maze, forced swim and tail suspension tests. Next, we examined the effect of peripheral ghrelin administration...... and ghrelin receptor deficiency on stress in a familiar and social environment using the Intellicage system. Importantly, we also used a novel approach to study ghrelin receptor signaling in the brain by overexpressing the ghrelin receptor in the amygdala. We examined the effect of ghrelin receptor...

  2. Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications

    Directory of Open Access Journals (Sweden)

    Andreas eStengel

    2013-01-01

    Full Text Available Somatostatin is an important modulator of neurotransmission in the central nervous system and acts as a potent inhibitor of hormone and exocrine secretion and regulator of cell proliferation in the periphery. These pleiotropic actions occur through interaction with five G-protein coupled somatostatin receptor subtypes (sst1-5 that are widely expressed in the brain and peripheral organs. The characterization of somatostatin’s effects can be investigated by pharmacological or genetic approaches using newly developed selective sst agonists and antagonists and mice lacking specific sst subtypes. Recent evidence points towards a divergent action of somatostatin in the brain and in the periphery to regulate circulating levels of ghrelin, an orexigenic hormone produced by the endocrine X/A-like cells in the gastric mucosa. Somatostatin interacts with the sst2 in the brain to induce an increase in basal ghrelin plasma levels and counteracts the visceral stress-related decrease in circulating ghrelin in rats. By contrast, stimulation of peripheral somatostatin-sst2 signaling results in the inhibition of basal ghrelin release and mediates the postoperative decrease in circulating ghrelin in rats. The peripheral sst2-mediated reduction of plasma ghrelin is likely to involve a paracrine action of D-cell derived somatostatin acting on sst2 bearing X/A-like ghrelin cells in the gastric mucosa. The other member of the somatostatin family, named cortistatin, in addition to binding to sst1-5 also directly interacts with the ghrelin receptor and therefore may simultaneously modulate ghrelin release and actions at target sites bearing ghrelin receptors representing a link between the ghrelin and somatostatin systems.

  3. Neuronal deletion of ghrelin receptor almost completely prevents diet-induced obesity

    Science.gov (United States)

    Ghrelin signaling has major effects on energy- and glucose-homeostasis, but it is unknown whether ghrelin's functions are centrally and/or peripherally mediated. The ghrelin receptor, Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in brain and detectable in some peripheral tissues...

  4. Functionally biased signalling properties of 7TM receptors - opportunities for drug development for the ghrelin receptor

    DEFF Research Database (Denmark)

    Sivertsen, B; Holliday, N; Madsen, A N

    2013-01-01

    UNLABELLED: The ghrelin receptor is a 7 transmembrane (7TM) receptor involved in a variety of physiological functions including growth hormone secretion, increased food intake and fat accumulation as well as modulation of reward and cognitive functions. Because of its important role in metabolism...... and energy expenditure, the ghrelin receptor has become an important therapeutic target for drug design and the development of anti-obesity compounds. However, none of the compounds developed so far have been approved for commercial use. Interestingly, the ghrelin receptor is able to signal through several...... review, we have described how ligands and mutations in the 7TM receptor may bias the receptors to favour either one G-protein over another or to promote G-protein independent signalling pathways rather than G-protein-dependent pathways. For the ghrelin receptor, both agonist and inverse agonists have...

  5. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells

    DEFF Research Database (Denmark)

    Engelstoft, Maja S; Park, Won-Mee; Sakata, Ichiro

    2013-01-01

    The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro......, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi....../o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi...

  6. Sequence genomic organization and expression of two channel catfish Ictalurus punctatus Ghrelin receptors

    Science.gov (United States)

    Two ghrelin receptor (GHS-R) genes were isolated from channel catfish tissue and a bacterial artificial chromosome (BAC) library. The two receptors were characterized by determining tissue distribution, ontogeny of receptor mRNA expression, and effects of exogenous homologous ghrelin administration ...

  7. Unique interaction pattern for a functionally biased ghrelin receptor agonist

    DEFF Research Database (Denmark)

    Sivertsen, Bjørn Behrens; Lang, Manja; Frimurer, Thomas M.

    2011-01-01

    Based on the conformationally constrained D-Trp-Phe-D-Trp (wFw) core of the prototype inverse agonist [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]substance P, a series of novel, small, peptide-mimetic agonists for the ghrelin receptor were generated. By using various simple, ring-constrained spacers...... connecting the D-Trp-Phe-D-Trp motif with the important C-terminal carboxyamide group, 40 nm agonism potency was obtained and also in one case (wFw-Isn-NH(2), where Isn is isonipecotic acid) ~80% efficacy. However, in contrast to all previously reported ghrelin receptor agonists, the piperidine-constrained w......Fw-Isn-NH(2) was found to be a functionally biased agonist. Thus, wFw-Isn-NH(2) mediated potent and efficacious signaling through the Ga(q) and ERK1/2 signaling pathways, but in contrast to all previous ghrelin receptor agonists it did not signal through the serum response element, conceivably the Ga(12...

  8. Ghrelin receptor regulates adipose tissue inflammation in aging.

    Science.gov (United States)

    Lin, Ligen; Lee, Jong Han; Buras, Eric D; Yu, Kaijiang; Wang, Ruitao; Smith, C Wayne; Wu, Huaizhu; Sheikh-Hamad, David; Sun, Yuxiang

    2016-01-01

    Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr(-/-) mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsrp(-/-) mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsrp(-/-) mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance.

  9. β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

    Science.gov (United States)

    Mani, Bharath K.; Osborne-Lawrence, Sherri; Vijayaraghavan, Prasanna; Hepler, Chelsea; Zigman, Jeffrey M.

    2016-01-01

    Ghrelin is an orexigenic gastric peptide hormone secreted when caloric intake is limited. Ghrelin also regulates blood glucose, as emphasized by the hypoglycemia that is induced by caloric restriction in mouse models of deficient ghrelin signaling. Here, we hypothesized that activation of β1-adrenergic receptors (β1ARs) localized to ghrelin cells is required for caloric restriction–associated ghrelin release and the ensuing protective glucoregulatory response. In mice lacking the β1AR specifically in ghrelin-expressing cells, ghrelin secretion was markedly blunted, resulting in profound hypoglycemia and prevalent mortality upon severe caloric restriction. Replacement of ghrelin blocked the effects of caloric restriction in β1AR-deficient mice. We also determined that treating calorically restricted juvenile WT mice with beta blockers led to reduced plasma ghrelin and hypoglycemia, the latter of which is similar to the life-threatening, fasting-induced hypoglycemia observed in infants treated with beta blockers. These findings highlight the critical functions of ghrelin in preventing hypoglycemia and promoting survival during severe caloric restriction and the requirement for ghrelin cell–expressed β1ARs in these processes. Moreover, these results indicate a potential role for ghrelin in mediating beta blocker–associated hypoglycemia in susceptible individuals, such as young children. PMID:27548523

  10. Ghrelin

    Directory of Open Access Journals (Sweden)

    T.D. Müller

    2015-06-01

    Major conclusions: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

  11. High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist

    DEFF Research Database (Denmark)

    Holst, Birgitte; Cygankiewicz, Adam; Jensen, Tine Halkjaer

    2003-01-01

    Ghrelin is a GH-releasing peptide that also has an important role as an orexigenic hormone-stimulating food intake. By measuring inositol phosphate turnover or by using a reporter assay for transcriptional activity controlled by cAMP-responsive elements, the ghrelin receptor showed strong, ligand......-independent signaling in transfected COS-7 or human embryonic kidney 293 cells. Ghrelin and a number of the known nonpeptide GH secretagogues acted as agonists stimulating inositol phosphate turnover further. In contrast, the low potency ghrelin antagonist, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P was surprisingly...... found to be a high potency (EC50 = 5.2 nm) full inverse agonist as it decreased the constitutive signaling of the ghrelin receptor down to that observed in untransfected cells. The homologous motilin receptor functioned as a negative control as it did not display any sign of constitutive activity...

  12. Epistatic interaction between haplotypes of the ghrelin ligand and receptor genes influence susceptibility to myocardial infarction and coronary artery disease.

    Science.gov (United States)

    Baessler, Andrea; Fischer, Marcus; Mayer, Bjoern; Koehler, Martina; Wiedmann, Silke; Stark, Klaus; Doering, Angela; Erdmann, Jeanette; Riegger, Guenter; Schunkert, Heribert; Kwitek, Anne E; Hengstenberg, Christian

    2007-04-15

    Data from both experimental models and humans provide evidence that ghrelin and its receptor, the growth hormone secretagogue receptor (ghrelin receptor, GHSR), possess a variety of cardiovascular effects. Thus, we hypothesized that genetic variants within the ghrelin system (ligand ghrelin and its receptor GHSR) are associated with susceptibility to myocardial infarction (MI) and coronary artery disease (CAD). Seven single nucleotide polymorphisms (SNPs) covering the GHSR region as well as eight SNPs across the ghrelin gene (GHRL) region were genotyped in index MI patients (864 Caucasians, 'index MI cases') from the German MI family study and in matched controls without evidence of CAD (864 Caucasians, 'controls', MONICA Augsburg). In addition, siblings of these MI patients with documented severe CAD (826 'affected sibs') were matched likewise with controls (n = 826 Caucasian 'controls') and used for verification. The effect of interactions between genetic variants of both genes of the ghrelin system was explored by conditional classification tree models. We found association of several GHSR SNPs with MI [best SNP odds ratio (OR) 1.7 (1.2-2.5); P = 0.002] using a recessive model. Moreover, we identified a common GHSR haplotype which significantly increases the risk for MI [multivariate adjusted OR for homozygous carriers 1.6 (1.1-2.5) and CAD OR 1.6 (1.1-2.5)]. In contrast, no relationship between genetic variants and the disease could be revealed for GHRL. However, the increase in MI/CAD frequency related to the susceptible GHSR haplotype was abolished when it coincided with a common GHRL haplotype. Multivariate adjustments as well as permutation-based methods conveyed the same results. These data are the first to demonstrate an association of SNPs and haplotypes within important genes of the ghrelin system and the susceptibility to MI, whereas association with MI/CAD could be identified for genetic variants across GHSR, no relationship could be revealed for GHRL

  13. Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice

    Science.gov (United States)

    The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob (Ghrelin(-/-):ob/ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth ...

  14. Ghrelin interacts with neuropeptide Y Y1 and opioid receptors to increase food reward.

    Science.gov (United States)

    Skibicka, Karolina P; Shirazi, Rozita H; Hansson, Caroline; Dickson, Suzanne L

    2012-03-01

    Ghrelin, a stomach-derived hormone, is an orexigenic peptide that was recently shown to potently increase food reward behavior. The neurochemical circuitry that links ghrelin to the mesolimbic system and food reward behavior remains unclear. Here we examined the contribution of neuropeptide Y (NPY) and opioids to ghrelin's effects on food motivation and intake. Both systems have well-established links to the mesolimbic ventral tegmental area (VTA) and reward/motivation control. NPY mediates the effect of ghrelin on food intake via activation of NPY-Y1 receptor (NPY-Y1R); their connection with respect to motivated behavior is unexplored. The role of opioids in any aspect of ghrelin's action on food-oriented behaviors is unknown. Rats were trained in a progressive ratio sucrose-induced operant schedule to measure food reward/motivation behavior. Chow intake was measured immediately after the operant test. In separate experiments, we explored the suppressive effects of a selective NPY-Y1R antagonist or opioid receptor antagonist naltrexone, injected either intracerebroventricularly or intra-VTA, on ghrelin-induced food reward behavior. The ventricular ghrelin-induced increase in sucrose-motivated behavior and chow intake were completely blocked by intracerebroventricular pretreatment with either an NPY-Y1R antagonist or naltrexone. The intra-VTA ghrelin-induced sucrose-motivated behavior was blocked only by intra-VTA naltrexone. In contrast, the intra-VTA ghrelin-stimulated chow intake was attenuated only by intra-VTA NPY-Y1 blockade. Finally, ghrelin infusion was associated with an elevated VTA μ-opioid receptor expression. Thus, we identify central NPY and opioid signaling as the necessary mediators of food intake and reward effects of ghrelin and localize these interactions to the mesolimbic VTA.

  15. Modulation of the constitutive activity of the ghrelin receptor by use of pharmacological tools and mutagenesis

    DEFF Research Database (Denmark)

    Mokrosinski, Jacek; Holst, Birgitte

    2010-01-01

    Ghrelin and its receptor are important regulators of metabolic functions, including appetite, energy expenditure, fat accumulation, and growth hormone (GH) secretion. The ghrelin receptor is characterized by an ability to signal even without any ligand present with approximately 50......% of the maximally ghrelin-induced efficacy-a feature that may have important physiological implications. The high basal signaling can be modulated either by administration of specific ligands or by engineering of mutations in the receptor structure. [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P...... was the first inverse agonist to be identified for the ghrelin receptor, and this peptide has been used as a starting point for identification of the structural requirements for inverse agonist properties in the ligand. The receptor binding core motif was identified as D-Trp-Phe-D-Trp-Leu-Leu, and elongation...

  16. Ghrelin receptors mediate ghrelin-induced excitation of agouti-related protein/neuropeptide Y but not pro-opiomelanocortin neurons.

    Science.gov (United States)

    Chen, Shao-Rui; Chen, Hong; Zhou, Jing-Jing; Pradhan, Geetali; Sun, Yuxiang; Pan, Hui-Lin; Li, De-Pei

    2017-08-01

    Ghrelin increases food intake and body weight by stimulating orexigenic agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons and inhibiting anorexic pro-opiomelanocortin (POMC) neurons in the hypothalamus. Growth hormone secretagogue receptor (Ghsr) mediates the effect of ghrelin on feeding behavior and energy homeostasis. However, the role of Ghsr in the ghrelin effect on these two populations of neurons is unclear. We hypothesized that Ghsr mediates the effect of ghrelin on AgRP and POMC neurons. In this study, we determined whether Ghsr similarly mediates the effects of ghrelin on AgRP/NPY and POMC neurons using cell type-specific Ghsr-knockout mice. Perforated whole-cell recordings were performed on green fluorescent protein-tagged AgRP/NPY and POMC neurons in the arcuate nucleus in hypothalamic slices. In Ghsr +/+ mice, ghrelin (100 nM) significantly increased the firing activity of AgRP/NPY neurons but inhibited the firing activity of POMC neurons. In Ghsr -/- mice, the excitatory effect of ghrelin on AgRP/NPY neurons was abolished. Ablation of Ghsr also eliminated ghrelin-induced increases in the frequency of GABAergic inhibitory postsynaptic currents of POMC neurons. Strikingly, ablation of Ghsr converted the ghrelin effect on POMC neurons from inhibition to excitation. Des-acylated ghrelin had no such effect on POMC neurons in Ghsr -/- mice. In both Ghsr +/+ and Ghsr -/- mice, blocking GABA A receptors with gabazine increased the basal firing activity of POMC neurons, and ghrelin further increased the firing activity of POMC neurons in the presence of gabazine. Our findings provide unequivocal evidence that Ghsr is essential for ghrelin-induced excitation of AgRP/NPY neurons. However, ghrelin excites POMC neurons through an unidentified mechanism that is distinct from conventional Ghsr. © 2017 International Society for Neurochemistry.

  17. Importance of constitutive activity and arrestin-independent mechanisms for intracellular trafficking of the ghrelin receptor

    DEFF Research Database (Denmark)

    Holliday, Nicholas D; Holst, Birgitte; Rodionova, Elena A

    2007-01-01

    . Furthermore the interaction between phosphorylated receptors and beta-arrestin adaptor proteins has been examined. Replacement of the FLAG-tagged GhrelinR C tail with the equivalent GPR39 domain (GhR-39 chimera) preserved G(q) signaling. However in contrast to the GhrelinR, GhR-39 receptors exhibited no basal......,9), Leu(11)] substance P and a naturally occurring mutant GhrelinR (A204E) with eliminated constitutive activity inhibited basal GhrelinR internalization. Surprisingly, we found that noninternalizing GPR39 was highly phosphorylated and that basal and agonist-induced phosphorylation of the GhR-39 chimera......, but the high levels of GPR39 phosphorylation, and of the GhR-39 chimera, are not sufficient to drive endocytosis. In addition, basal GhrelinR internalization occurs independently of beta-arrestins....

  18. Association study of ghrelin receptor gene polymorphisms in rheumatoid arthritis.

    Science.gov (United States)

    Robledo, G; Rueda, B; Gonzalez-Gay, M A; Fernández, B; Lamas, J R; Balsa, A; Pascual-Salcedo, D; García, A; Raya, E; Martín, J

    2010-01-01

    Ghrelin is a newly characterised growth hormone (GH) releasing peptide widely distributed that may play an important role in the regulation of metabolic balance in inflammatory diseases such as rheumatoid arthritis (RA) by decreasing the pro-inflammatory Th1 responses. In this study we investigated the possible contribution of several polymorphisms in the functional Ghrelin receptor to RA susceptibility. A screening of 3 single nucleotide polymorphisms (SNPs) was performed in a total of 950 RA patients and 990 healthy controls of Spanish Caucasian origin. Genotyping of all 3 SNPs was performed by real-time polymerase chain reaction technology, using the TaqMan 5'-allele discrimination assay. We observed no statistically significant deviation between RA patients and controls for the GHSR SNPs analysed. In addition, we performed a haplotype analysis that did not reveal an association with RA susceptibility. The stratification analysis for the presence of shared epitope (SE), rheumatoid factor (RF) or antibodies anti cyclic citrullinated peptide (anti-CCP) did not detect significant association of the GHSR polymorphisms with RA. These findings suggest that the GHSR gene polymorphisms do not appear to play a major role in RA genetic predisposition in our population.

  19. The role of ghrelin and ghrelin-receptor gene variants and promoter activity in type 2 diabetes.

    Science.gov (United States)

    Garcia, Edwin A; King, Peter; Sidhu, Kally; Ohgusu, Hideko; Walley, Andrew; Lecoeur, Cecile; Gueorguiev, Maria; Khalaf, Sahira; Davies, Derek; Grossman, Ashley B; Kojima, Masayasu; Petersenn, Stephan; Froguel, Phillipe; Korbonits, Márta

    2009-08-01

    Ghrelin and its receptor play an important role in glucose metabolism and energy homeostasis, and therefore they are functional candidates for genes carrying susceptibility alleles for type 2 diabetes. We assessed common genetic variation of the ghrelin (GHRL; five single nucleotide polymorphisms (SNP)) and the ghrelin-receptor (GHSR) genes (four SNPs) in 610 Caucasian patients with type 2 diabetes and 820 controls. In addition, promoter reporter assays were conducted to model the regulatory regions of both genes. Neither GHRL nor GHSR gene SNPs were associated with type 2 diabetes. One of the ghrelin haplotypes showed a marginal protective role in type 2 diabetes. We observed profound differences in the regulation of the GHRL gene according to promoter sequence variants. There are three different GHRL promoter haplotypes represented in the studied cohort causing up to 45% difference in the level of gene expression, while the promoter region of GHSR gene is primarily represented by a single haplotype. The GHRL and GHSR gene variants are not associated with type 2 diabetes, although GHRL promoter variants have significantly different activities.

  20. Abalation of Ghrelin receptor in leptin-deficient mice has paradoxical effects on glucose homeostasis compared to Ghrelin-abalated Leptin-deficient mice

    Science.gov (United States)

    Ghrelin is produced predominantly in stomach and is known to be the endogenous ligand of the growth hormone secretagogue receptor (GHSR). Ghrelin is a GH stimulator and an orexigenic hormone. In contrast, leptin is an anorexic hormone, and leptin-deficient ob/ob mice are obese and diabetic. To study...

  1. Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward.

    Science.gov (United States)

    Schellekens, Harriët; Dinan, Timothy G; Cryan, John F

    2013-08-30

    The gut hormone, ghrelin, is the only known peripherally derived orexigenic signal. It activates its centrally expressed receptor, the growth hormone secretagogue receptor (GHS-R1a), to stimulate food intake. The ghrelin signaling system has recently been suggested to play a key role at the interface of homeostatic control of appetite and the hedonic aspects of food intake, as a critical role for ghrelin in dopaminergic mesolimbic circuits involved in reward signaling has emerged. Moreover, enhanced plasma ghrelin levels are associated with conditions of physiological stress, which may underline the drive to eat calorie-dense "comfort-foods" and signifies a role for ghrelin in stress-induced food reward behaviors. These complex and diverse functionalities of the ghrelinergic system are not yet fully elucidated and likely involve crosstalk with additional signaling systems. Interestingly, accumulating data over the last few years has shown the GHS-R1a receptor to dimerize with several additional G-protein coupled receptors (GPCRs) involved in appetite signaling and reward, including the GHS-R1b receptor, the melanocortin 3 receptor (MC3), dopamine receptors (D1 and D2), and more recently, the serotonin 2C receptor (5-HT2C). GHS-R1a dimerization was shown to affect downstream signaling and receptor trafficking suggesting a potential novel mechanism for fine-tuning GHS-R1a receptor mediated activity. This review summarizes ghrelin's role in food reward and stress and outlines the GHS-R1a dimer pairs identified to date. In addition, the downstream signaling and potential functional consequences of dimerization of the GHS-R1a receptor in appetite and stress-induced food reward behavior are discussed. The existence of multiple GHS-R1a heterodimers has important consequences for future pharmacotherapies as it significantly increases the pharmacological diversity of the GHS-R1a receptor and has the potential to enhance specificity of novel ghrelin-targeted drugs.

  2. Identification of neurons that express ghrelin receptors in autonomic pathways originating from the spinal cord.

    Science.gov (United States)

    Furness, John B; Cho, Hyun-Jung; Hunne, Billie; Hirayama, Haruko; Callaghan, Brid P; Lomax, Alan E; Brock, James A

    2012-06-01

    Functional studies have shown that subsets of autonomic preganglionic neurons respond to ghrelin and ghrelin mimetics and in situ hybridisation has revealed receptor gene expression in the cell bodies of some preganglionic neurons. Our present goal has been to determine which preganglionic neurons express ghrelin receptors by using mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoter for the ghrelin receptor (also called growth hormone secretagogue receptor). The retrograde tracer Fast Blue was injected into target organs of reporter mice under anaesthesia to identify specific functional subsets of postganglionic sympathetic neurons. Cryo-sections were immunohistochemically stained by using anti-EGFP and antibodies to neuronal markers. EGFP was detected in nerve terminal varicosities in all sympathetic chain, prevertebral and pelvic ganglia and in the adrenal medulla. Non-varicose fibres associated with the ganglia were also immunoreactive. No postganglionic cell bodies contained EGFP. In sympathetic chain ganglia, most neurons were surrounded by EGFP-positive terminals. In the stellate ganglion, neurons with choline acetyltransferase immunoreactivity, some being sudomotor neurons, lacked surrounding ghrelin-receptor-expressing terminals, although these terminals were found around other neurons. In the superior cervical ganglion, the ghrelin receptor terminals innervated subgroups of neurons including neuropeptide Y (NPY)-immunoreactive neurons that projected to the anterior chamber of the eye. However, large NPY-negative neurons projecting to the acini of the submaxillary gland were not innervated by EGFP-positive varicosities. In the celiaco-superior mesenteric ganglion, almost all neurons were surrounded by positive terminals but the VIP-immunoreactive terminals of intestinofugal neurons were EGFP-negative. The pelvic ganglia contained groups of neurons without ghrelin receptor terminal innervation and other groups with

  3. In vivo characterization of high Basal signaling from the ghrelin receptor

    DEFF Research Database (Denmark)

    Petersen, Pia Steen; Woldbye, David P D; Madsen, Andreas Nygaard

    2009-01-01

    The receptor for the orexigenic peptide, ghrelin, is one of the most constitutively active 7TM receptors known, as demonstrated under in vitro conditions. Change in expression of a constitutively active receptor is associated with change in signaling independent of the endogenous ligand. In the f......The receptor for the orexigenic peptide, ghrelin, is one of the most constitutively active 7TM receptors known, as demonstrated under in vitro conditions. Change in expression of a constitutively active receptor is associated with change in signaling independent of the endogenous ligand....... In the following study, we found that the expression of the ghrelin receptor in the hypothalamus was up-regulated approximately 2-fold in rats both during 48-h fasting and by streptozotocin-induced hyperphagia. In a separate experiment, to probe for the effect of the high basal signaling of the ghrelin receptor...... in vivo, we used intracerebroventricular administration by osmotic pumps of a peptide [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P. This peptide selectively displays inverse agonism at the ghrelin receptor as compared with an inactive control peptide with just a single amino acid substitution...

  4. Ghrelin is produced in taste cells and ghrelin receptor null mice show reduced taste responsivity to salty (NaCl and sour (citric acid tastants.

    Directory of Open Access Journals (Sweden)

    Yu-Kyong Shin

    2010-09-01

    Full Text Available The gustatory system plays a critical role in determining food preferences, food intake and energy balance. The exact mechanisms that fine tune taste sensitivity are currently poorly defined, but it is clear that numerous factors such as efferent input and specific signal transduction cascades are involved.Using immunohistochemical analyses, we show that ghrelin, a hormone classically considered to be an appetite-regulating hormone, is present within the taste buds of the tongue. Prepro-ghrelin, prohormone convertase 1/3 (PC 1/3, ghrelin, its cognate receptor (GHSR, and ghrelin-O-acyltransferase (GOAT , the enzyme that activates ghrelin are expressed in Type I, II, III and IV taste cells of mouse taste buds. In addition, ghrelin and GHSR co-localize in the same taste cells, suggesting that ghrelin works in an autocrine manner in taste cells. To determine a role for ghrelin in modifying taste perception, we performed taste behavioral tests using GHSR null mice. GHSR null mice exhibited significantly reduced taste responsivity to sour (citric acid and salty (sodium chloride tastants.These findings suggest that ghrelin plays a local modulatory role in determining taste bud signaling and function and could be a novel mechanism for the modulation of salty and sour taste responsivity.

  5. Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin

    OpenAIRE

    Asakawa, A; Inui, A; Fujimiya, M; Sakamaki, R; Shinfuku, N; Ueta, Y; Meguid, M M; Kasuga, M

    2005-01-01

    Background/Aims: The gastric peptide ghrelin, an endogenous ligand for growth-hormone secretagogue receptor, has two major molecular forms: acylated ghrelin and desacyl ghrelin. Acylated ghrelin induces a positive energy balance, while desacyl ghrelin has been reported to be devoid of any endocrine activities. The authors examined the effects of desacyl ghrelin on energy balance.

  6. The Pentapeptide RM-131 Promotes Food Intake and Adiposity in Wildtype Mice but Not in Mice Lacking the Ghrelin Receptor

    DEFF Research Database (Denmark)

    Fischer, Katrin; Finan, Brian; Clemmensen, Christoffer

    2014-01-01

    The gastrointestinal peptide hormone ghrelin is the endogenous ligand of the growth hormone secretagogue receptor (a.k.a. ghrelin receptor, GHR). Currently, ghrelin is the only circulating peripheral hormone with the ability to promote a positive energy balance by stimulating food intake while...... decreasing energy expenditure and body fat utilization, as defined in rodents. Based on these and additional, beneficial effects on metabolism, the endogenous ghrelin system is considered an attractive target to treat diverse pathological conditions including those associated with eating/wasting disorders...... and cachexia. As the pharmacological potential of ghrelin is hampered by its relatively short half-life, ghrelin analogs with enhanced pharmacokinetics offer the potential to sustainably improve metabolism. One of these ghrelin analogs is the pentapeptide RM-131, which promotes food intake and adiposity...

  7. Impact of food restriction and cocaine on locomotion in ghrelin- and ghrelin-receptor knockout mice.

    Science.gov (United States)

    Clifford, Shane; Zeckler, Rosie Albarran; Buckman, Sam; Thompson, Jeff; Hart, Nigel; Wellman, Paul J; Smith, Roy G

    2011-07-01

    Food restriction (FR) augments the behavioral and reinforcing effects of psychomotor stimulants such as cocaine or amphetamine; effects that may be related to the capacity of FR to increase plasma levels of ghrelin (GHR), a 28-amino acid orexigenenic peptide linked to activation of brain dopamine systems. The present study used wild-type (WT) mice or mutant mice sustaining knockout of either GHR [GHR((-/-)) ] or of the growth hormone secretagogue receptor [GHS-R((-/-)) ] and subjected to FR or not to evaluate the role of GHR and GHS-R in cocaine-stimulated locomotion. WT, GHR((-/-)) , and GHS-R((-/-)) mice were either restricted to 60% of baseline caloric intake or allowed to free-feed (FF). Mice were treated with 0, 1.25, 2.5 and 5.0 mg/kg cocaine on separate test days (in random dose order) and forward locomotion was recorded on each drug day for 45 minutes after drug dosing. Food (and water) was available immediately after (but not during) each activity test. For FF mice, there was no interaction between cocaine and GHR status on locomotion. FR-WT mice treated with saline exhibited significant increases in anticipatory locomotion (relative to FF-WT mice), whereas FR-GHS-R((-/-)) mice did not. Cocaine significantly increased locomotion in FR-GHR((-/-)) and FR-GHS-R((-/-)) mice to the levels noted in FR-WT mice. These results suggest that GHS-R activity, but not GHR activity, is required for FR to augment food-associated anticipatory locomotion, but do not support the contention that GHR pathways are required for the capacity of FR to augment the acute effect of cocaine on locomotion. © 2010 The Authors, Addiction Biology © 2010 Society for the Study of Addiction.

  8. Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor

    DEFF Research Database (Denmark)

    Holst, Birgitte; Lang, Manja; Brandt, Erik

    2006-01-01

    [D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P functions as a low-potency antagonist but a high-potency full inverse agonist on the ghrelin receptor. Through a systematic deletion and substitution analysis of this peptide, the C-terminal carboxyamidated pentapeptide wFwLX was identified as the core...... structure, which itself displayed relatively low inverse agonist potency. Mutational analysis at 17 selected positions in the main ligand-binding crevice of the ghrelin receptor demonstrated that ghrelin apparently interacts only with residues in the middle part of the pocket [i.e., between transmembrane...... upon both AspII:20 and GluIII:09. The identified pharmacophore can possibly serve as the basis for targeted discovery of also nonpeptide inverse agonists for the ghrelin receptor....

  9. Regulation of Ghrelin Receptor by Periodontal Bacteria In Vitro and In Vivo

    OpenAIRE

    Nokhbehsaim, Marjan; Damanaki, Anna; Nogueira, Andressa Vilas Boas; Eick, Sigrun; Memmert, Svenja; Zhou, Xiaoyan; Nanayakkara, Shanika; Götz, Werner; Cirelli, Joni Augusto; Jäger, Andreas; Deschner, James

    2017-01-01

    Ghrelin plays a major role in obesity-related diseases which have been shown to be associated with periodontitis. This study sought to analyze the expression of the functional receptor for ghrelin (GHS-R1a) in periodontal cells and tissues under microbial conditions in vitro and in vivo. The GHS-R1a expression in human periodontal cells challenged with the periodontopathogen Fusobacterium nucleatum, in gingival biopsies from periodontally healthy and diseased individuals, and from rats with a...

  10. A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons.

    Science.gov (United States)

    Navarro, Gemma; Aguinaga, David; Angelats, Edgar; Medrano, Mireia; Moreno, Estefanía; Mallol, Josefa; Cortés, Antonio; Canela, Enric I; Casadó, Vicent; McCormick, Peter J; Lluís, Carme; Ferré, Sergi

    2016-06-17

    The truncated non-signaling ghrelin receptor growth hormone secretagogue R1b (GHS-R1b) has been suggested to simply exert a dominant negative role in the trafficking and signaling of the full and functional ghrelin receptor GHS-R1a. Here we reveal a more complex modulatory role of GHS-R1b. Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in striatal and hippocampal neurons in culture, demonstrates that GHS-R1b acts as a dual modulator of GHS-R1a function: low relative GHS-R1b expression potentiates and high relative GHS-R1b expression inhibits GHS-R1a function by facilitating GHS-R1a trafficking to the plasma membrane and by exerting a negative allosteric effect on GHS-R1a signaling, respectively. We found a preferential Gi/o coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpectedly, a preferential Gs/olf coupling in both striatal and hippocampal neurons in culture. A dopamine D1 receptor (D1R) antagonist blocked ghrelin-induced cAMP accumulation in striatal but not hippocampal neurons, indicating the involvement of D1R in the striatal GHS-R1a-Gs/olf coupling. Experiments in HEK-293T cells demonstrated that D1R co-expression promotes a switch in GHS-R1a-G protein coupling from Gi/o to Gs/olf, but only upon co-expression of GHS-R1b. Furthermore, resonance energy transfer experiments showed that D1R interacts with GHS-R1a, but only in the presence of GHS-R1b. Therefore, GHS-R1b not only determines the efficacy of ghrelin-induced GHS-R1a-mediated signaling but also determines the ability of GHS-R1a to form oligomeric complexes with other receptors, promoting profound qualitative changes in ghrelin-induced signaling. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons*

    Science.gov (United States)

    Navarro, Gemma; Aguinaga, David; Angelats, Edgar; Medrano, Mireia; Moreno, Estefanía; Mallol, Josefa; Cortés, Antonio; Canela, Enric I.; Casadó, Vicent; McCormick, Peter J.; Lluís, Carme; Ferré, Sergi

    2016-01-01

    The truncated non-signaling ghrelin receptor growth hormone secretagogue R1b (GHS-R1b) has been suggested to simply exert a dominant negative role in the trafficking and signaling of the full and functional ghrelin receptor GHS-R1a. Here we reveal a more complex modulatory role of GHS-R1b. Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in striatal and hippocampal neurons in culture, demonstrates that GHS-R1b acts as a dual modulator of GHS-R1a function: low relative GHS-R1b expression potentiates and high relative GHS-R1b expression inhibits GHS-R1a function by facilitating GHS-R1a trafficking to the plasma membrane and by exerting a negative allosteric effect on GHS-R1a signaling, respectively. We found a preferential Gi/o coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpectedly, a preferential Gs/olf coupling in both striatal and hippocampal neurons in culture. A dopamine D1 receptor (D1R) antagonist blocked ghrelin-induced cAMP accumulation in striatal but not hippocampal neurons, indicating the involvement of D1R in the striatal GHS-R1a-Gs/olf coupling. Experiments in HEK-293T cells demonstrated that D1R co-expression promotes a switch in GHS-R1a-G protein coupling from Gi/o to Gs/olf, but only upon co-expression of GHS-R1b. Furthermore, resonance energy transfer experiments showed that D1R interacts with GHS-R1a, but only in the presence of GHS-R1b. Therefore, GHS-R1b not only determines the efficacy of ghrelin-induced GHS-R1a-mediated signaling but also determines the ability of GHS-R1a to form oligomeric complexes with other receptors, promoting profound qualitative changes in ghrelin-induced signaling. PMID:27129257

  12. Blockade of central nicotine acetylcholine receptor signaling attenuate ghrelin-induced food intake in rodents.

    Science.gov (United States)

    Dickson, S L; Hrabovszky, E; Hansson, C; Jerlhag, E; Alvarez-Crespo, M; Skibicka, K P; Molnar, C S; Liposits, Z; Engel, J A; Egecioglu, E

    2010-12-29

    Here we sought to determine whether ghrelin's central effects on food intake can be interrupted by nicotine acetylcholine receptor (nAChR) blockade. Ghrelin regulates mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens, partly via cholinergic VTA afferents originating in the laterodorsal tegmental area (LDTg). Given that these cholinergic projections to the VTA have been implicated in natural as well as drug-induced reinforcement, we sought to investigate the role of cholinergic signaling in ghrelin-induced food intake as well as fasting-induced food intake, for which endogenous ghrelin has been implicated. We found that i.p. treatment with the non-selective centrally active nAChR antagonist, mecamylamine decreased fasting-induced food intake in both mice and rats. Moreover, central administration of mecamylamine decreased fasting-induced food intake in rats. I.c.v. ghrelin-induced food intake was suppressed by mecamylamine i.p. but not by hexamethonium i.p., a peripheral nAChR antagonist. Furthermore, mecamylamine i.p. blocked food intake following ghrelin injection into the VTA. Expression of the ghrelin receptor, the growth hormone secretagogue receptor 1A, was found to co-localize with choline acetyltransferase, a marker of cholinergic neurons, in the LDTg. Finally, mecamylamine treatment i.p. decreased the ability of palatable food to condition a place preference. These data suggest that ghrelin-induced food intake is partly mediated via nAChRs and that nicotinic blockade decreases the rewarding properties of food. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. The Association of Polymorphisms in Leptin/Leptin Receptor Genes and Ghrelin/Ghrelin Receptor Genes With Overweight/Obesity and the Related Metabolic Disturbances: A Review.

    Science.gov (United States)

    Ghalandari, Hamid; Hosseini-Esfahani, Firoozeh; Mirmiran, Parvin

    2015-07-01

    Leptin and ghrelin are two important appetite and energy balance-regulating peptides. Common polymorphisms in the genes coding these peptides and their related receptors are shown to be associated with body weight, different markers of obesity and metabolic abnormalities. This review article aims to investigate the association of common polymorphisms of these genes with overweight/obesity and the metabolic disturbances related to it. The keywords leptin, ghrelin, polymorphism, single-nucleotide polymorphism (SNP), obesity, overweight, Body Mass Index, metabolic syndrome, and type 2 diabetes mellitus (T2DM) (MeSH headings) were used to search in the following databases: Pubmed, Sciencedirect (Elsevier), and Google scholar. Overall, 24 case-control studies, relevant to our topic, met the criteria and were included in the review. The most prevalent leptin/leptin receptor genes (LEP/LEPR) and ghrelin/ghrelin receptor genes (GHRL/GHSR) single nucleotide polymorphisms studied were LEP G-2548A, LEPR Q223R, and Leu72Met, respectively. Nine studies of the 17 studies on LEP/LEPR, and three studies of the seven studies on GHRL/GHSR showed significant relationships. In general, our study suggests that the association between LEP/LEPR and GHRL/GHSR with overweight/obesity and the related metabolic disturbances is inconclusive. These results may be due to unidentified gene-environment interactions. More investigations are needed to further clarify this association.

  14. Ghrelin receptor antagonism of hyperlocomotion in cocaine-sensitized mice requires βarrestin-2.

    Science.gov (United States)

    Toth, Krisztian; Slosky, Lauren M; Pack, Thomas F; Urs, Nikhil M; Boone, Peter; Mao, Lan; Abraham, Dennis; Caron, Marc G; Barak, Lawrence S

    2018-01-01

    The "brain-gut" peptide ghrelin, which mediates food-seeking behaviors, is recognized as a very strong endogenous modulator of dopamine (DA) signaling. Ghrelin binds the G protein-coupled receptor GHSR1a, and administration of ghrelin increases the rewarding properties of psychostimulants while ghrelin receptor antagonists decrease them. In addition, the GHSR1a signals through βarrestin-2 to regulate actin/stress fiber rearrangement, suggesting βarrestin-2 participation in the regulation of actin-mediated synaptic plasticity for addictive substances like cocaine. The effects of ghrelin receptor ligands on reward strongly suggest that modulation of ghrelin signaling could provide an effective strategy to ameliorate undesirable behaviors arising from addiction. To investigate this possibility, we tested the effects of ghrelin receptor antagonism in a cocaine behavioral sensitization paradigm using DA neuron-specific βarrestin-2 KO mice. Our results show that these mice sensitize to cocaine as well as wild-type littermates. The βarrestin-2 KO mice, however, no longer respond to the locomotor attenuating effects of the GHSR1a antagonist YIL781. The data presented here suggest that the separate stages of addictive behavior differ in their requirements for βarrestin-2 and show that pharmacological inhibition of βarrestin-2 function through GHSR1a antagonism is not equivalent to the loss of βarrestin-2 function achieved by genetic ablation. These data support targeting GHSR1a signaling in addiction therapy but indicate that using signaling biased compounds that modulate βarrestin-2 activity differentially from G protein activity may be required. © 2017 Wiley Periodicals, Inc.

  15. Caloric Restriction Protects against Lactacystin-Induced Degeneration of Dopamine Neurons Independent of the Ghrelin Receptor

    Directory of Open Access Journals (Sweden)

    Jessica Coppens

    2017-03-01

    Full Text Available Parkinson’s disease (PD is a neurodegenerative disorder, characterized by a loss of dopamine (DA neurons in the substantia nigra pars compacta (SNc. Caloric restriction (CR has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP-based animal model for PD. We here investigated whether CR is neuroprotective in the lactacystin (LAC mouse model for PD, in which proteasome disruption leads to the destruction of the DA neurons of the SNc, and whether this effect is mediated via the ghrelin receptor. Adult male ghrelin receptor wildtype (WT and knockout (KO mice were maintained on an ad libitum (AL diet or on a 30% CR regimen. After 3 weeks, LAC was injected unilaterally into the SNc, and the degree of DA neuron degeneration was evaluated 1 week later. In AL mice, LAC injection significanty reduced the number of DA neurons and striatal DA concentrations. CR protected against DA neuron degeneration following LAC injection. However, no differences were observed between ghrelin receptor WT and KO mice. These results indicate that CR can protect the nigral DA neurons from toxicity related to proteasome disruption; however, the ghrelin receptor is not involved in this effect.

  16. Regulation of Ghrelin Receptor by Periodontal Bacteria In Vitro and In Vivo.

    Science.gov (United States)

    Nokhbehsaim, Marjan; Damanaki, Anna; Nogueira, Andressa Vilas Boas; Eick, Sigrun; Memmert, Svenja; Zhou, Xiaoyan; Nanayakkara, Shanika; Götz, Werner; Cirelli, Joni Augusto; Jäger, Andreas; Deschner, James

    2017-01-01

    Ghrelin plays a major role in obesity-related diseases which have been shown to be associated with periodontitis. This study sought to analyze the expression of the functional receptor for ghrelin (GHS-R1a) in periodontal cells and tissues under microbial conditions in vitro and in vivo . The GHS-R1a expression in human periodontal cells challenged with the periodontopathogen Fusobacterium nucleatum , in gingival biopsies from periodontally healthy and diseased individuals, and from rats with and without ligature-induced periodontitis was analyzed by real-time PCR, immunocytochemistry, and immunofluorescence. F. nucleatum induced an initial upregulation and subsequent downregulation of GHS-R1a in periodontal cells. In rat experimental periodontitis, the GHS-R1a expression at periodontitis sites was increased during the early stage of periodontitis, but significantly reduced afterwards, when compared with healthy sites. In human gingival biopsies, periodontally diseased sites showed a significantly lower GHS-R1a expression than the healthy sites. The expression of the functional ghrelin receptor in periodontal cells and tissues is modulated by periodontal bacteria. Due to the downregulation of the functional ghrelin receptor by long-term exposure to periodontal bacteria, the anti-inflammatory actions of ghrelin may be diminished in chronic periodontal infections, which could lead to an enhanced periodontal inflammation and tissue destruction.

  17. The Ghrelin Receptor (Ghsr) Gene Polymorphism in Indonesian Local Chicken and Crossbreed is Associated with Carcass Traits

    OpenAIRE

    Khaerunnisa, Isyana; Jakaria, Jakaria; Arief, Irma Isnafia; Budiman, Cahyo; Sumantri, Cece

    2017-01-01

    Ghrelin receptor (GHSR) gene is candidate gene for growth performance in chicken by modulating growth hormone release from the pituitary by binding to its ligand of ghrelin. Ghrelin gene, or growth hormone secretagogue (GHS) gene, is well known as feed intake and energy homeostasis regulator in mammals and birds. The objectives of this study were to identify the polymorphism of the T1857C GHSR locus in Indonesian local chicken and to evaluate its effects on carcass traits. The gene polymorphi...

  18. Hypothalamic peroxisome proliferator-activated receptor gamma regulates ghrelin production and food intake.

    Science.gov (United States)

    Li, Qingjie; Yu, Quan; Lin, Li; Zhang, Heng; Peng, Miao; Jing, Chunxia; Xu, Geyang

    2018-04-09

    Peroxisome proliferator-activated receptor-γ (PPARγ) regulates fatty acid storage, glucose metabolism, and food intake. Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate appetite. However, the effects of PPARγ on ghrelin production are still unclear. In the present study, the effects of PPARγ on ghrelin production were examined in lean- or high-fat diet-induced obese (DIO) C57BL/6J mice and mHypoE-42 cells, a hypothalamic cell line. 3rd intracerebroventricular injection of adenoviral-directed overexpression of PPARγ (Ad-PPARγ) reduced hypothalamic and plasma ghrelin, food intake in both lean C57BL/6J mice and diet-induced obese mice. These changes were associated with a significant increase in mechanistic target of rapamycin complex 1 (mTORC1) activity. Overexpression of PPARγ enhanced mTORC1 signaling and suppressed ghrelin production in cultured mHypoE-42 cells. Our results suggest that hypothalamic PPARγ plays a vital role in ghrelin production and food intake in mice. Copyright © 2018 Elsevier Ltd. All rights reserved.

  19. Association of ghrelin receptor gene polymorphism with bulimia nervosa in a Japanese population.

    Science.gov (United States)

    Miyasaka, K; Hosoya, H; Sekime, A; Ohta, M; Amono, H; Matsushita, S; Suzuki, K; Higuchi, S; Funakoshi, A

    2006-09-01

    Eating disorders (EDs) have a highly heterogeneous etiology and multiple genetic factors might contribute to their pathogenesis. Ghrelin, a novel growth hormone-releasing peptide, enhances appetite and increases food intake, and human ghrelin plasma levels are inversely correlated with body mass index. In the present study, we examined the 171T/C polymorphism of the ghrelin receptor (growth hormone secretagogue receptor, GHSR) gene in patients diagnosed with EDs, because the subjects having ghrelin gene polymorphism (Leu72Met) was not detected in a Japanese population, previously. In addition, beta3 adrenergic receptor gene polymorphism (Try64Arg) and cholecystokinin (CCK)-A receptor (R) gene polymorphism (-81A/G, -128G/T), which are both associated with obesity, were investigated. The subjects consisted of 228 Japanese patients with EDs [96 anorexia nervosa (AN), 116 bulimia nervosa (BN) and 16 not otherwise specified (NOS)]. The age- and gender-matched control group consisted of 284 unrelated Japanese subjects. The frequency of the CC type of the GHSR gene was significantly higher in BN subjects than in control subjects (chi(2) = 4.47, p = 0.035, odds ratio = 2.05, Bonferroni correction: p = 0.070), while the frequency in AN subjects was not different from that in controls. The distribution of neither beta3 adrenergic receptor gene nor CCK-AR polymorphism differed between EDs and control subjects. Therefore, the CC type of GHSR gene polymorphism (171T/C) is a risk factor for BN, but not for AN.

  20. The Association of Polymorphisms in Leptin/Leptin Receptor Genes and Ghrelin/Ghrelin Receptor Genes With Overweight/Obesity and the Related Metabolic Disturbances: A Review

    OpenAIRE

    Ghalandari; Hosseini-Esfahani; Mirmiran

    2015-01-01

    Context Leptin and ghrelin are two important appetite and energy balance-regulating peptides. Common polymorphisms in the genes coding these peptides and their related receptors are shown to be associated with body weight, different markers of obesity and metabolic abnormalities. This review article aims to investigate the association of common polymorphisms of these genes with overweight/obesity and the metabolic disturbances related to it. E...

  1. From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation

    Directory of Open Access Journals (Sweden)

    Ken Howick

    2017-01-01

    Full Text Available Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrallymediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry.

  2. Taking Two to Tango: A Role for Ghrelin Receptor Heterodimerization in Stress and Reward

    Directory of Open Access Journals (Sweden)

    Harriet eSchellekens

    2013-08-01

    Full Text Available The gut hormone, ghrelin, is the only known peripherally derived orexigenic signal. It activates its centrally expressed receptor, the growth hormone secretagogue receptor (GHS-R1a, to stimulate food intake. The ghrelin signalling system has recently been suggested to play a key role at the interface of homeostatic control of appetite and the hedonic aspects of food intake, as a critical role for ghrelin in dopaminergic mesolimbic circuits involved in reward signalling has emerged. Moreover, enhanced plasma ghrelin levels are associated with conditions of physiological stress, which may underline the drive to eat calorie-dense ‘comfort-foods’ and signifies a role for ghrelin in stress-induced food reward behaviours. These complex and diverse functionalities of the ghrelinergic system are not yet fully elucidated and likely involve crosstalk with additional signalling systems. Interestingly, accumulating data over the last few years has shown the GHS-R1a receptor to dimerize with several additional G-protein coupled receptors (GPCRs involved in appetite signalling and reward, including the GHS-R1b receptor, the melanocortin 3 receptor (MC3, dopamine receptors (D1 and D2, and more recently, the serotonin 2C receptor (5-HT2C. GHS-R1a dimerization was shown to affect downstream signalling and receptor trafficking suggesting a potential novel mechanism for fine-tuning GHS-R1a receptor mediated activity. This review summarizes ghrelin’s role in food reward and stress and outlines the GHS-R1a dimer pairs identified to date. In addition, the downstream signalling and potential functional consequences of dimerization of the GHS-R1a receptor in appetite and stress-induced food reward behaviour are discussed. The existence of multiple GHS-R1a heterodimers has important consequences for future pharmacotherapies as it significantly increases the pharmacological diversity of the GHS-R1a receptor and has the potential to enhance specificity of novel

  3. Ghrelin receptor agonists as novel breast cancer therapeutics

    OpenAIRE

    CHEUK MAN CHERIE AU

    2017-01-01

    The human cell studies and the live mouse studies are intended to provide the information that is needed to apply therapies to treat breast cancer patients, based on our novel discoveries. We believe that des-acyl ghrelin-like compounds will be novel breast cancer therapeutics while avoiding well-documented serious side effects, including joint pain, osteoporosis or endometrial cancer. Our findings could therefore improve the quality of life of women treated for breast cancer, improve complia...

  4. Circulating Ghrelin, Leptin, and Soluble Leptin Receptor Concentrations and Cardiometabolic Risk Factors in a Community-Based Sample

    OpenAIRE

    Ingelsson, Erik; Larson, Martin G.; Yin, Xiaoyan; Wang, Thomas J.; Meigs, James B.; Lipinska, Izabella; Benjamin, Emelia J.; Keaney, John F.; Vasan, Ramachandran S.

    2008-01-01

    Context: The conjoint effects and relative importance of ghrelin, leptin, and soluble leptin receptor (sOB-R), adipokines involved in appetite control and energy expenditure in mediating cardiometabolic risk, is unknown.

  5. In Situ Localization and Rhythmic Expression of Ghrelin and ghs-r1 Ghrelin Receptor in the Brain and Gastrointestinal Tract of Goldfish (Carassius auratus.

    Directory of Open Access Journals (Sweden)

    Aída Sánchez-Bretaño

    Full Text Available Ghrelin is a gut-brain peptide hormone, which binds to the growth hormone secretagogue receptor (GHS-R to regulate a wide variety of biological processes in fish. Despite these prominent physiological roles, no studies have reported the anatomical distribution of preproghrelin transcripts using in situ hybridization in a non-mammalian vertebrate, and its mapping within the different encephalic areas remains unknown. Similarly, no information is available on the possible 24-h variations in the expression of preproghrelin and its receptor in any vertebrate species. The first aim of this study was to investigate the anatomical distribution of ghrelin and GHS-R1a ghrelin receptor subtype in brain and gastrointestinal tract of goldfish (Carassius auratus using immunohistochemistry and in situ hybridization. Our second aim was to characterize possible daily variations of preproghrelin and ghs-r1 mRNA expression in central and peripheral tissues using real-time reverse transcription-quantitative PCR. Results show ghrelin expression and immunoreactivity in the gastrointestinal tract, with the most abundant signal observed in the mucosal epithelium. These are in agreement with previous findings on mucosal cells as the primary synthesizing site of ghrelin in goldfish. Ghrelin receptor was observed mainly in the hypothalamus with low expression in telencephalon, pineal and cerebellum, and in the same gastrointestinal areas as ghrelin. Daily rhythms in mRNA expression were found for preproghrelin and ghs-r1 in hypothalamus and pituitary with the acrophase occurring at nighttime. Preproghrelin, but not ghs-r1a, displayed a similar daily expression rhythm in the gastrointestinal tract with an amplitude 3-fold higher than the rest of tissues. Together, these results described for the first time in fish the mapping of preproghrelin and ghrelin receptor ghs-r1a in brain and gastrointestinal tract of goldfish, and provide the first evidence for a daily regulation

  6. An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor

    DEFF Research Database (Denmark)

    Els, Sylvia; Schild, Enrico; Petersen, Pia Steen

    2012-01-01

    The ghrelin receptor displays a high constitutive activity suggested to be involved in the regulation of appetite and food intake. Here, we have created peptides with small changes in the core binding motif -wFw- of the hexapeptide KwFwLL-NH(2) that can swap the peptide behavior from inverse......-tryptophane at position 4 with 1-naphthyl-d-alanine (d-1-Nal) and 2-naphthyl-d-alanine (d-2-Nal) induces agonism in functional assays. Competitive binding studies showed a high affinity of the inverse agonist K-(d-1-Nal)-FwLL-NH(2) at the ghrelin receptor. Moreover, mutagenesis studies of the receptor revealed key...

  7. A Novel Non-Peptidic Agonist of the Ghrelin Receptor with Orexigenic Activity In vivo

    Science.gov (United States)

    Pastor-Cavada, Elena; Pardo, Leticia M.; Kandil, Dalia; Torres-Fuentes, Cristina; Clarke, Sarah L.; Shaban, Hamdy; McGlacken, Gerard P.; Schellekens, Harriet

    2016-11-01

    Loss of appetite in the medically ill and ageing populations is a major health problem and a significant symptom in cachexia syndromes, which is the loss of muscle and fat mass. Ghrelin is a gut-derived hormone which can stimulate appetite. Herein we describe a novel, simple, non-peptidic, 2-pyridone which acts as a selective agonist for the ghrelin receptor (GHS-R1a). The small 2-pyridone demonstrated clear agonistic activity in both transfected human cells and mouse hypothalamic cells with endogenous GHS-R1a receptor expression. In vivo tests with the hit compound showed significant increased food intake following peripheral administration, which highlights the potent orexigenic effect of this novel GHS-R1a receptor ligand.

  8. Expression of the gene encoding the ghrelin receptor in rats selected for differential alcohol preference.

    Science.gov (United States)

    Landgren, Sara; Engel, Jörgen A; Hyytiä, Petri; Zetterberg, Henrik; Blennow, Kaj; Jerlhag, Elisabet

    2011-08-01

    The mechanisms involved in alcohol use disorder, a chronic relapsing brain disorder, are complex and involve various signalling systems in the brain. Recently, the orexigenic peptide ghrelin was shown to be required for alcohol-induced reward, an effect mediated via ghrelin receptors, GHS-R1A, at the level of the cholinergic-dopaminergic reward link. Moreover, ghrelin increases and GHR-R1A antagonists reduce moderate alcohol consumption in mice, and a single nucleotide polymorphism in the GHS-R1A gene has been associated with high alcohol consumption in humans. Therefore, GHS-R1A gene expression and alcohol intake were investigated in high, AA (Alko, Alcohol), versus low, ANA (Alko, Non-Alcohol), alcohol consuming rats as well as in Wistar rats. In the AA and ANA rats plasma ghrelin levels were also measured. GHS-R1A gene expression was increased in AA compared to ANA rats in nucleus accumbens, ventral tegmental area, amygdala, prefrontal cortex and hippocampus. A similar trend was observed in the ventral tegmental area of Wistar rats consuming high amounts of alcohol. Furthermore, the AA rats had significantly smaller reduction of plasma ghrelin levels over time, after several weeks of alcohol exposure, than had the ANA rats. The present study provides further evidence for that the ghrelin signalling system, in particular at the level of the mesocortocolimbic dopamine system, is involved in alcohol consumption, and thus possibly contributes to alcohol use disorder. Therefore the GHS-R1A may constitute a novel candidate for development of new treatment strategies for alcohol dependence. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Modulation of the constitutive activity of the ghrelin receptor by use of pharmacological tools and mutagenesis.

    Science.gov (United States)

    Mokrosiński, Jacek; Holst, Birgitte

    2010-01-01

    Ghrelin and its receptor are important regulators of metabolic functions, including appetite, energy expenditure, fat accumulation, and growth hormone (GH) secretion. The ghrelin receptor is characterized by an ability to signal even without any ligand present with approximately 50% of the maximally ghrelin-induced efficacy-a feature that may have important physiological implications. The high basal signaling can be modulated either by administration of specific ligands or by engineering of mutations in the receptor structure. [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P was the first inverse agonist to be identified for the ghrelin receptor, and this peptide has been used as a starting point for identification of the structural requirements for inverse agonist properties in the ligand. The receptor binding core motif was identified as D-Trp-Phe-D-Trp-Leu-Leu, and elongation of this peptide in the amino-terminal end determined the efficacy. Attachment of a positively charged amino acid was responsible for full inverse agonism, whereas an alanin converted the peptide into a partial agonist. Importantly, by use of mutational mapping of the residues critical for the modified D-Trp-Phe-D-Trp-Leu-Leu peptides, it was found that space-generating mutations in the deeper part of the receptor improved inverse agonism, whereas similar mutations located in the more extracellular part improved agonism. Modulation of the basal signaling by mutations in the receptor structure is primarily obtained by substitutions in an aromatic cluster that keep TMs VI and VII in close proximity to TM III and thus stabilize the active conformation. Also, substitution of a Phe in TM V is crucial for the high basal activity of the receptor as this residue serves as a partner for Trp VI:13 in the active conformation. It is suggested that inverse agonist and antagonist against the ghrelin receptor provide an interesting possibility in the development of drugs for treatment of obesity and

  10. Overlapping binding site for the endogenous agonist, small-molecule agonists, and ago-allosteric modulators on the ghrelin receptor

    DEFF Research Database (Denmark)

    Holst, Birgitte; Frimurer, Thomas M; Mokrosinski, Jacek

    2008-01-01

    A library of robust ghrelin receptor mutants with single substitutions at 22 positions in the main ligand-binding pocket was employed to map binding sites for six different agonists: two peptides (the 28-amino-acid octanoylated endogenous ligand ghrelin and the hexapeptide growth hormone......, and PheVI:23 on the opposing face of transmembrane domain (TM) VI. Each of the agonists was also affected selectively by specific mutations. The mutational map of the ability of L-692,429 and GHRP-6 to act as allosteric modulators by increasing ghrelin's maximal efficacy overlapped with the common....... It is concluded that although each of the ligands in addition exploits other parts of the receptor, a large, common binding site for both small-molecule agonists--including ago-allosteric modulators--and the endogenous agonist is found on the opposing faces of TM-III and -VI of the ghrelin receptor....

  11. Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a.

    Science.gov (United States)

    Casanueva, Felipe F; Camiña, Jesus P; Carreira, Marcos C; Pazos, Yolanda; Varga, Jozsef L; Schally, Andrew V

    2008-12-23

    Ghrelin synergizes with growth hormone-releasing hormone (GHRH) to potentiate growth hormone (GH) response through a mechanism not yet fully characterized. This study was conducted to analyze the role of GHRH as a potential ligand of the ghrelin receptor, GHS-R1a. The results show that hGHRH(1-29)NH(2) (GHRH) induces a dose-dependent calcium mobilization in HEK 293 cells stably transfected with GHS-R1a an effect not observed in wild-type HEK 293 cells. This calcium rise is also observed using the GHRH receptor agonists JI-34 and JI-36. Radioligand binding and cross-linking studies revealed that calcium response to GHRH is mediated by the ghrelin receptor GHS-R1a. GHRH activates the signaling route of inositol phosphate and potentiates the maximal response to ghrelin measured in inositol phosphate turnover. The presence of GHRH increases the binding capacity of (125)I-ghrelin in a dose dependent-fashion showing a positive binding cooperativity. In addition, confocal microscopy in CHO cells transfected with GHS-R1a tagged with enhanced green fluorescent protein shows that GHRH activates the GHS-R1a endocytosis. Furthermore, the selective GHRH-R antagonists, JV-1-42 and JMR-132, act also as antagonists of the ghrelin receptor GHS-R1a. Our findings suggest that GHRH interacts with ghrelin receptor GHS-R1a, and, in consequence, modifies the ghrelin-associated intracellular signaling pathway. This interaction may represent a form of regulation, which could play a putative role in the physiology of GH regulation and appetite control.

  12. Molecular Characterization of the Ghrelin and Ghrelin Receptor Genes and Effects on Fat Deposition in Chicken and Duck

    Directory of Open Access Journals (Sweden)

    Q. Nie

    2009-01-01

    Full Text Available Ghrelin (GHRL and its receptor (GHSR are involved in various bioactivities. In this study, the complete cDNA and 5′ flanking region of the duck GHRL (dGHRL gene and a 3717 bp fragment of the duck GHSR (dGHSR gene were obtained. A total of 19, 8, 43, and 48 SNPs identified in 2751, 1358, 3671, and 3567 bp of the chicken GHRL (cGHRL, chicken GHSR (cGHSR, dGHRL, and dGHSR genes, respectively. Both cGHRL and dGHRL were expressed predominantly in the proventriculus, whereas the highest mRNA levels of cGHSR and dGHSR were detected in the breast muscle and pituitary. Association analysis showed that C-2047G, A-2355C, and A-2220C of the cGHRL gene were significantly associated with abdominal fat weight (AFW; P=.01, crude protein content of leg muscle (CPCLM; P=.02, and CPCLM (P=.0009, respectively. C-1459T of the cGHSR gene was also significantly associated with CPCLM (P=.0004. C-729T of dGHRL and A3427T of dGHSR were both significantly associated with subcutaneous fat thickness (SFT; P=.04. It was indicated by this study that the GHRL and GHSR genes were related to fat deposition in both chicken and duck.

  13. Both acyl and des-acyl ghrelin regulate adiposity and glucose metabolism via central nervous system ghrelin receptors.

    Science.gov (United States)

    Heppner, Kristy M; Piechowski, Carolin L; Müller, Anne; Ottaway, Nickki; Sisley, Stephanie; Smiley, David L; Habegger, Kirk M; Pfluger, Paul T; Dimarchi, Richard; Biebermann, Heike; Tschöp, Matthias H; Sandoval, Darleen A; Perez-Tilve, Diego

    2014-01-01

    Growth hormone secretagogue receptors (GHSRs) in the central nervous system (CNS) mediate hyperphagia and adiposity induced by acyl ghrelin (AG). Evidence suggests that des-AG (dAG) has biological activity through GHSR-independent mechanisms. We combined in vitro and in vivo approaches to test possible GHSR-mediated biological activity of dAG. Both AG (100 nmol/L) and dAG (100 nmol/L) significantly increased inositol triphosphate formation in human embryonic kidney-293 cells transfected with human GHSR. As expected, intracerebroventricular infusion of AG in mice increased fat mass (FM), in comparison with the saline-infused controls. Intracerebroventricular dAG also increased FM at the highest dose tested (5 nmol/day). Chronic intracerebroventricular infusion of AG or dAG increased glucose-stimulated insulin secretion (GSIS). Subcutaneously infused AG regulated FM and GSIS in comparison with saline-infused control mice, whereas dAG failed to regulate these parameters even with doses that were efficacious when delivered intracerebroventricularly. Furthermore, intracerebroventricular dAG failed to regulate FM and induce hyperinsulinemia in GHSR-deficient (Ghsr(-/-)) mice. In addition, a hyperinsulinemic-euglycemic clamp suggests that intracerebroventricular dAG impairs glucose clearance without affecting endogenous glucose production. Together, these data demonstrate that dAG is an agonist of GHSR and regulates body adiposity and peripheral glucose metabolism through a CNS GHSR-dependent mechanism.

  14. Association Analysis of the Leptin and Ghrelin Receptor Gene Polymorphism in the Human with BMI

    Directory of Open Access Journals (Sweden)

    Zuzana Lieskovská

    2011-05-01

    Full Text Available The aim of this work was identification of Leptin and Ghrelin receptor gene polymorphism in the population. Leptin is a product of obese (ob gene expression that plays a role in energy metabolism and body weight. The human leptin gene is located in the 17 chromosome. The restriction site is located at the position 2549 bp (C→A. 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. The present study included 35 human samples. The average value of BMI was estimate on 24.45. The size of amplified PCR product is 242bp. Subsequently we used the specific restriction enzyme HhaI and length of fragments is 181+61 bp in the homozygote CC, 242+181+61 bp in the heterozygote AC and 242 bp in the homozygote AA. The restriction site is located at the position 171T/C. Examination of the polymorphism of the GHSR gene was accomplished used PCR-RFLP method. We used amplified the 593 bp product, which was subsequently digested with restriction enzyme LweI and length of fragmetnts is 593 bp in the homozygote TT, 593+567+26 bp in the heterozygote TC and 593+26 bp in the homozygote CC. We assume that this mutation has connection with human obesity level.

  15. Apo-ghrelin receptor (apo-GHSR1a Regulates Dopamine Signaling in the Brain

    Directory of Open Access Journals (Sweden)

    Andras eKern

    2014-08-01

    Full Text Available The orexigenic peptide hormone ghrelin is synthesized in the stomach and its receptor growth hormone secretagogue receptor (GHSR1a is expressed mainly in the central nervous system (CNS. In this review we confine our discussion to the physiological role of GHSR1a in the brain. Paradoxically, despite broad expression of GHSR1a in the CNS, other than trace amounts in the hypothalamus, ghrelin is undetectable in the brain. In our efforts to elucidate the function of the ligand-free ghrelin receptor (apo-GHSR1a we identified subsets of neurons that co-express GHSR1a and dopamine receptors. In this review we focus on interactions between apo-GHSR1a and dopamine-2 receptor (DRD2 and formation of GHSR1a:DRD2 heteromers in hypothalamic neurons that regulate appetite, and discuss implications for the treatment of Prader-Willi syndrome. GHSR1a antagonists of distinct chemical structures, a quinazolinone and a triazole, respectively enhance and inhibit dopamine signaling through GHSR1a:DRD2 heteromers by an allosteric mechanism. This finding illustrates a potential strategy for designing the next generation of drugs for treating eating disorders as well as psychiatric disorders caused by abnormal dopamine signaling. Treatment with a GHSR1a antagonist that enhances dopamine/DRD2 activity in GHSR1a:DRD2 expressing hypothalamic neurons has the potential to inhibit the uncontrollable hyperphagia associated with Prader-Willi syndrome. DRD2 antagonists are prescribed for treating schizophrenia, but these block dopamine signaling in all DRD2 expressing neurons and are associated with adverse side effects, including enhanced appetite and excessive weight gain. A GHSR1a antagonist of structural class that allosterically blocks dopamine/DRD2 action in GHSR1a:DRD2 expressing neurons would have no effect on neurons expressing DRD2 alone; therefore, the side effects of DRD2 antagonists would potentially be reduced thereby enhancing patient compliance.

  16. Modulation of constitutive activity and signaling bias of the ghrelin receptor by conformational constraint in the second extracellular loop

    DEFF Research Database (Denmark)

    Mokrosinski, Jacek; Frimurer, Thomas M; Sivertsen, Bjoern

    2012-01-01

    Based on a rare, natural Glu for Ala204(C+6) variant located six residues after the conserved Cys residue in extracellular loop 2 (ECL2b) associated with selective elimination of the high constitutive signaling of the ghrelin receptor, this loop was subjected to a detailed structure functional....... Moreover, the constitutive activity of the receptor was inhibited by Zn(2+) binding in an engineered metal-ion site stabilizing an a-helical conformation of this loop segment. It is concluded that the high constitutive activity of the ghrelin receptor is dependent upon flexibility in the C-terminal segment...

  17. Central neuropeptide Y receptors are involved in 3rd ventricular ghrelin induced alteration of colonic transit time in conscious fed rats

    Directory of Open Access Journals (Sweden)

    Ritter Michael

    2005-02-01

    Full Text Available Abstract Background Feeding related peptides have been shown to be additionally involved in the central autonomic control of gastrointestinal functions. Recent studies have shown that ghrelin, a stomach-derived orexigenic peptide, is involved in the autonomic regulation of GI function besides feeding behavior. Pharmacological evidence indicates that ghrelin effects on food intake are mediated by neuropeptide Y in the central nervous system. Methods In the present study we examine the role of ghrelin in the central autonomic control of GI motility using intracerobroventricular and IP microinjections in a freely moving conscious rat model. Further the hypothesis that a functional relationship between NPY and ghrelin within the CNS exists was addressed. Results ICV injections of ghrelin (0.03 nmol, 0.3 nmol and 3.0 nmol/5 μl and saline controls decreased the colonic transit time up to 43%. IP injections of ghrelin (0.3 nmol – 3.0 nmol kg-1 BW and saline controls decreased colonic transit time dose related. Central administration of the NPY1 receptor antagonist, BIBP-3226, prior to centrally or peripherally administration of ghrelin antagonized the ghrelin induced stimulation of colonic transit. On the contrary ICV-pretreatment with the NPY2 receptor antagonist, BIIE-0246, failed to modulate the ghrelin induced stimulation of colonic motility. Conclusion The results suggest that ghrelin acts in the central nervous system to modulate gastrointestinal motor function utilizing NPY1 receptor dependent mechanisms.

  18. Polymorphisms in genes encoding leptin, ghrelin and their receptors in German multiple sclerosis patients.

    Science.gov (United States)

    Rey, Linda K; Wieczorek, Stefan; Akkad, Denis A; Linker, Ralf A; Chan, Andrew; Hoffjan, Sabine

    2011-01-01

    Multiple sclerosis (MS) is a neuro-inflammatory, autoimmune disease influenced by environmental and polygenic components. There is growing evidence that the peptide hormone leptin, known to regulate energy homeostasis, as well as its antagonist ghrelin play an important role in inflammatory processes in autoimmune diseases, including MS. Recently, single nucleotide polymorphisms (SNPs) in the genes encoding leptin, ghrelin and their receptors were evaluated, amongst others, in Wegener's granulomatosis and Churg-Strauss syndrome. The Lys656Asn SNP in the LEPR gene showed a significant but contrasting association with these vasculitides. We therefore aimed at investigating these polymorphisms in a German MS case-control cohort. Twelve SNPs in the LEP, LEPR, GHRL and GHSR genes were genotyped in 776 MS patients and 878 control subjects. We found an association of a haplotype in the GHSR gene with MS that could not be replicated in a second cohort. Otherwise, no significant differences in allele or genotype frequencies were observed between patients and controls in this particular cohort. Thus, the present results do not support the hypothesis that genetic variation in the leptin/ghrelin system contributes substantially to the pathogenesis of MS. However, a modest effect of GHSR variation cannot be ruled out and needs to be further evaluated in future studies. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. Ghrelin receptor expression and colocalization with anterior pituitary hormones using a GHSR-GFP mouse line.

    Science.gov (United States)

    Reichenbach, Alex; Steyn, Frederik J; Sleeman, Mark W; Andrews, Zane B

    2012-11-01

    Ghrelin is the endogenous ligand for the GH secretagogue receptor (GHSR) and robustly stimulates GH release from the anterior pituitary gland. Ghrelin also regulates the secretion of anterior pituitary hormones including TSH, LH, prolactin (PRL), and ACTH. However, the relative contribution of a direct action at the GHSR in the anterior pituitary gland vs. an indirect action at the GHSR in the hypothalamus remains undefined. We used a novel GHSR-enhanced green fluorescent protein (eGFP) reporter mouse to quantify GHSR coexpression with GH, TSH, LH, PRL, and ACTH anterior pituitary cells in males vs. females and in chow-fed or calorie-restricted (CR) mice. GHSR-eGFP-expressing cells were only observed in anterior pituitary. The number of GHSR-eGFP-expressing cells was higher in male compared with females, and CR did not affect the GHSR-eGFP cell number. Double staining revealed 77% of somatotrophs expressed GHSR-eGFP in both males and females. Nineteen percent and 12.6% of corticotrophs, 21% and 9% of lactotrophs, 18% and 19% of gonadotrophs, and 3% and 9% of males and females, respectively, expressed GHSR-eGFP. CR increased the number of TSH cells, but suppressed the number of lactotrophs and gonadotrophs, expressing GHSR-eGFP compared with controls. These studies support a robust stimulatory action of ghrelin via the GHSR on GH secretion and identify a previously unknown sexual dimorphism in the GHSR expression in the anterior pituitary. CR affects GHSR-eGFP expression on lactotrophs, gonadotrophs, and thyrotrophs, which may mediate reproductive function and energy metabolism during periods of negative energy balance. The low to moderate expression of GHSR-eGFP suggests that ghrelin plays a minor direct role on remaining anterior pituitary cells.

  20. Devil's Claw to suppress appetite--ghrelin receptor modulation potential of a Harpagophytum procumbens root extract.

    Directory of Open Access Journals (Sweden)

    Cristina Torres-Fuentes

    Full Text Available Ghrelin is a stomach-derived peptide that has been identified as the only circulating hunger hormone that exerts a potent orexigenic effect via activation of its receptor, the growth hormone secretagogue receptor (GHS-R1a. Hence, the ghrelinergic system represents a promising target to treat obesity and obesity-related diseases. In this study we analysed the GHS-R1a receptor activating potential of Harpagophytum procumbens, popularly known as Devil's Claw, and its effect on food intake in vivo. H. procumbens is an important traditional medicinal plant from Southern Africa with potent anti-inflammatory and analgesic effects. This plant has been also used as an appetite modulator but most evidences are anecdotal and to our knowledge, no clear scientific studies relating to appetite modulation have been done to this date. The ghrelin receptor activation potential of an extract derived from the dried tuberous roots of H. procumbens was analysed by calcium mobilization and receptor internalization assays in human embryonic kidney cells (Hek stably expressing the GHS-R1a receptor. Food intake was investigated in male C57BL/6 mice following intraperitoneal administration of H. procumbens root extract in ad libitum and food restricted conditions. Exposure to H. procumbens extract demonstrated a significant increased cellular calcium influx but did not induce subsequent GHS-R1a receptor internalization, which is a characteristic for full receptor activation. A significant anorexigenic effect was observed in male C57BL/6 mice following peripheral administration of H. procumbens extract. We conclude that H. procumbens root extract is a potential novel source for potent anti-obesity bioactives. These results reinforce the promising potential of natural bioactives to be developed into functional foods with weight-loss and weight maintenance benefits.

  1. G Protein and β-arrestin signaling bias at the ghrelin receptor.

    Science.gov (United States)

    Evron, Tama; Peterson, Sean M; Urs, Nikhil M; Bai, Yushi; Rochelle, Lauren K; Caron, Marc G; Barak, Larry S

    2014-11-28

    The G protein-coupled ghrelin receptor GHSR1a is a potential pharmacological target for treating obesity and addiction because of the critical role ghrelin plays in energy homeostasis and dopamine-dependent reward. GHSR1a enhances growth hormone release, appetite, and dopamine signaling through G(q/11), G(i/o), and G(12/13) as well as β-arrestin-based scaffolds. However, the contribution of individual G protein and β-arrestin pathways to the diverse physiological responses mediated by ghrelin remains unknown. To characterize whether a signaling bias occurs for GHSR1a, we investigated ghrelin signaling in a number of cell-based assays, including Ca(2+) mobilization, serum response factor response element, stress fiber formation, ERK1/2 phosphorylation, and β-arrestin translocation, utilizing intracellular second loop and C-tail mutants of GHSR1a. We observed that GHSR1a and β-arrestin rapidly form metastable plasma membrane complexes following exposure to an agonist, but replacement of the GHSR1a C-tail by the tail of the vasopressin 2 receptor greatly stabilizes them, producing complexes observable on the plasma membrane and also in endocytic vesicles. Mutations of the contiguous conserved amino acids Pro-148 and Leu-149 in the GHSR1a intracellular second loop generate receptors with a strong bias to G protein and β-arrestin, respectively, supporting a role for conformation-dependent signaling bias in the wild-type receptor. Our results demonstrate more balance in GHSR1a-mediated ERK signaling from G proteins and β-arrestin but uncover an important role for β-arrestin in RhoA activation and stress fiber formation. These findings suggest an avenue for modulating drug abuse-associated changes in synaptic plasticity via GHSR1a and indicate the development of GHSR1a-biased ligands as a promising strategy for selectively targeting downstream signaling events. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Adaptive upregulation of gastric and hypothalamic ghrelin receptors and increased plasma ghrelin in a model of cancer chemotherapy-induced dyspepsia.

    Science.gov (United States)

    Malik, N M; Moore, G B T; Kaur, R; Liu, Y-L; Wood, S L; Morrow, R W; Sanger, G J; Andrews, P L R

    2008-06-05

    Chemotherapy treatment can lead to delayed gastric emptying, early satiety, anorexia, nausea and vomiting, described collectively as the cancer-associated dyspepsia syndrome (CADS). Administration of ghrelin (GHRL), an endogenous orexigenic peptide known to stimulate gastric motility, has been shown to reduce the symptoms of CADS induced in relevant animal models with the potent chemotherapeutic agent, cisplatin. We examined the effects in the rat of cisplatin (6 mg/kg i.p.) treatment on the expression of GHRL and ghrelin receptor (GHSR) mRNAs in the hypothalamus and the stomach at a time-point (2 days) when the effects of cisplatin are pronounced. In addition, plasma levels of GHRL (acylated and total including des-acyl GHRL) were measured and the effect on these levels of treatment with the synthetic glucocorticoid dexamethasone (2 mg/kg s.c. bd.) was investigated. Cisplatin increased GHSR mRNA expression in the stomach (67%) and hypothalamus (52%) but not GHRL mRNA expression and increased the percentage of acylated GHRL (7.03+/-1.35% vs. 11.38+/-2.40%) in the plasma. Dexamethasone reduced the plasma level of acylated GHRL and the percentage of acylated GHRL to values below those in animals treated with saline alone (7.03+/-1.35% vs. 2.60+/-0.49%). Our findings support the hypothesis that an adaptive upregulation of the ghrelin receptor may occur during cancer chemotherapy-associated dyspepsia. This may have a role in defensive responses to toxic challenges to the gut. In addition, our results provide preliminary evidence for glucocorticoid modulation of plasma ghrelin levels.

  3. A Novel Human Ghrelin Variant (In1-Ghrelin) and Ghrelin-O-Acyltransferase Are Overexpressed in Breast Cancer: Potential Pathophysiological Relevance

    Science.gov (United States)

    Gahete, Manuel D.; Córdoba-Chacón, José; Hergueta-Redondo, Marta; Martínez-Fuentes, Antonio J.; Kineman, Rhonda D.; Moreno-Bueno, Gema

    2011-01-01

    The human ghrelin gene, which encodes the ghrelin and obestatin peptides, contains 5 exons (Ex), with Ex1-Ex4 encoding a 117 amino-acid (aa) preproprotein that is known to be processed to yield a 28-aa (ghrelin) and/or a 23-aa (obestatin) mature peptides, which possess biological activities in multiple tissues. However, the ghrelin gene also encodes additional peptides through alternative splicing or post-translational modifications. Indeed, we previously identified a spliced mRNA ghrelin variant in mouse (In2-ghrelin-variant), which is regulated in a tissue-dependent manner by metabolic status and may thus be of biological relevance. Here, we have characterized a new human ghrelin variant that contains Ex0-1, intron (In) 1, and Ex2 and lacks Ex3-4. This human In1-ghrelin variant would encode a new prepropeptide that conserves the first 12aa of native-ghrelin (including the Ser3-potential octanoylation site) but has a different C-terminal tail. Expression of In1-variant was detected in 22 human tissues and its levels were positively correlated with those of ghrelin-O-acyltransferase (GOAT; p = 0.0001) but not with native-ghrelin expression, suggesting that In1-ghrelin could be a primary substrate for GOAT in human tissues. Interestingly, levels of In1-ghrelin variant expression in breast cancer samples were 8-times higher than those of normal mammary tissue, and showed a strong correlation in breast tumors with GOAT (p = 0.0001), ghrelin receptor-type 1b (GHSR1b; p = 0.049) and cyclin-D3 (a cell-cycle inducer/proliferation marker; p = 0.009), but not with native-ghrelin or GHSR1a expression. Interestingly, In1-ghrelin variant overexpression increased basal proliferation of MDA-MB-231 breast cancer cells. Taken together, our results provide evidence that In1-ghrelin is a novel element of the ghrelin family with a potential pathophysiological role in breast cancer. PMID:21829727

  4. Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging.

    Science.gov (United States)

    Smith, Roy G; Sun, Yuxiang; Jiang, Hong; Albarran-Zeckler, Rosie; Timchenko, Nikolai

    2007-11-01

    Administration of an orally active agonist (MK-0677) of the growth hormone secretagogue receptor (GHS-R1a) to elderly subjects restored the amplitude of endogenous episodic growth hormone (GH) release to that of young adults. Functional benefits include increased lean mass and bone density and modest improvements in strength. In old mice, a similar agonist partially restored function to the thymus and reduced tumor cell growth and metastasis. Treatment of old mice with the endogenous GHS-R1a agonist ghrelin restored a young liver phenotype. The mechanism involves inhibition of cyclin D3:cdk4/cdk6 activity and increased protein phosphatase-2A (PP2A) activity in liver nuclei, which stabilizes the dephosphorylated form of the transcription factor C/EBPalpha preventing the age-dependent formation of the C/EBPalpha-Rb-E2F4-Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de-repressed and C/EBPalpha regulated expression of Pepck, a regulator of gluconeogenesis, is normalized, thereby restoring a young liver phenotype. In the brain, aging is associated with decline in dopamine function. We investigated the potential neuromodulatory role of GHS-R1a on dopamine action. Neurons were identified in the hippocampus, cortex, substantia nigra, and ventral tegmental areas that coexpressed GHS-R1a and dopamine receptor subtype-1 (D1R). Cell culture studies showed that, in the presence of ghrelin and dopamine, GHS-R and D1R form heterodimers, which modified G-protein signal transduction resulting in amplification of dopamine signaling. We speculate that aging is associated with deficient endogenous ghrelin signaling that can be rescued by intervention with GHS-R1a agonists to improve quality of life and maintain independence.

  5. Mechanisms of anorexia-cachexia syndrome and rational for treatment with selective ghrelin receptor agonist.

    Science.gov (United States)

    Esposito, Angela; Criscitiello, Carmen; Gelao, Lucia; Pravettoni, Gabriella; Locatelli, Marzia; Minchella, Ida; Di Leo, Maria; Liuzzi, Rita; Milani, Alessandra; Massaro, Mariangela; Curigliano, Giuseppe

    2015-11-01

    Cancer cachexia is a multi-organ, multifactorial and often irreversible syndrome affecting many patients with cancer. Cancer cachexia is invariably associated with weight loss, mainly from loss of skeletal muscle and body fat, conditioning a reduced quality of life due to asthenia, anorexia, anaemia and fatigue. Treatment options for treating cancer cachexia are limited. The approach is multimodal and may include: treatment of secondary gastrointestinal symptoms, nutritional treatments, drug, and non-drug treatments. Nutritional counselling and physical training may be beneficial in delaying or preventing the development of anorexia-cachexia. However, these interventions are limited in their effect, and no definitive pharmacological treatment is available to address the relevant components of the syndrome. Anamorelin is a first-in-class, orally active ghrelin receptor agonist that binds and stimulates the growth hormone secretagogue receptor centrally, thereby mimicking the appetite-enhancing and anabolic effects of ghrelin. It represents a new class of drug and an additional treatment option for this patient group, whose therapeutic options are currently limited. In this review we examine the mechanisms of anamorelin by which it contrasts catabolic states, its role in regulation of metabolism and energy homeostasis, the data of recent trials in the setting of cancer cachexia and its safety profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism

    DEFF Research Database (Denmark)

    Holst, Birgitte; Mokrosinski, Jacek; Lang, Manja

    2007-01-01

    The carboxyamidated wFwLL peptide was used as a core ligand to probe the structural basis for agonism versus inverse agonism in the constitutively active ghrelin receptor. In the ligand, an efficacy switch could be built at the N terminus, as exemplified by AwFwLL, which functioned as a high...

  7. Circulating ghrelin, leptin, and soluble leptin receptor concentrations and cardiometabolic risk factors in a community-based sample.

    Science.gov (United States)

    Ingelsson, Erik; Larson, Martin G; Yin, Xiaoyan; Wang, Thomas J; Meigs, James B; Lipinska, Izabella; Benjamin, Emelia J; Keaney, John F; Vasan, Ramachandran S

    2008-08-01

    The conjoint effects and relative importance of ghrelin, leptin, and soluble leptin receptor (sOB-R), adipokines involved in appetite control and energy expenditure in mediating cardiometabolic risk, is unknown. The objective of the study was to study the cross-sectional relations of these adipokines to cardiometabolic risk factors in a community-based sample. We measured circulating ghrelin, leptin, and sOB-R in 362 participants (mean age 45 yr; 54% women) of the Framingham Third Generation Cohort. Body mass index, waist circumference (WC), blood pressure, lipid measures, fasting glucose, smoking, and metabolic syndrome (MetS) were measured. Ghrelin and leptin concentrations were significantly higher in women (P risk.

  8. Development of Fluorinated Non-Peptidic Ghrelin Receptor Ligands for Potential Use in Molecular Imaging

    Directory of Open Access Journals (Sweden)

    Rareş-Petru Moldovan

    2017-04-01

    Full Text Available The ghrelin receptor (GhrR is a widely investigated target in several diseases. However, the current knowledge of its role and distribution in the brain is limited. Recently, the small and non-peptidic compound (S-6-(4-bromo-2-fluorophenoxy-3-((1-isopropylpiperidin-3-ylmethyl-2-methylpyrido[3,2-d]pyrimidin-4(3H-one ((S-9 has been described as a GhrR ligand with high binding affinity. Here, we describe the synthesis of fluorinated derivatives, the in vitro evaluation of their potency as partial agonists and selectivity at GhrRs, and their physicochemical properties. These results identified compounds (S-9, (R-9, and (S-16 as suitable parent molecules for 18F-labeled positron emission tomography (PET radiotracers to enable future investigation of GhrR in the brain.

  9. Opposite Regulation of Ghrelin and Glucagon-like Peptide-1 by Metabolite G-Protein-Coupled Receptors

    DEFF Research Database (Denmark)

    Engelstoft, M S; Schwartz, T W

    2016-01-01

    Gut hormones send information about incoming nutrients to the rest of the body and thereby control many aspects of metabolism. The secretion of ghrelin and glucagon-like protein (GLP)-1, two hormones with opposite secretory patterns and opposite actions on multiple targets, is controlled by a lim......Gut hormones send information about incoming nutrients to the rest of the body and thereby control many aspects of metabolism. The secretion of ghrelin and glucagon-like protein (GLP)-1, two hormones with opposite secretory patterns and opposite actions on multiple targets, is controlled...... by a limited number of G-protein coupled receptors (GPCRs); half of which recognize and bind dietary nutrient metabolites, metabolites generated by gut microbiota, and metabolites of the host's intermediary metabolism. Most metabolite GPCRs controlling ghrelin secretion are inhibitory, whereas all metabolite...... receptors controlling GLP-1 secretion are stimulatory. This dichotomy in metabolite sensor function, which is obtained through a combination of differential expression and cell-dependent signaling bias, offers pharmacological targets to stimulate GLP-1 and inhibit ghrelin through the same mechanism....

  10. Expression of the ghrelin receptor gene in neurons of the medulla oblongata of the rat.

    Science.gov (United States)

    Bron, Romke; Yin, Lei; Russo, Domenico; Furness, John B

    2013-08-15

    There is ambiguity concerning the distribution of neurons that express the ghrelin receptor (GHSR) in the medulla oblongata. In the current study we used a sensitive nonradioactive method to investigate GHSR mRNA distribution by in situ hybridization. Strong expression of the GHSR gene was confirmed in neurons of the facial nucleus (FacN, 7), the dorsal vagal complex (DVC), and the semicompact (but not compact) nucleus ambiguus (AmbSC and AmbC). In addition, expression of GHSR was found in other regions, where it had not been described before. GHSR-positive neurons were observed in the gustatory rostral nucleus tractus solitarius and in areas involved in vestibulo-ocular processing (such as the medial vestibular nucleus and the nucleus abducens). GHSR expression was also noted in ventral areas associated with cardiorespiratory control, including the gigantocellular reticular nucleus, the lateral paragigantocellular nucleus, the rostral and caudal ventrolateral medulla, the (pre)-Bötzinger complex, and the rostral and caudal ventrolateral respiratory group. However, GHSR-positive neurons in ventrolateral areas did not express markers for cardiovascular presympathetic vasomotor neurons, respiratory propriobulbar rhythmogenic neurons, or sensory interneurons. GHSR-positive cells were intermingled with catecholamine neurons in the dorsal vagal complex but these populations did not overlap. Thus, the ghrelin receptor occurs in the medulla oblongata in 1) second-order sensory neurons processing gustatory, vestibulo-ocular, and visceral sensation; 2) cholinergic somatomotor neurons of the FacN and autonomic preganglionic neurons of the DMNX and AmbSC; 3) cardiovascular neurons in the DVC, Gi, and LPGi; 4) neurons of as yet unknown function in the ventrolateral medulla. Copyright © 2013 Wiley Periodicals, Inc., A Wiley Company.

  11. Ghrelin: ghrelin as a regulatory Peptide in growth hormone secretion.

    Science.gov (United States)

    Khatib, Nazli; Gaidhane, Shilpa; Gaidhane, Abhay M; Khatib, Mahanaaz; Simkhada, Padam; Gode, Dilip; Zahiruddin, Quazi Syed

    2014-08-01

    Ghrelin is a type of growth hormone (GH) secretagogue that stimulates the release of GH. It is a first hormone linking gastrointestinal-pituitary axis. This review highlights the interaction of ghrelin with GHRH and somatostatin to regulate the secretion of GH and intends to explore the possible physiological role of the ghrelin-pituitary-GH axis linkage system. Ghrelin is highly conserved among species and is classified into octanoylated (C8:0), decanoylated (C10:0), decenoylated (C10:1) and nonacylated,ghrelin. Acylated ghrelin is the major active form of human ghrelin. The primary production site of ghrelin is the stomach, and it interacts with stomach ghrelin as well as hypothalamic GHRH and somatostatin in the regulation of pituitary GH secretion. Ghrelin stimulate GH release through the GHS receptor to increase intracellular Ca2+ ([Ca2+] levels via IP3 signal transduction pathway. Ghrelin is a specific endogenous ligand for the GHS receptor and provides a definitive proof of the occurance of a GHS-GHS receptor signalling system in the regulation of GH secretion. Studies suggests that ghrelin is a powerful pharmacological agent that exerts a potent, time-dependent stimulation of pulsatile secretion of GH.

  12. Evidence Supporting a Role for Constitutive Ghrelin Receptor Signaling in Fasting-Induced Hyperphagia in Male Mice.

    Science.gov (United States)

    Fernandez, Gimena; Cabral, Agustina; Andreoli, María F; Labarthe, Alexandra; M'Kadmi, Céline; Ramos, Jorge G; Marie, Jacky; Fehrentz, Jean-Alain; Epelbaum, Jacques; Tolle, Virginie; Perello, Mario

    2018-02-01

    Ghrelin is a potent orexigenic peptide hormone that acts through the growth hormone secretagogue receptor (GHSR), a G protein-coupled receptor highly expressed in the hypothalamus. In vitro studies have shown that GHSR displays a high constitutive activity, whose physiological relevance is uncertain. As GHSR gene expression in the hypothalamus is known to increase in fasting conditions, we tested the hypothesis that constitutive GHSR activity at the hypothalamic level drives the fasting-induced hyperphagia. We found that refed wild-type (WT) mice displayed a robust hyperphagia that continued for 5 days after refeeding and changed their food intake daily pattern. Fasted WT mice showed an increase in plasma ghrelin levels, as well as in GHSR expression levels and ghrelin binding sites in the hypothalamic arcuate nucleus. When fasting-refeeding responses were evaluated in ghrelin- or GHSR-deficient mice, only the latter displayed an ∼15% smaller hyperphagia, compared with WT mice. Finally, fasting-induced hyperphagia of WT mice was significantly smaller in mice centrally treated with the GHSR inverse agonist K-(D-1-Nal)-FwLL-NH2, compared with mice treated with vehicle, whereas it was unaffected in mice centrally treated with the GHSR antagonists D-Lys3-growth hormone-releasing peptide 6 or JMV2959. Taken together, genetic models and pharmacological results support the notion that constitutive GHSR activity modulates the magnitude of the compensatory hyperphagia triggered by fasting. Thus, the hypothalamic GHSR signaling system could affect the set point of daily food intake, independently of plasma ghrelin levels, in situations of negative energy balance. Copyright © 2018 Endocrine Society.

  13. Expression and localization of ghrelin and its functional receptor in corpus luteum during different stages of estrous cycle and the modulatory role of ghrelin on progesterone production in cultured luteal cells in buffalo.

    Science.gov (United States)

    Gupta, M; Dangi, S S; Chouhan, V S; Hyder, I; Babitha, V; Yadav, V P; Khan, F A; Sonwane, A; Singh, G; Das, G K; Mitra, A; Bag, S; Sarkar, M

    2014-07-01

    Evidence obtained during recent years provided has insight into the regulation of corpus luteum (CL) development, function, and regression by locally produced ghrelin. The present study was carried out to evaluate the expression and localization of ghrelin and its receptor (GHS-R1a) in bubaline CL during different stages of the estrous cycle and investigate the role of ghrelin on progesterone (P4) production along with messenger RNA (mRNA) expression of P4 synthesis intermediates. The mRNA and protein expression of ghrelin and GHS-R1a was significantly greater in mid- and late luteal phases. Both factors were localized in luteal cells, exclusively in the cytoplasm. Immunoreactivity of ghrelin and GHS-R1a was greater during mid- and late luteal phases. Luteal cells were cultured in vitro and treated with ghrelin each at 1, 10, and 100 ng/mL concentrations for 48 h after obtaining 75% to 80% confluence. At a dose of 1 ng/mL, there was no significant difference in P4 secretion between control and treatment group. At 10 and 100 ng/mL, there was a decrease (P production in buffalo. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference.

    Science.gov (United States)

    Jerlhag, Elisabet; Egecioglu, Emil; Dickson, Suzanne L; Engel, Jörgen A

    2010-09-01

    Recently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine. We found that amphetamine-as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist. Thus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

  15. Effect of ghrelin receptor agonist and antagonist on the activity of arcuate nucleus tyrosine hydroxylase containing neurons in C57BL/6 male mice exposed to normal or high fat diet

    Czech Academy of Sciences Publication Activity Database

    Pirník, Z.; Majerčíková, Z.; Holubová, Martina; Pirník, R.; Železná, Blanka; Maletínská, Lenka; Kiss, A.

    2014-01-01

    Roč. 65, č. 4 (2014), s. 477-486 ISSN 0867-5910 Institutional support: RVO:61388963 Keywords : growth hormone secretagogue receptor * ghrelin receptor agonist * ghrelin receptor antagonist * high fat diet * tyrosine hydroxylase * arcuate nucleus * food intake Subject RIV: CE - Biochemistry Impact factor: 2.386, year: 2014

  16. Clinical application of ghrelin.

    Science.gov (United States)

    Strasser, Florian

    2012-01-01

    Ghrelin as a human natural hormone is involved in fundamental regulatory processes of eating and energy balance. Ghrelin signals the nutrient availability from the gastrointestinal tract to the central nervous system, up-regulates food intake and lowers energy expenditure mainly through hypothalamic mediators acting both centrally and peripherally including the gastrointestinal tract (motility, epithelium), promotes both neuro-endocrine and inflammatory signals to increase skeletal muscle growth and decrease protein breakdown, and increases lipolysis while body fat utilization is reduced. Ghrelin does more to exert its probably sentinel role around "human energy": it influences through mainly extra-hypothalamic actions the hedonic and incentive value of food, mood and anxiety, sleep-wake regulation, learning and memory, and neurogenesis. Recently numerous ghrelin gene-derived peptides were discovered, demonstrating the complexity within the ghrelin/ghrelin receptor axis. For clinical applications, not only the natural ghrelin and its slice variants, but also several modified or artificial molecules acting at ghrelin-associated receptors were and are developed. Current clinical applications are limited to clinical studies, focusing mainly on cachexia in chronic heart failure, COPD, cancer, endstage- renal-disease or cystic fibrosis, but also on frailty in elderly, gastrointestinal motility (e.g., gastroparesis, functional dyspepsia, postoperative ileus), after curative gastrectomy, anorexia nervosa, growth hormone deficient patients, alcohol craving, sleep-wake regulation (e.g. major depression), or sympathetic nervous activity in obesity. The results of completed, preliminary studies support the clinical potential of ghrelin, ghrelin gene-derived peptides, and artificial analogues, suggesting that larger clinical trials are demanded to move ghrelin towards an available and reimbursed pharmaceutical intervention.

  17. Orexin A/Hypocretin Modulates Leptin Receptor-Mediated Signaling by Allosteric Modulations Mediated by the Ghrelin GHS-R1A Receptor in Hypothalamic Neurons.

    Science.gov (United States)

    Medrano, Mireia; Aguinaga, David; Reyes-Resina, Irene; Canela, Enric I; Mallol, Josefa; Navarro, Gemma; Franco, Rafael

    2018-06-01

    The hypothalamus is a key integrator of nutrient-seeking signals in the form of hormones and metabolites originated in both the central nervous system and the periphery. The main autocrine and paracrine target of orexinergic-related hormones such as leptin, orexin/hypocretin, and ghrelin are neuropeptide Y neurons located in the arcuate nucleus of the hypothalamus. The aim of this study was to investigate the expression and the molecular and functional relationships between leptin, orexin/hypocretin and ghrelin receptors. Biophysical studies in a heterologous system showed physical interactions between them, with potential formation of heterotrimeric complexes. Functional assays showed robust allosteric interactions particularly different when the three receptors are expressed together. Further biochemical and pharmacological assays provided evidence of heterotrimer functional expression in primary cultures of hypothalamic neurons. These findings constitute evidence of close relationships in the action of the three hormones already starting at the receptor level in hypothalamic cells.

  18. Ghrelin: much more than a hunger hormone

    Science.gov (United States)

    Ghrelin is a multifaceted gut hormone that activates its receptor, growth hormone secretagogue receptor (GHS-R). Ghrelin's hallmark functions are its stimulatory effects on growth hormone release, food intake and fat deposition. Ghrelin is famously known as the 'hunger hormone'. However, ample recen...

  19. Leptin receptor and ghrelin genes polymorphisms in relation to the metabolism of lipids

    Directory of Open Access Journals (Sweden)

    Anna Trakovická

    2015-10-01

    Full Text Available The aim of this work was to analyse genetic polymorphisms in genes encoding leptin receptor (LEPR and ghrelin (GHR as genetic markers of metabolic disorders in human nutrition. Genomic DNA was obtained from in total 84 human blood samples. Effect of analysed genetic markers was evaluated for three biochemical parameters: total cholesterol, HDL and LDL cholesterol. The PCR-RFLP method was used for identification of SNPs in LEPR (Gln223Arg and GHR (171T/C genes. In analysed population prevalence of heterozygous LEPRAG (47.62% and GHRCT (40.48% genotypes was observed. Frequency of LEPRA and LEPRB alleles were 0.55 and 0.45, respectively. Similar the GHRC allele had only slight predominance than GHRT allele (0.54/0.46. In population was found higher level of observed heterozygosity across loci (0.44. For both SNPs was found high effective allele number (1.98 which was also transferred to the median level of polymorphic information content (0.37. Association analysis of LEPR and GHR genotypes effect on selected biochemical parameters was performed using GLM procedure. Significant association was found only for levels of LDL cholesterol (P<0.01. Our study shows that both genes are involved in nutritional status and therefore can be considered as candidate genes of lipids metabolism disorders and obesity.

  20. In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters

    Science.gov (United States)

    Gahete, Manuel D.; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D.; Castaño, Justo P.; Marazuela, Mónica

    2015-01-01

    Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value. PMID:26124083

  1. Ghrelin in the human myometrium

    LENUS (Irish Health Repository)

    O'Brien, Margaret

    2010-05-28

    Abstract Background Ghrelin is a 28-amino acid octanolyated peptide, synthesised primarily in the stomach. It stimulates growth hormone release, food intake and exhibits many other diverse effects. Our group have previously determined that ghrelin inhibited human contractility in vitro. The aim of this study therefore, was to investigate the expression of ghrelin, its receptor, the growth hormone secretagogue receptor type 1 (GHS-R1), ghrelin O-acyltransferase (GOAT) which catalyses ghrelin octanoylation, prohormone convertase 1\\/3 (PC1\\/3) responsible for pro-ghrelin processing, in human myometrium, during pregnancy prior to labour, during labour and in the non-pregnant state. Modulation of ghrelin and ghrelin receptor expression in cultured myometrial cells was also investigated. Methods mRNA and protein were isolated from human myometrium and the myometrial smooth muscle cell line hTERT-HM; and real-time fluorescence RT-PCR, western blotting and fluorescence microscopy performed. The effects of β-Estradiol and bacterial lipopolysaccharide (LPS) on hTERT-HM gene expression were evaluated by western blotting. Results We have reported for the first time the expression and processing of ghrelin, GHS-R1, GOAT and PC1\\/3 expression in human myometrium, and also the down-regulation of ghrelin mRNA and protein expression during labour. Furthermore, GHS-R1 protein expression significantly decreased at labour. Myometrial GOAT expression significantly increased during term non-labouring pregnancy in comparison to both non-pregnant and labouring myometrium. Mature PC1\\/3 protein expression was significantly decreased at term pregnancy and labour in comparison to non-pregnant myometrium. Ghrelin, GHS-R1, GOAT and PC1\\/3 mRNA and protein expression was also detected in the hTERT-HM cells. Ghrelin protein expression decreased upon LPS treatment in these cells while β-Estradiol treatment increased GHS-R1 expression. Conclusions Ghrelin processing occurred in the human

  2. Ghrelin in the human myometrium.

    LENUS (Irish Health Repository)

    O'Brien, Margaret

    2010-01-01

    BACKGROUND: Ghrelin is a 28-amino acid octanolyated peptide, synthesised primarily in the stomach. It stimulates growth hormone release, food intake and exhibits many other diverse effects. Our group have previously determined that ghrelin inhibited human contractility in vitro. The aim of this study therefore, was to investigate the expression of ghrelin, its receptor, the growth hormone secretagogue receptor type 1 (GHS-R1), ghrelin O-acyltransferase (GOAT) which catalyses ghrelin octanoylation, prohormone convertase 1\\/3 (PC1\\/3) responsible for pro-ghrelin processing, in human myometrium, during pregnancy prior to labour, during labour and in the non-pregnant state. Modulation of ghrelin and ghrelin receptor expression in cultured myometrial cells was also investigated. METHODS: mRNA and protein were isolated from human myometrium and the myometrial smooth muscle cell line hTERT-HM; and real-time fluorescence RT-PCR, western blotting and fluorescence microscopy performed. The effects of beta-Estradiol and bacterial lipopolysaccharide (LPS) on hTERT-HM gene expression were evaluated by western blotting. RESULTS: We have reported for the first time the expression and processing of ghrelin, GHS-R1, GOAT and PC1\\/3 expression in human myometrium, and also the down-regulation of ghrelin mRNA and protein expression during labour. Furthermore, GHS-R1 protein expression significantly decreased at labour. Myometrial GOAT expression significantly increased during term non-labouring pregnancy in comparison to both non-pregnant and labouring myometrium. Mature PC1\\/3 protein expression was significantly decreased at term pregnancy and labour in comparison to non-pregnant myometrium. Ghrelin, GHS-R1, GOAT and PC1\\/3 mRNA and protein expression was also detected in the hTERT-HM cells. Ghrelin protein expression decreased upon LPS treatment in these cells while beta-Estradiol treatment increased GHS-R1 expression. CONCLUSIONS: Ghrelin processing occurred in the human

  3. Ghrelin upregulates the phosphorylation of the GluN2B subunit of the NMDA receptor by activating GHSR1a and Fyn in the rat hippocampus.

    Science.gov (United States)

    Berrout, Liza; Isokawa, Masako

    2018-01-01

    Ghrelin and its receptor GHSR1a have been shown to exert numerous physiological functions in the brain, in addition to the well-established orexigenic role in the hypothalamus. Earlier work indicated that ghrelin stimulated the phosphorylation of the GluN1 subunit of the NMDA receptor (NMDAR) and enhanced synaptic transmission in the hippocampus. In the present study, we report that the exogenous application of ghrelin increased GluN2B phosphorylation. This increase was independent of GluN2B subunit activity or NMDAR channel activity. However, it depended on the activation of GHSR1a and Fyn as it was blocked by D-Lys3-GHRP-6 and PP2, respectively. Inhibitors for G-protein-regulated second messengers, such as Rp-cAMP, H89, TBB, ryanodine, and thapsigargin, unexpectedly enhanced GluN2B phosphorylation, suggesting that cAMP, PKA, casein kinase II, and cytosolic calcium signaling may oppose to the effect of ghrelin on the phosphorylation of GluN2B. Our findings suggest that 1) GluN2B is likely a molecular target of ghrelin and GHSR1a-driven signaling cascades, and 2) the ghrelin-mediated phosphorylation of GluN2B depends on Fyn activation under complex negative regulation by other second messengers. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Ghrelin receptor regulates appetite and satiety during aging in mice by regulating meal frequency and portion size but not total food intake

    Science.gov (United States)

    Aging is often associated with overweight and obesity. There exists a long-standing debate about whether meal pattern also contributes to the development of obesity. The orexigenic hormone ghrelin regulates appetite and satiety by activating its receptor, growth hormone secretagogue receptor (GHS-R)...

  5. Ghrelin receptor antagonism of morphine-induced conditioned place preference and behavioral and accumbens dopaminergic sensitization in rats.

    Science.gov (United States)

    Jerabek, Pavel; Havlickova, Tereza; Puskina, Nina; Charalambous, Chrysostomos; Lapka, Marek; Kacer, Petr; Sustkova-Fiserova, Magdalena

    2017-11-01

    An increasing number of studies over the past few years have demonstrated ghrelin's role in alcohol, cocaine and nicotine abuse. However, the role of ghrelin in opioid effects has rarely been examined. Recently we substantiated in rats that ghrelin growth hormone secretagogue receptors (GHS-R1A) appear to be involved in acute opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit morphine-induced biased conditioned place preference and challenge-morphine-induced accumbens dopaminergic sensitization and behavioral sensitization in adult male rats. In the place preference model, the rats were conditioned for 8 days with morphine (10 mg/kg s.c.). On the experimental day, JMV2959 (3 and 6 mg/kg i.p.) or saline were administered before testing. We used in vivo microdialysis to determine changes of dopamine and its metabolites in the nucleus accumbens in rats following challenge-morphine dose (5 mg/kg s.c.) with or without JMV2959 (3 and 6 mg/kg i.p.) pretreatment, administered on the 12th day of spontaneous abstinence from morphine repeated treatment (5 days, 10-40 mg/kg). Induced behavioral changes were simultaneously monitored. Pretreatment with JMV2959 significantly and dose dependently reduced the morphine-induced conditioned place preference and significantly and dose dependently reduced the challenge-morphine-induced dopaminergic sensitization and affected concentration of by-products associated with dopamine metabolism in the nucleus accumbens. JMV2959 pretreatment also significantly reduced challenge-morphine-induced behavioral sensitization. Our present data suggest that GHS-R1A antagonists deserve to be further investigated as a novel treatment strategy for opioid addiction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. The oncogenic role of the In1-ghrelin splicing variant in prostate cancer aggressiveness.

    Science.gov (United States)

    Hormaechea-Agulla, Daniel; Gahete, Manuel D; Jiménez-Vacas, Juan M; Gómez-Gómez, Enrique; Ibáñez-Costa, Alejandro; L-López, Fernando; Rivero-Cortés, Esther; Sarmento-Cabral, André; Valero-Rosa, José; Carrasco-Valiente, Julia; Sánchez-Sánchez, Rafael; Ortega-Salas, Rosa; Moreno, María M; Tsomaia, Natia; Swanson, Steve M; Culler, Michael D; Requena, María J; Castaño, Justo P; Luque, Raúl M

    2017-08-29

    The Ghrelin-system is a complex, pleiotropic family composed of several peptides, including native-ghrelin and its In1-ghrelin splicing variant, and receptors (GHSR 1a/b), which are dysregulated in various endocrine-related tumors, where they associate to pathophysiological features, but the presence, functional role, and mechanisms of actions of In1-ghrelin splicing variant in prostate-cancer (PCa), is completely unexplored. Herein, we aimed to determine the presence of key ghrelin-system components (native-ghrelin, In1-ghrelin, GHSR1a/1b) and their potential pathophysiological role in prostate cancer (PCa). In1-ghrelin and native-ghrelin expression was evaluated by qPCR in prostate tissues from patients with high PCa-risk (n = 52; fresh-tumoral biopsies), and healthy-prostates (n = 12; from cystoprostatectomies) and correlated with clinical parameters using Spearman-test. In addition, In1-ghrelin and native-ghrelin was measured in plasma from an additional cohort of PCa-patients with different risk levels (n = 30) and control-healthy patients (n = 20). In vivo functional (proliferation/migration) and mechanistic (gene expression/signaling-pathways) assays were performed in PCa-cell lines in response to In1-ghrelin and native-ghrelin treatment, overexpression and/or silencing. Finally, tumor progression was monitored in nude-mice injected with PCa-cells overexpressing In1-ghrelin, native-ghrelin and empty vector (control). In1-ghrelin, but not native-ghrelin, was overexpressed in high-risk PCa-samples compared to normal-prostate (NP), and this expression correlated with that of PSA. Conversely, GHSR1a/1b expression was virtually absent. Remarkably, plasmatic In1-ghrelin, but not native-ghrelin, levels were also higher in PCa-patients compared to healthy-controls. Furthermore, In1-ghrelin treatment/overexpression, and to a much lesser extent native-ghrelin, increased aggressiveness features (cell-proliferation, migration and PSA secretion) of NP and PCa

  7. Polymorphisms of genes coding for ghrelin and its receptor in relation to colorectal cancer risk: a two-step gene-wide case-control study.

    Science.gov (United States)

    Campa, Daniele; Pardini, Barbara; Naccarati, Alessio; Vodickova, Ludmila; Novotny, Jan; Steinke, Verena; Rahner, Nils; Holinski-Feder, Elke; Morak, Monika; Schackert, Hans K; Görgens, Heike; Kötting, Judith; Betz, Beate; Kloor, Matthias; Engel, Christoph; Büttner, Reinhard; Propping, Peter; Försti, Asta; Hemminki, Kari; Barale, Roberto; Vodicka, Pavel; Canzian, Federico

    2010-09-28

    Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also indicates a role of ghrelin in cancer development. We conducted a case-control study to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with colorectal cancer risk. Pairwise tagging was used to select the 11 polymorphisms included in the study. The selected polymorphisms were genotyped in 680 cases and 593 controls from the Czech Republic. We found two SNPs associated with lower risk of colorectal cancer, namely SNPs rs27647 and rs35683. We replicated the two hits, in additional 569 cases and 726 controls from Germany. A joint analysis of the two populations indicated that the T allele of rs27647 SNP exerted a protective borderline effect (Ptrend = 0.004).

  8. Rikkunshito, a Japanese Kampo Medicine, Ameliorates Decreased Feeding Behavior via Ghrelin and Serotonin 2B Receptor Signaling in a Novelty Stress Murine Model

    Directory of Open Access Journals (Sweden)

    Chihiro Yamada

    2013-01-01

    Full Text Available We investigated the effects of rikkunshito (RKT, a ghrelin signal enhancer, on the decrease in food intake after exposure to novelty stress in mice. RKT administration (500 mg/kg, per os improved the decrease in 6 h cumulative food intake. In control mice, the plasma acylated ghrelin levels significantly increased by 24 h fasting. In contrast, the acylated ghrelin levels did not increase by fasting in mice exposed to the novelty stress. RKT administration to the novelty stress mice showed a significant increase in the acylated ghrelin levels compared with that in the distilled-water-treated control mice. Food intake after administering serotonin 2B (5-HT2B receptor antagonists was evaluated to clarify the role of 5-HT2B receptor activation in the decrease in feeding behavior after novelty stress. SB215505 and SB204741, 5-HT2B receptor antagonists, significantly improved the decrease in food intake after exposure to novelty stress. A component of RKT, isoliquiritigenin, prevented the decrease in 6 h cumulative food intake. Isoliquiritigenin showed 5-HT2B receptor antagonistic activity in vitro. In conclusion, the results suggested that RKT improves the decrease in food intake after novelty stress probably via 5-HT2B receptor antagonism of isoliquiritigenin contained in RKT.

  9. Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis

    DEFF Research Database (Denmark)

    Ejskjaer, N; Vestergaard, E T; Hellström, P M

    2009-01-01

    BACKGROUND: TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis. AIM: To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis. METHODS: Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600...... between TZP-101 and placebo. CONCLUSIONS: This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying....

  10. Exploring the Behavioral and Metabolic Phenotype Generated by Re-Introduction of the Ghrelin Receptor in the Ventral Tegmental Area

    DEFF Research Database (Denmark)

    Skov, Louise J; Jensen, Morten; Christiansen, Søren H

    2017-01-01

    Ghrelin receptor (Ghr-R) signaling in neurons of the ventral tegmental area (VTA) can modulate dopaminergic function and the reward-related effects of both palatable foods and drugs of abuse. In this study, we re-introduced the Ghr-R in VTA neurons in Ghr-R knockout mice (Ghr-R(VTA) mice) to spec...... for the reward-related effects of activation of VTA neurons. Overall, our data suggest that re-introduction of the Ghr-R in the mesolimbic reward system of Ghr-R knockout mice increases the level of activation induced by both cocaine and novelty stress.......Ghrelin receptor (Ghr-R) signaling in neurons of the ventral tegmental area (VTA) can modulate dopaminergic function and the reward-related effects of both palatable foods and drugs of abuse. In this study, we re-introduced the Ghr-R in VTA neurons in Ghr-R knockout mice (Ghr-R(VTA) mice...

  11. Is there an effect of ghrelin/ghrelin analogs on cancer? A systematic review

    Science.gov (United States)

    Sever, Sakine; White, Donna L

    2016-01-01

    Ghrelin is a hormone with multiple physiologic functions, including promotion of growth hormone release, stimulation of appetite and regulation of energy homeostasis. Treatment with ghrelin/ghrelin-receptor agonists is a prospective therapy for disease-related cachexia and malnutrition. In vitro studies have shown high expression of ghrelin in cancer tissue, although its role including its impact in cancer risk and progression has not been established. We performed a systematic literature review to identify peer-reviewed human or animal in vivo original research studies of ghrelin, ghrelin-receptor agonists, or ghrelin genetic variants and the risk, presence, or growth of cancer using structured searches in PubMed database as well as secondary searches of article reference lists, additional reviews and meta-analyses. Overall, 45 (73.8%) of the 61 studies reviewed, including all 11 involving exogenous ghrelin/ghrelin-receptor agonist treatment, reported either a null (no statistically significant difference) or inverse association of ghrelin/ghrelin-receptor agonists or ghrelin genetic variants with cancer risk, presence or growth; 10 (16.7%) studies reported positive associations; and 6 (10.0%) reported both negative or null and positive associations. Differences in serum ghrelin levels in cancer cases vs controls (typically lower) were reported for some but not all cancers. The majority of in vivo studies showed a null or inverse association of ghrelin with risk and progression of most cancers, suggesting that ghrelin/ghrelin-receptor agonist treatment may have a favorable safety profile to use for cancer cachexia. Additional large-scale prospective clinical trials as well as basic bioscientific research are warranted to further evaluate the safety and benefits of ghrelin treatment in patients with cancer. PMID:27552970

  12. Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps

    Directory of Open Access Journals (Sweden)

    Morgan Kristen

    2011-01-01

    Full Text Available Abstract Background We and others have demonstrated previously that ghrelin receptor (GhrR knock out (KO mice fed a high fat diet (HFD have increased insulin sensitivity and metabolic flexibility relative to WT littermates. A striking feature of the HFD-fed GhrR KO mouse is the dramatic decrease in hepatic steatosis. To characterize further the underlying mechanisms of glucose homeostasis in GhrR KO mice, we conducted both hyperglycemic (HG and hyperinsulinemic-euglycemic (HI-E clamps. Additionally, we investigated tissue glucose uptake and specifically examined liver insulin sensitivity. Results Consistent with glucose tolerance-test data, in HG clamp experiments, GhrR KO mice showed a reduction in glucose-stimulated insulin release relative to WT littermates. Nevertheless, a robust 1st phase insulin secretion was still achieved, indicating that a healthy β-cell response is maintained. Additionally, GhrR KO mice demonstrated both a significantly increased glucose infusion rate and significantly reduced insulin requirement for maintenance of the HG clamp, consistent with their relative insulin sensitivity. In HI-E clamps, both LFD-fed and HFD-fed GhrR KO mice showed higher peripheral insulin sensitivity relative to WT littermates as indicated by a significant increase in insulin-stimulated glucose disposal (Rd, and decreased hepatic glucose production (HGP. HFD-fed GhrR KO mice showed a marked increase in peripheral tissue glucose uptake in a variety of tissues, including skeletal muscle, brown adipose tissue and white adipose tissue. GhrR KO mice fed a HFD also showed a modest, but significant decrease in conversion of pyruvate to glucose, as would be anticipated if these mice displayed increased liver insulin sensitivity. Additionally, the levels of UCP2 and UCP1 were reduced in the liver and BAT, respectively, in GhrR KO mice relative to WT mice. Conclusions These results indicate that improved glucose homeostasis of GhrR KO mice is

  13. Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling

    DEFF Research Database (Denmark)

    Holst, Birgitte; Brandt, Erik; Bach, Anders

    2005-01-01

    Two nonpeptide (L692,429 and MK-677) and two peptide [GH-releasing peptide (GHRP)-6 and ghrelin] agonists were compared in binding and in signal transduction assays: calcium mobilization, inositol phosphate turnover, cAMP-responsive element (CRE), and serum-responsive element (SRE) controlled tra...

  14. Ghrelin and cancer progression.

    Science.gov (United States)

    Lin, Tsung-Chieh; Hsiao, Michael

    2017-08-01

    Ghrelin is a small peptide with 28 amino acids, and has been characterized as the ligand of the growth hormone secretagogue receptor (GHSR). In addition to its original function in stimulating pituitary growth hormone release, ghrelin is multifunctional and plays a role in the regulation of energy balance, gastric acid release, appetite, insulin secretion, gastric motility and the turnover of gastric and intestinal mucosa. The discovery of ghrelin and GHSR expression beyond normal tissues suggests its role other than physiological function. Emerging evidences have revealed ghrelin's function in regulating several processes related to cancer progression, especially in metastasis and proliferation. We further show the relative GHRL and GHSR expression in pan-cancers from The Cancer Genome Atlas (TCGA), suggesting the potential pathological role of the axis in cancers. This review focuses on ghrelin's biological function in cancer progression, and reveals its clinical significance especially the impact on cancer patient outcome. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  15. A new family of insect tyramine receptors

    DEFF Research Database (Denmark)

    Cazzamali, Giuseppe; Klærke, Dan Arne; Grimmelikhuijzen, Cornelis J P

    2005-01-01

    in the genomic databases from the malaria mosquito Anopheles gambiae and the honeybee Apis mellifera. These four tyramine or tyramine-like receptors constitute a new receptor family that is phylogenetically distinct from the previously identified insect octopamine/tyramine receptors. The Drosophila tyramine...

  16. On the regulation of ghrelin secretion

    International Nuclear Information System (INIS)

    Schmidt, A.

    2003-04-01

    The newly discovered endogenous ligand of the growth hormone secretagogue receptor, ghrelin, is not only a potent stimulus for growth hormone secretion, but exerts also potent orexigenic (appetite stimulatory) effects. The purpose of this thesis was to elucidate the mechanisms underlying the regulation of this peptide in three different studies. Ghrelin serum levels were analyzed with a commercially available radioimmunoassay (RIA). In 18 patients on chronic hemodialysis ghrelin levels were investigated and acetomorphine parameters were determined in order to correlate the nutritional status to the ghrelin serum levels. The potential elimination of ghrelin during dialysis was also tested. Ghrelin levels were significantly elevated compared to controls. No correlation was found between Ghrelin serum levels and anthropometric parameters. It can be speculated that chronic hemodialysis patients are not only resistant to growth hormone, but also to ghrelin. In 8 healthy volunteers a potential involvement of ghrelin in the response of growth hormone to acute exercise was tested. During three different exercise intensities (low, submaximal and maximal exercise) ghrelin levels were measured. No changes in ghrelin plasma concentrations could be detected. These findings suggest that ghrellin is not involved in the growth hormone response to acute exercise. The purpose of the third study was to enlighten the mechanisms underlying the postprandial decrease of ghrelin. During a double-blind placebo-controlled study increasing systemic glucose concentrations were attained with infusion of glucose, in order to represent fasting and postprandial conditions. Ghrelin levels were studied during coinfusion of insulin, somatostatin and placebo. It could be demonstrated that, the regulation of the postprandial decrease in ghrelin is not regulated by insulin or glucose, but by somatostatin. (author)

  17. Ghrelin and gastrointestinal stromal tumors.

    Science.gov (United States)

    Zhu, Chang-Zhen; Liu, Dong; Kang, Wei-Ming; Yu, Jian-Chun; Ma, Zhi-Qiang; Ye, Xin; Li, Kang

    2017-03-14

    Ghrelin, as a kind of multifunctional protein polypeptide, is mainly produced in the fundus of the stomach and can promote occurrence and development of many tumors, including gastrointestinal tumors, which has been proved by the relevant researches. Most gastrointestinal stromal tumors (GISTs, about 80%), as the most common mesenchymal tumor, also develop in the fundus. Scientific research has confirmed that ghrelin, its receptors and mRNA respectively can be found in GISTs, which demonstrated the existence of a ghrelin autocrine/paracrine loop in GIST tissues. However, no reports to date have specified the mechanism whether ghrelin can promote the occurrence and development of GISTs. Studies of pulmonary artery endothelial cells in a low-oxygen environment and cardiac muscle cells in an ischemic environment have shown that ghrelin can activate the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Moreover, some studies of GISTs have confirmed that activation of the PI3K/AKT/mTOR pathway can indeed promote the growth and progression of GISTs. Whether ghrelin is involved in the development or progression of GISTs through certain pathways remains unknown. Can we find a new target for the treatment of GISTs? This review explores and summaries the relationship among ghrelin, the PI3K/AKT/mTOR pathway and the development of GISTs.

  18. Acylation type determines ghrelin's effects on energy homeostasis in rodents

    DEFF Research Database (Denmark)

    Heppner, Kristy; Chaudhary, Nilika; Müller, Timo D

    2012-01-01

    Ghrelin is a gastrointestinal polypeptide that acts through the ghrelin receptor (GHSR) to promote food intake and increase adiposity. Activation of GHSR requires the presence of a fatty-acid (FA) side chain on amino acid residue serine 3 of the ghrelin molecule. However, little is known about th...

  19. Distinct phosphorylation sites on the ghrelin receptor, GHSR1a, establish a code that determines the functions of ß-arrestins

    Science.gov (United States)

    Bouzo-Lorenzo, Monica; Santo-Zas, Icía; Lodeiro, Maria; Nogueiras, Rubén; Casanueva, Felipe F.; Castro, Marian; Pazos, Yolanda; Tobin, Andrew B; Butcher, Adrian J.; Camiña, Jesús P.

    2016-01-01

    The growth hormone secretagogue receptor, GHSR1a, mediates the biological activities of ghrelin, which includes the secretion of growth hormone, as well as the stimulation of appetite, food intake and maintenance of energy homeostasis. Mapping phosphorylation sites on GHSR1a and knowledge of how these sites control specific functional consequences unlocks new strategies for the development of therapeutic agents targeting individual functions. Herein, we have identified the phosphorylation of different sets of sites within GHSR1a which engender distinct functionality of ß-arrestins. More specifically, the Ser362, Ser363 and Thr366 residues at the carboxyl-terminal tail were primarily responsible for ß-arrestin 1 and 2 binding, internalization and ß-arrestin-mediated proliferation and adipogenesis. The Thr350 and Ser349 are not necessary for ß-arrestin recruitment, but are involved in the stabilization of the GHSR1a-ß-arrestin complex in a manner that determines the ultimate cellular consequences of ß-arrestin signaling. We further demonstrated that the mitogenic and adipogenic effect of ghrelin were mainly dependent on the ß-arrestin bound to the phosphorylated GHSR1a. In contrast, the ghrelin function on GH secretion was entirely mediated by G protein signaling. Our data is consistent with the hypothesis that the phosphorylation pattern on the C terminus of GHSR1a determines the signaling and physiological output. PMID:26935831

  20. Recurrent LDL-receptor mutation causes familial ...

    African Journals Online (AJOL)

    1995-05-05

    May 5, 1995 ... 3. eaudet . New. Recurrent LDL-receptor mutation causes familial hypercholesterolaemia in ... amplification refractory mutation system (ARMS)" and single- strand conformation .... Location. Afrikaner. Mixed race. ApaLl.

  1. Effect of ghrelin on the motor deficit caused by the ablation of nigrostriatal dopaminergic cells or the inhibition of striatal dopamine receptors.

    Science.gov (United States)

    Suda, Yukari; Kuzumaki, Naoko; Narita, Michiko; Hamada, Yusuke; Shibasaki, Masahiro; Tanaka, Kenichi; Tamura, Hideki; Kawamura, Takashi; Kondo, Takashige; Yamanaka, Akihiro; Narita, Minoru

    2018-02-19

    Ghrelin plays roles in a wide range of central functions by activating the growth hormone secretagogue receptor (GHSR). This receptor has recently been found in the substantia nigra (SN) to control dopamine (DA)-related physiological functions. The dysregulation of DA neurons in the SN pars compacta (SNc) and the consequent depletion of striatal DA are known to underlie the motor deficits observed in Parkinson's disease (PD). In the present study, we further investigated the role of the SN-ghrelin system in motor function under the stereotaxic injection of AAV-CMV-FLEX-diphtheria toxin A (DTA) into the SN of dopamine transporter (DAT)-Cre (DAT SN ::DTA) mice to expunge DA neurons of the SNc. First, we confirmed the dominant expression of GHSR1a, which is a functional GHSR, in tyrosine hydroxylase (TH)-positive DA neurons in the SNc of control mice. In DAT SN ::DTA mice, we clearly observed motor dysfunction using several behavioral tests. An immunohistochemical study revealed a dramatic loss of TH-positive DA neurons in the SNc and DAT-labeled axon terminals in the striatum, and an absence of mRNAs for TH and DAT in the SN of DAT SN ::DTA mice. The mRNA level of GHSR1a was drastically decreased in the SN of these mice. In normal mice, we also found the mRNA expression of GHSR1a within GABAergic neurons in the SN pars reticulata (SNr). Under these conditions, a single injection of ghrelin into the SN failed to improve the motor deficits caused by ablation of the nigrostriatal DA network using DAT SN ::DTA mice, whereas intra-SN injection of ghrelin suppressed the motor dysfunction caused by the administration of haloperidol, which is associated with the transient inhibition of DA transmission. These findings suggest that phasic activation of the SNc-ghrelin system could improve the dysregulation of nigrostriatal DA transmission related to the initial stage of PD, but not the motor deficits under the depletion of nigrostriatal DA. Although GHSRs are found in non

  2. Ghrelin and Obesity: Identifying Gaps and Dispelling Myths. A Reappraisal.

    Science.gov (United States)

    Makris, Marinos C; Alexandrou, Andreas; Papatsoutsos, Efstathios G; Malietzis, George; Tsilimigras, Diamantis I; Guerron, Alfredo D; Moris, Demetrios

    2017-01-01

    The etiology of obesity is complex. Environmental and genetic causes have been implicated in the development of this disease. Ghrelin is a hormone known to stimulate appetite. There are numerous possible actions through which ghrelin exerts its effect in the body: a) Overproduction of ghrelin, b) reduced ghrelin following meals, and c) increased receptor sensitivity to ghrelin action. Sleeve gastrectomy, a bariatric procedure, leads to reduction of ghrelin levels and subsequently to weight loss. However, there are many limitations to measurement of the fasting plasma level of the active form of ghrelin. The establishment of the exact correlation between ghrelin, appetite and obesity could be vital for the fight against obesity. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  3. Intrahippocampal injection of Cortistatin-14 impairs recognition memory consolidation in mice through activation of sst2, ghrelin and GABAA/B receptors.

    Science.gov (United States)

    Jiang, Jinhong; Peng, Yali; He, Zhen; Wei, Lijuan; Jin, Weidong; Wang, Xiaoli; Chang, Min

    2017-07-01

    Cortistatin-14 (CST-14), a neuropeptide related to somatostatin, is primarily localized within the cortex and hippocampus. In the hippocampus, CST-14 inhibits CA1 neuronal pyramidal cell firing and co-exists with GABA. However, its role in cognitive is still not clarified. The first aim of our study was to elucidate the role of CST-14 signaling in consolidation and reconsolidation of recognition memory in mice, using novel object recognition task. The results showed that central CST-14 induced in impairment of long-term and short-term recognition memory, indicating memory consolidation impairment effect. Similarly, we found that CST-14 did not impaired long-term and short-term reconsolidation recognition memory. To further investigate the underlying mechanisms of CST-14 in memory process, we used cyclosomatostatin (c-SOM, a selective sst 1-5 receptor antagonist), cyanamid154806 (a selective sst 2 receptor antagonist), ODN-8 (a high affinity and selectivity compound for sst 3 receptor), [d-Lys 3 ]GHRP-6 (a selective ghrelin receptor antagonist), picrotoxin (PTX, a GABA A receptor antagonist), and sacolfen (a GABA B receptor antagonist) to research its effects in recognition. Our results firstly indicated that the memory-impairing effects of CST-14 were significantly reversed by c-SOM, cyanamid154806, [d-Lys 3 ]GHRP-6, PTX and sacolfen, but not ODN-8, suggesting that the blockage of recognition memory consolidation induced by CST-14 involves sst 2 , ghrelin and GABA system. The present study provides a potential strategy to regulate memory processes, providing new evidence that reconsolidation is not a simple reiteration of consolidation. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Is Ghrelin Synthesized in the Central Nervous System?

    Science.gov (United States)

    Cabral, Agustina; López Soto, Eduardo J; Epelbaum, Jacques; Perelló, Mario

    2017-03-15

    Ghrelin is an octanoylated peptide that acts via its specific receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a), and regulates a vast variety of physiological functions. It is well established that ghrelin is predominantly synthesized by a distinct population of endocrine cells located within the gastric oxyntic mucosa. In addition, some studies have reported that ghrelin could also be synthesized in some brain regions, such as the hypothalamus. However, evidences of neuronal production of ghrelin have been inconsistent and, as a consequence, it is still as a matter of debate if ghrelin can be centrally produced. Here, we provide a comprehensive review and discussion of the data supporting, or not, the notion that the mammalian central nervous system can synthetize ghrelin. We conclude that no irrefutable and reproducible evidence exists supporting the notion that ghrelin is synthetized, at physiologically relevant levels, in the central nervous system of adult mammals.

  5. Is Ghrelin Synthesized in the Central Nervous System?

    Directory of Open Access Journals (Sweden)

    Agustina Cabral

    2017-03-01

    Full Text Available Ghrelin is an octanoylated peptide that acts via its specific receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a, and regulates a vast variety of physiological functions. It is well established that ghrelin is predominantly synthesized by a distinct population of endocrine cells located within the gastric oxyntic mucosa. In addition, some studies have reported that ghrelin could also be synthesized in some brain regions, such as the hypothalamus. However, evidences of neuronal production of ghrelin have been inconsistent and, as a consequence, it is still as a matter of debate if ghrelin can be centrally produced. Here, we provide a comprehensive review and discussion of the data supporting, or not, the notion that the mammalian central nervous system can synthetize ghrelin. We conclude that no irrefutable and reproducible evidence exists supporting the notion that ghrelin is synthetized, at physiologically relevant levels, in the central nervous system of adult mammals.

  6. Effects of ghrelin and des-acyl ghrelin on neurogenesis of the rat fetal spinal cord

    International Nuclear Information System (INIS)

    Sato, Miho; Nakahara, Keiko; Goto, Shintaro; Kaiya, Hiroyuki; Miyazato, Mikiya; Date, Yukari; Nakazato, Masamitsu; Kangawa, Kenji; Murakami, Noboru

    2006-01-01

    Expressions of the growth hormone secretagogue receptor (GHS-R) mRNA and its protein were confirmed in rat fetal spinal cord tissues by RT-PCR and immunohistochemistry. In vitro, over 3 nM ghrelin and des-acyl ghrelin induced significant proliferation of primary cultured cells from the fetal spinal cord. The proliferating cells were then double-stained using antibodies against the neuronal precursor marker, nestin, and the cell proliferation marker, 5-bromo-2'-deoxyuridine (BrdU), and the nestin-positive cells were also found to be co-stained with antibody against GHS-R. Furthermore, binding studies using [ 125 I]des-acyl ghrelin indicated the presence of a specific binding site for des-acyl ghrelin, and confirmed that the binding was displaced with unlabeled des-acyl ghrelin or ghrelin. These results indicate that ghrelin and des-acyl ghrelin induce proliferation of neuronal precursor cells that is both dependent and independent of GHS-R, suggesting that both ghrelin and des-acyl ghrelin are involved in neurogenesis of the fetal spinal cord

  7. The role of ghrelin in the organism

    Directory of Open Access Journals (Sweden)

    Beata Polińska

    2011-01-01

    Full Text Available Ghrelin was discovered in 1999 as an endogenous ligand of the growth hormone secretagogue receptor (GHS-R. About 60–70�0of ghrelin in the blood is released from oxyntic cells (X/A-like cells of the stomach body and fundus. Ghrelin acts via interactions with specific receptors located, for example, in the hypothalamus, pituitary gland, pancreas, kidneys, myocardium, blood vessels, adipose tissue, ovaries and placenta. Ghrelin is directly related to the control of energy balance through appetite stimulation, food intake increase and meal initiation as well as reduction of adipose tissue utilization. Moreover, ghrelin increases hydrochloric acid secretion and gastrin release, controls gastric motility, and also protects the mucous membrane of the stomach and intestine. Besides its effects on the gastrointestinal tract, ghrelin influences the cardiovascular system, bone metabolism, insulin secretion, gonad function and the immune system. It exerts anti-inflammatory effects and inhibits apoptosis of cardiomyocytes and endothelium. The plasma ghrelin level depends on the nutrition level and lifestyle factors. This article describes the most important functions of ghrelin in the organism.

  8. Genetic polymorphisms and protein structures in growth hormone, growth hormone receptor, ghrelin, insulin-like growth factor 1 and leptin in Mehraban sheep.

    Science.gov (United States)

    Bahrami, A; Behzadi, Sh; Miraei-Ashtiani, S R; Roh, S-G; Katoh, K

    2013-09-15

    The somatotropic axis, the control system for growth hormone (GH) secretion and its endogenous factors involved in the regulation of metabolism and energy partitioning, has promising potentials for producing economically valuable traits in farm animals. Here we investigated single nucleotide polymorphisms (SNPs) of the genes of factors involved in the somatotropic axis for growth hormone (GH1), growth hormone receptor (GHR), ghrelin (GHRL), insulin-like growth factor 1 (IGF-I) and leptin (LEP), using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods in 452 individual Mehraban sheep. A nonradioactive method to allow SSCP detection was used for genomic DNA and PCR amplification of six fragments: exons 4 and 5 of GH1; exon 10 of GH receptor (GHR); exon 1 of ghrelin (GHRL); exon 1 of insulin-like growth factor-I (IGF-I), and exon 3 of leptin (LEP). Polymorphisms were detected in five of the six PCR products. Two electrophoretic patterns were detected for GH1 exon 4. Five conformational patterns were detected for GH1 exon 5 and LEP exon 3, and three for IGF-I exon 1. Only GHR and GHRL were monomorphic. Changes in protein structures due to variable SNPs were also analyzed. The results suggest that Mehraban sheep, a major breed that is important for the animal industry in Middle East countries, has high genetic variability, opening interesting prospects for future selection programs and preservation strategies. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Polymorphisms of genes coding for ghrelin and its receptor in relation to anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer risk : a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)

    NARCIS (Netherlands)

    Dossus, Laure; Mckay, James D.; Canzian, Federico; Wilkening, Stefan; Rinaldi, Sabina; Biessy, Carine; Olsen, Anja; Tjonneland, Anne; Jakobsen, Marianne U.; Overvad, Kim; Clavel-Chapelon, Francoise; Boutron-Ruault, Marie-Christine; Fournier, Agnes; Linseisen, Jakob; Lukanova, Annekatrin; Boeing, Heiner; Fisher, Eva; Trichopoulou, Antonia; Georgila, Christina; Trichopoulos, Dimitrios; Palli, Domenico; Krogh, Vittorio; Tumino, Rosario; Vineis, Paolo; Quiros, Jose Ramon; Sala, Nuria; Martinez-Garcia, Carmen; Dorronsoro, Miren; Chirlaque, Maria-Dolores; Barricarte, Aurelio; van Duijnhoven, Franzel J. B.; Bueno-de-Mesquita, H. B.; van Gils, Carla H.; Peeters, Petra H. M.; Hallmans, Goran; Lenner, Per; Bingham, Sheila; Khaw, Kay Tee; Key, Tim J.; Travis, Ruth C.; Ferrari, Pietro; Jenab, Mazda; Riboli, Elio; Kaaks, Rudolf

    Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also suggests a role of ghrelin in cancer development. We conducted a case-control study on

  10. Metabolic and cardiovascular effects of ghrelin

    Directory of Open Access Journals (Sweden)

    2012-03-01

    Full Text Available Ghrelin is an endogenous ligand for growth hormone receptor, which is synthesized as a prohormone, and then proteolytically converted into 28-amino acid peptide. This peptide stimulates the secretion of growth hormone, regulates food intake, effect on carbohydrate and lipid metabolism. Ghrelin enhances the bioavailability of nitric oxide and maintains the balance between endothelin-1 and nitric oxide in the vascular wall. It increases cardiac output, and reduces blood pressure and systemic vascular resistance. Antiinflammatory effect of ghrelin is also appreciated. Since ghrelin is a circulating peptide that stimulates appetite and regulate energy balance, and its role in the development of obesity and type 2 diabetes it is the subject of intense research. A variety of metabolic functions of ghrelin requires extreme caution in the use of therapeutic approaches aimed at the stimulation or blockade of its action.

  11. Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory.

    Science.gov (United States)

    Harmatz, Elia S; Stone, Lauren; Lim, Seh Hong; Lee, Graham; McGrath, Anna; Gisabella, Barbara; Peng, Xiaoyu; Kosoy, Eliza; Yao, Junmei; Liu, Elizabeth; Machado, Nuno J; Weiner, Veronica S; Slocum, Warren; Cunha, Rodrigo A; Goosens, Ki A

    2017-06-15

    There are many contradictory findings about the role of the hormone ghrelin in aversive processing, with studies suggesting that ghrelin signaling can both inhibit and enhance aversion. Here, we characterize and reconcile the paradoxical role of ghrelin in the acquisition of fearful memories. We used enzyme-linked immunosorbent assay to measure endogenous acyl-ghrelin and corticosterone at time points surrounding auditory fear learning. We used pharmacological (systemic and intra-amygdala) manipulations of ghrelin signaling and examined several aversive and appetitive behaviors. We also used biotin-labeled ghrelin to visualize ghrelin binding sites in coronal brain sections of amygdala. All work was performed in rats. In unstressed rodents, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala and accounts for virtually all interindividual variability in long-term fear memory strength. Higher levels of endogenous ghrelin after fear learning were associated with weaker long-term fear memories, and pharmacological agonism of the ghrelin receptor during the memory consolidation period reduced fear memory strength. These fear-inhibitory effects cannot be explained by changes in appetitive behavior. In contrast, we show that chronic stress, which increases both circulating endogenous acyl-ghrelin and fear memory formation, promotes profound loss of ghrelin binding sites in the amygdala and behavioral insensitivity to ghrelin receptor agonism. These studies provide a new link between stress, a novel type of metabolic resistance, and vulnerability to excessive fear memory formation and reveal that ghrelin can regulate negative emotionality in unstressed animals without altering appetite. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  12. Genetic manipulation of the ghrelin signaling system in male mice reveals bone compartment specificity of acylated and unacylated ghrelin in the regulation of bone remodeling

    Science.gov (United States)

    Ghrelin receptor-deficient (Ghsr-/-) mice that lack acylated ghrelin (AG) signaling retain a metabolic response to unacylated ghrelin (UAG). Recently, we showed that Ghsr-deficiency affects bone metabolism. The aim of this study was to further establish the impact of AG and UAG on bone metabolism. W...

  13. Reduced ghrelin secretion in the hypothalamus of rats due to cisplatin-induced anorexia.

    Science.gov (United States)

    Yakabi, Koji; Sadakane, Chiharu; Noguchi, Masamichi; Ohno, Shino; Ro, Shoki; Chinen, Katsuya; Aoyama, Toru; Sakurada, Tomoya; Takabayashi, Hideaki; Hattori, Tomohisa

    2010-08-01

    Although chemotherapy with cisplatin is a widely used and effective cancer treatment, the undesirable gastrointestinal side effects associated with it, such as nausea, vomiting, and anorexia, markedly decrease patients' quality of life. To elucidate the mechanism underlying chemotherapy-induced anorexia, focusing on the hypothalamic ghrelin secretion-anorexia association, we measured hypothalamic ghrelin secretion in fasted and cisplatin-treated rats. Hypothalamic ghrelin secretion changes after vagotomy or administration of cisplatin. Cisplatin + rikkunshito, a serotonin 2C receptor antagonist or serotonin 3 receptor antagonist, was investigated. The effects of intracerebroventricular (icv) administration of ghrelin or the serotonin 2C receptor antagonist SB242084 on food intake were also evaluated in cisplatin-treated rats. Hypothalamic ghrelin secretion significantly increased in 24-h-fasted rats compared to freely fed rats and was markedly reduced 24 and 48 h after cisplatin treatment in cisplatin-treated rats compared to saline-treated rats, although their plasma ghrelin levels were comparable. In cisplatin-treated rats, icv ghrelin administration reversed the decrease in food intake, vagotomy partially restored hypothalamic ghrelin secretion, and hypothalamic serotonin 2C receptor mRNA expression increased significantly. Administration of rikkunshito (an endogenous ghrelin enhancer) or a serotonin 2C receptor antagonist reversed the decrease in hypothalamic ghrelin secretion and food intake 24 h after cisplatin treatment. Cisplatin-induced anorexia is mediated through reduced hypothalamic ghrelin secretion. Cerebral serotonin 2C receptor activation partially induces decrease in hypothalamic ghrelin secretion, and rikkunshito suppresses cisplatin-induced anorexia by enhancing this secretion.

  14. Involvement of Astrocytes in Mediating the Central Effects of Ghrelin

    Science.gov (United States)

    Frago, Laura M.; Chowen, Julie A.

    2017-01-01

    Although astrocytes are the most abundant cells in the mammalian brain, much remains to be learned about their molecular and functional features. Astrocytes express receptors for numerous hormones and metabolic factors, including the appetite-promoting hormone ghrelin. The metabolic effects of ghrelin are largely opposite to those of leptin, as it stimulates food intake and decreases energy expenditure. Ghrelin is also involved in glucose-sensing and glucose homeostasis. The widespread expression of the ghrelin receptor in the central nervous system suggests that this hormone is not only involved in metabolism, but also in other essential functions in the brain. In fact, ghrelin has been shown to promote cell survival and neuroprotection, with some studies exploring the use of ghrelin as a therapeutic agent against metabolic and neurodegenerative diseases. In this review, we highlight the possible role of glial cells as mediators of ghrelin’s actions within the brain. PMID:28257088

  15. Ghrelin administered spinally increases the blood glucose level in mice.

    Science.gov (United States)

    Sim, Yun-Beom; Park, Soo-Hyun; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Suh, Hong-Won

    2014-04-01

    Ghrelin is known as a regulator of the blood glucose homeostasis and food intake. In the present study, the possible roles of ghrelin located in the spinal cord in the regulation of the blood glucose level were investigated in ICR mice. We found that intrathecal (i.t.) injection with ghrelin (from 1 to 10 μg) caused an elevation of the blood glucose level. In addition, i.t. pretreatment with YIL781 (ghrelin receptor antagonist; from 0.1 to 5 μg) markedly attenuated ghrelin-induced hyperglycemic effect. The plasma insulin level was increased by ghrelin. The enhanced plasma insulin level by ghrelin was reduced by i.t. pretreatment with YIL781. However, i.t. pretreatment with glucagon-like peptide-1 (GLP-1; 5 μg) did not affect the ghrelin-induced hyperglycemia. Furthermore, i.t. administration with ghrelin also elevated the blood glucose level, but in an additive manner, in d-glucose-fed model. Our results suggest that the activation of ghrelin receptors located in the spinal cord plays important roles for the elevation of the blood glucose level. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Induced Ablation of Ghrelin Cells in Adult Mice Does Not Decrease Food Intake, Body Weight, or Response to High Fat Diet

    Science.gov (United States)

    McFarlane, Matthew R.; Brown, Michael S.; Goldstein, Joseph L.; Zhao, Tong-Jin

    2014-01-01

    SUMMARY Injection of the peptide hormone ghrelin stimulates food intake in mice and humans. However, mice born without ghrelin demonstrate no significant loss of appetite. This paradox suggests either that compensation develops in mice born without ghrelin or that ghrelin is not essential for appetite control. To distinguish these possibilities, we generated transgenic mice (Ghrl-DTR) that express the diphtheria toxin receptor in ghrelin-secreting cells. Injection of diphtheria toxin in adulthood ablated ghrelin cells and reduced plasma ghrelin by 80-95%. Ghrelin cell-ablated mice exhibited no loss of appetite or body weight and no resistance to a high fat diet. To stimulate food intake in mice by ghrelin injection, we had to raise plasma levels many-fold above normal. Like germline ghrelin-deficient mice, the ghrelin cell-ablated mice developed profound hypoglycemia when subjected to prolonged calorie restriction, confirming that ghrelin acts to maintain blood glucose under famine conditions. PMID:24836560

  17. Familial hypocalciuric hypercalcemia and calcium sensing receptor

    DEFF Research Database (Denmark)

    Mrgan, Monija; Nielsen, Sanne; Brixen, Kim

    2014-01-01

    Familial hypocalciuric hypercalcemia (FHH) is a lifelong, benign autosomal dominant disease characterized by hypercalcemia, normal to increased parathyroid hormone level, and a relatively low renal calcium excretion. Inactivation of the calcium-sensing receptor in heterozygous patients results...... in FHH, while in homozygous patients as well as in compound heterozygous or dominant negative heterozygous patients, it may result in neonatal severe hyperparathyroidism (NSHPT). Parathyroid surgery is not indicated in FHH and does not lower plasma calcium unless total parathyroidectomy is performed...

  18. Receptor-interacting protein (RIP) kinase family

    OpenAIRE

    Zhang, Duanwu; Lin, Juan; Han, Jiahuai

    2010-01-01

    Receptor-interacting protein (RIP) kinases are a group of threonine/serine protein kinases with a relatively conserved kinase domain but distinct non-kinase regions. A number of different domain structures, such as death and caspase activation and recruitment domain (CARD) domains, were found in different RIP family members, and these domains should be keys in determining the specific function of each RIP kinase. It is known that RIP kinases participate in different biological processes, incl...

  19. Maternal serum ratio of ghrelin to obestatin decreased in preeclampsia.

    Science.gov (United States)

    Wu, Weiguang; Fan, Xiaobin; Yu, Yuecheng; Wang, Yingchun

    2015-10-01

    Ghrelin, an endogenous for the growth hormone secretagogue receptor, has been shown to participate in blood pressure regulation. Obestatin, encoded by the same gene as ghrelin, is described as a physiological opponent of ghrelin. We hypothesized that ghrelin/obestatin imbalance played a role in the pathogenesis. This study was designed to determine the alterations of ghrelin and obestatin concentrations and ghrelin/obestatin ratio in maternal serum in preeclampsia. This retrospective case-control study included 31 preeclampsia and 31 gestational week-matched normal pregnancies. Ghrelin and obestatin concentrations in maternal serum were determined by radioimmunoassay, and the ghrelin/obestatin ratio was calculated. The ghrelin concentration and ghrelin/obestatin ratio in maternal serum were significantly lower in preeclampsia than in normal pregnancies (214.34±14.27pg/mL vs 251.49±16.15pg/mL, P=0.041, 1.07±0.09 vs 0.82±0.08, P=0.023). The obestatin concentration in maternal serum was significantly higher in preeclampsia than in normal pregnancies (276.35±15.38pg/mL vs 223.53±18.61pg/mL, P=0.019). The systolic blood pressure in preeclampsia was negatively correlated with ghrelin concentration and ghrelin/obestatin ratio (r=-0.549, P=0.003; r=-0.491, P=0.004) and was positively correlated with obestatin concentrations in preeclampsia (r=0.388, P=0.013). The findings of this study suggested disturbance of ghrelin and obestatin in maternal serum in preeclampsia, and ghrelin/obestatin imbalance might play a role in the pathogenesis of preeclampsia. Copyright © 2015 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.

  20. Endogenous ghrelin-O-acyltransferase (GOAT) acylates local ghrelin in the hippocampus.

    Science.gov (United States)

    Murtuza, Mohammad I; Isokawa, Masako

    2018-01-01

    Ghrelin is an appetite-stimulating peptide. Serine 3 on ghrelin must be acylated by octanoate via the enzyme ghrelin-O-acyltransferase (GOAT) for the peptide to bind and activate the cognate receptor, growth hormone secretagogue receptor type 1a (GHSR1a). Interest in GHSR1a increased dramatically when GHSR1a mRNA was demonstrated to be widespread in the brain, including the cortex and hippocampus, indicating that it has multifaceted functions beyond the regulation of metabolism. However, the source of octanoylated ghrelin for GHSR1a in the brain, outside of the hypothalamus, is not well understood. Here, we report the presence of GOAT and its ability to acylate non-octanoylated ghrelin in the hippocampus. GOAT immunoreactivity is aggregated at the base of the dentate granule cell layer in the rat and wild-type mouse. This immunoreactivity was not affected by the pharmacological inhibition of GHSR1a or the metabolic state-dependent fluctuation of systemic ghrelin levels. However, it was absent in the GHSR1a knockout mouse hippocampus, pointing the possibility that the expression of GHSR1a may be a prerequisite for the production of GOAT. Application of fluorescein isothiocyanate (FITC)-conjugated non-octanoylated ghrelin in live hippocampal slice culture (but not in fixed culture or in the presence of GOAT inhibitors) mimicked the binding profile of FITC-conjugated octanoylated ghrelin, suggesting that extracellularly applied non-octanoylated ghrelin was acylated by endogenous GOAT in the live hippocampus while GOAT being mobilized out of neurons. Our results will advance the understanding for the role of endogenous GOAT in the hippocampus and facilitate the search for the source of ghrelin that is intrinsic to the brain. © 2017 International Society for Neurochemistry.

  1. No association of defined variability in leptin, leptin receptor, adiponectin, proopiomelanocortin and ghrelin gene with food preferences in the Czech population.

    Science.gov (United States)

    Bienertova-Vasku, Julie; Bienert, Petr; Tomandl, Josef; Forejt, Martin; Vavrina, Martin; Kudelkova, Jana; Vasku, Anna

    2008-02-01

    Previously, it has been reported that mutations in the genes encoding for adipokines may be associated with impaired food intake and may serve as potential obesity biomarkers. The aim of this study was to investigate the possible associations of defined variability in leptin, leptin receptor, adiponectin, proopiomelanocortin and ghrelin genes with food preferences in the obese and non-obese Czech population and evaluate their potential as the obesity susceptibility genes. Using PCR followed by restriction analysis, we studied 185 volunteers. Basic anthropometrical characteristics associated to obesity were measured and the food intake was monitored using a 7-day record method. In the group of obese individuals, a subset of 34 morbidly obese patients was studied for plasma leptin and soluble leptin receptor levels. None of the examined polymorphisms was associated to anthropometrical or demographic characteristics of the study subjects. The Gln223Arg polymorphism within the leptin receptor gene was significantly associated with lower plasma leptin levels (the RR genotype being more frequent in patients with lower plasma leptin levels; P = 0.001). No associations of the examined polymorphisms with food preferences was observed. Based on our results, the examined polymorphisms in the adipokine genes do not seem to be the major risk factor for obesity development in the Czech population nor significantly affect food preferences.

  2. 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.

  3. Glucagon-like peptide 2 inhibits ghrelin secretion in humans

    DEFF Research Database (Denmark)

    Banasch, Matthias; Bulut, Kerem; Hagemann, Dirk

    2006-01-01

    INTRODUCTION: The growth hormone secretagogue receptor ligand ghrelin is known to play a pivotal role in the central nervous control of energy homeostasis. Circulating ghrelin levels are high under fasting conditions and decline after meal ingestion, but the mechanisms underlying the postprandial...... drop in ghrelin levels are poorly understood. In the present study we addressed, whether (1) exogenous GLP-2 administration decreases ghrelin levels and (2) what other endogenous factors are related to ghrelin secretion under fasting conditions. PATIENTS AND METHODS: Fifteen healthy male volunteers...... were studied with the intravenous infusion of GLP-2 (2 pmol l(-1) min(-1)) or placebo over 120 min in the fasting state. Plasma concentrations of glucose, insulin, C-peptide, glucagon, intact GLP-2 and ghrelin were determined. RESULTS: During the infusion of GLP-2, plasma concentrations of intact GLP-2...

  4. Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice

    NARCIS (Netherlands)

    Heijboer, A. C.; van den Hoek, A. M.; Parlevliet, E. T.; Havekes, L. M.; Romijn, J. A.; Pijl, H.; Corssmit, E. P. M.

    2006-01-01

    This study was conducted to evaluate the effects of ghrelin on insulin's capacity to suppress endogenous glucose production and promote glucose disposal in mice. To establish whether the growth hormone secretagogue (GHS) receptor can mediate the putative effect of ghrelin on the action of insulin,

  5. Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice

    NARCIS (Netherlands)

    Heijboer, A.C.; Hoek, A.M. van den; Parlevliet, E.T.; Havekes, L.M.; Romijn, J.A.; Pijl, H.; Corssmit, E.P.M.

    2006-01-01

    Aims/hypothesis: This study was conducted to evaluate the effects of ghrelin on insulin's capacity to suppress endogenous glucose production and promote glucose disposal in mice. To establish whether the growth hormone secretagogue (GHS) receptor can mediate the putative effect of ghrelin on the

  6. Ghrelin: Expression and Functions in the Central Nervous System

    NARCIS (Netherlands)

    Stoyanova, Irina; Yamada, H.; Takahashi, K.

    2011-01-01

    Ghrelin is a gastric peptide hormone and neurotransmitter, ligand for the growth hormone secretagogue receptor (GHS-R1). The hypothalamus was identified as the main source of ghrelin in the CNS, therefore the effects of the peptide have been mainly related to this part of the brain; numerous studies

  7. Receptor-interacting protein (RIP) kinase family

    Science.gov (United States)

    Zhang, Duanwu; Lin, Juan; Han, Jiahuai

    2010-01-01

    Receptor-interacting protein (RIP) kinases are a group of threonine/serine protein kinases with a relatively conserved kinase domain but distinct non-kinase regions. A number of different domain structures, such as death and caspase activation and recruitment domain (CARD) domains, were found in different RIP family members, and these domains should be keys in determining the specific function of each RIP kinase. It is known that RIP kinases participate in different biological processes, including those in innate immunity, but their downstream substrates are largely unknown. This review will give an overview of the structures and functions of RIP family members, and an update of recent progress in RIP kinase research. PMID:20383176

  8. Glucose-mediated control of ghrelin release from primary cultures of gastric mucosal cells

    Science.gov (United States)

    Sakata, Ichiro; Park, Won-Mee; Walker, Angela K.; Piper, Paul K.; Chuang, Jen-Chieh; Osborne-Lawrence, Sherri

    2012-01-01

    The peptide hormone ghrelin is released from a distinct group of gastrointestinal cells in response to caloric restriction, whereas its levels fall after eating. The mechanisms by which ghrelin secretion is regulated remain largely unknown. Here, we have used primary cultures of mouse gastric mucosal cells to investigate ghrelin secretion, with an emphasis on the role of glucose. Ghrelin secretion from these cells upon exposure to different d-glucose concentrations, the glucose antimetabolite 2-deoxy-d-glucose, and other potential secretagogues was assessed. The expression profile of proteins involved in glucose transport, metabolism, and utilization within highly enriched pools of mouse ghrelin cells and within cultured ghrelinoma cells was also determined. Ghrelin release negatively correlated with d-glucose concentration. Insulin blocked ghrelin release, but only in a low d-glucose environment. 2-Deoxy-d-glucose prevented the inhibitory effect of high d-glucose exposure on ghrelin release. mRNAs encoding several facilitative glucose transporters, hexokinases, the ATP-sensitive potassium channel subunit Kir6.2, and sulfonylurea type 1 receptor were expressed highly within ghrelin cells, although neither tolbutamide nor diazoxide exerted direct effects on ghrelin secretion. These findings suggest that direct exposure of ghrelin cells to low ambient d-glucose stimulates ghrelin release, whereas high d-glucose and glucose metabolism within ghrelin cells block ghrelin release. Also, low d-glucose sensitizes ghrelin cells to insulin. Various glucose transporters, channels, and enzymes that mediate glucose responsiveness in other cell types may contribute to the ghrelin cell machinery involved in regulating ghrelin secretion under these different glucose environments, although their exact roles in ghrelin release remain uncertain. PMID:22414807

  9. Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: association with subtype, body-mass index, severity and age of onset.

    Science.gov (United States)

    Dardennes, Roland M; Zizzari, Philippe; Tolle, Virginie; Foulon, Christine; Kipman, Amélie; Romo, Lucia; Iancu-Gontard, Dana; Boni, Claudette; Sinet, Pierre-Marie; Thérèse Bluet, Marie; Estour, Bruno; Mouren, Marie-Christine; Guelfi, Julien-Daniel; Rouillon, Frédéric; Gorwood, Philip; Epelbaum, Jacques

    2007-02-01

    Anorexia nervosa (AN) affects 0.3% of young girls with a mortality of 6%/decade and is strongly familial with genetic factors. Ghrelin is an upstream regulator of the orexigenic peptides NPY and AgRP and acts as a natural antagonist to leptin's effects on NPY/AgRP-expressing neurons, resulting in an increase in feeding and body weight. Obestatin which counteracts ghrelin action on feeding is derived from the same propeptide than ghrelin. BDNF has been involved in body weight regulation and its Val66Met polymorphism associated with AN. We therefore re-investigated the association between AN and the Leu72Met and Gln90Leu polymorphisms of the prepro-ghrelin/obestatin gene, the Ala67Thr polymorphism of AgRP and the Val66Met polymorphism of BDNF taking into account clinical subtypes (restrictive--ANR--and bingeing/purging--ANB--subtypes). Family trios study of these 4 single nucleotide polymorphisms were performed in 114 probands with AN and both their parents recruited in two specialized French centres. A transmission disequilibrium was observed for the Leu72Met SNP of the preproghrelin gene and for the Ala67Thr SNP of the AgRP gene. When stratified by clinical subtype, these two polymorphisms were preferentially transmitted for the trios with a bingeing/purging proband. An excess of transmission of the Gln90Leu72 preproghrelin/obestatin haplotype in patients with AN was observed. These results do not provide evidence for a preferential transmission of the 66Met allele of BDNF but support the hypothesis that ghrelin and AGRP polymorphisms confers susceptibility to AN. Further simultaneous analysis of genetic variants of the biological determinants of energy metabolism and feeding behaviour in very large populations should contribute to the understanding of the high degree of heritability of eating disorders and to the description of pathophysiological patterns leading to life-threatening conditions in a highly redundant system.

  10. Novel regulator of acylated ghrelin, CF801, reduces weight gain, rebound feeding after a fast, and adiposity in mice

    Directory of Open Access Journals (Sweden)

    Martin K Wellman

    2015-09-01

    Full Text Available Ghrelin is a 28 amino-acid hormonal peptide that is intimately related to the regulation of food intake and body weight. Once secreted, ghrelin binds to the growth hormone secretagogue receptor-1a (GHSR-1a, the only known receptor for ghrelin and is capable of activating a number of signaling cascades ultimately resulting in an increase in food intake and adiposity. Because ghrelin has been linked to overeating and the development of obesity, a number of pharmacological interventions have been generated in order to interfere with either the activation of ghrelin or interrupting ghrelin signaling as a means to reducing appetite and decrease weight gain. Here we present a novel peptide, CF801, capable of reducing circulating acylated ghrelin levels and subsequent body weight gain and adiposity. To this end, we show that IP administration of CF801 is sufficient to reduce circulating plasma acylated ghrelin levels. Acutely, intraperitoneal injections of CF801 resulted in decreased rebound feeding after an overnight fast. When delivered chronically decreased weight gain and adiposity without affecting caloric intake. CF801, however, did cause a change in diet preference, decreasing preference for a high fat diet and increasing preference for regular chow diet. Given the complexity of ghrelin receptor function, we propose that CF801 along with other compounds that regulate ghrelin secretion may prove to be a beneficial tool in the study of the ghrelin system, and potential targets for ghrelin based obesity treatments without altering the function of ghrelin receptors.

  11. Ghrelin and Neurodegenerative Disorders-a Review.

    Science.gov (United States)

    Shi, Limin; Du, Xixun; Jiang, Hong; Xie, Junxia

    2017-03-01

    Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor 1a (GHS-R1a), is a gut-derived, orexigenic peptide hormone that primarily regulates growth hormone secretion, food intake, and energy homeostasis. With the wide expression of GHS-R1a in extra-hypothalamic regions, the physiological role of ghrelin is more extensive than solely its involvement in metabolic function. Ghrelin has been shown to be involved in numerous higher brain functions, such as memory, reward, mood, and sleep. Some of these functions are disrupted in neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). This link between ghrelin and these neurodegenerative diseases is supported by numerous studies. This review aims to provide a comprehensive overview of the most recent evidence of the novel neuromodulatory role of ghrelin in PD, AD, and HD. Moreover, the changes in circulating and/or central ghrelin levels that are associated with disease progression are also postulated to be a biomarker for clinical diagnosis and therapy.

  12. Family C 7TM receptor dimerization and activation

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Sheikh, Søren P; Hansen, Jakob Lerche

    2006-01-01

    The family C seven transmembrane (7TM) receptors constitutes a small and especially well characterized subfamily of the large 7TM receptor superfamily. Approximately 50% of current prescription drugs target 7TM receptors, this biologically important family represents the largest class of drug...... to be fully defined. This review presents the biochemical support for family C 7TM receptor dimerization and discusses its importance for receptor biosynthesis, surface expression, ligand binding and activation, since lessons learnt here may well be applicable to the whole superfamily of 7TM receptors.......-targets today. It is well established that family C 7TM receptors form homo- or hetero-dimers on the cell surface of living cells. The large extra-cellular domains (ECD) have been crystallized as a dimer in the presence and absence of agonist. Upon agonist binding, the dimeric ECD undergoes large conformational...

  13. Structural determination, distribution, and physiological actions of ghrelin in the guinea pig.

    Science.gov (United States)

    Okuhara, Yuji; Kaiya, Hiroyuki; Teraoka, Hiroki; Kitazawa, Takio

    2018-01-01

    We identified guinea pig ghrelin (gp-ghrelin), and examined its distribution and physiological actions in the guinea-pig. Gp-ghrelin is a 28-amino acid peptide (GASFR SPEHH SAQQR KESRK LPAKI QPR); seven amino acids are different from that of rat ghrelin at positions 2, 5, 10, 11, 19, 21, and 25, which include the conserved region known in mammals. The third serine residue is mainly modified by n-decanoyl acid. Both gp-ghrelin and rat ghrelin increased intracellular Ca 2+ concentration of HEK293 cells expressing guinea pig growth hormone secretagogue receptor 1a (GHS-R1a), and the affinity of gp-ghrelin was slightly higher than that of rat ghrelin. In addition, gp-ghrelin was also effective in CHO cells expressing rat GHS-R1a with similar affinity to that of rat ghrelin. Gp-ghrelin mRNA was predominantly expressed in the stomach, whereas the expression levels in other organs was low. High levels of GHS-R1a mRNA expression were observed in the pituitary, medulla oblongata, and kidney, while medium levels were noted in the thalamus, pons, olfactory bulb, and heart. Immunohistochemistry identified gp-ghrelin-immunopositive cells in the gastric mucosa and pancreas. Intraperitoneal injection of gp-ghrelin increased food intake in the guinea pig. Gp-ghrelin did not cause any mechanical responses in isolated gastrointestinal smooth muscles in vitro, similar to rat ghrelin. In conclusion, the N-terminal structures that are conserved in mammals were different in gp-ghrelin. Moreover, the functional characteristics of gp-ghrelin, other than its distribution, were dissimilar from those in other Rodentia. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Ghrelin plasma levels in patients with idiopathic short stature.

    Science.gov (United States)

    Iñiguez, Germán; Román, Rossana; Youlton, Ronald; Cassorla, Fernando; Mericq, Verónica

    2011-02-01

    Novel molecular insights have suggested that ghrelin may be involved in the pathogenesis of some forms of short stature. Recently, growth hormone secretagogue receptor (GHSR) mutations that segregate with short stature have been reported. To study plasma ghrelin levels in prepubertal patients with idiopathic short stature (ISS). Fasting total plasma ghrelin levels (radioimmunoassay) in 41 prepubertal patients with ISS (18 females, age 7.9 ± 0.5 years) compared with 42 age- and sex-matched controls (27 females, age 8.0 ± 0.3 years) with normal height. In a subset of 28 patients, the ghrelin receptor was sequenced. ISS patients exhibited a higher level of ghrelin (1,458 ± 137 vs. 935 ± 55 pg/ml, p ghrelin levels greater than +2 SDS compared to controls. These patients did not differ in height, BMI or IGF-I SDS compared to ISS patients with ghrelin levels within the normal range. Molecular analysis of GHSR did not show any mutations, but showed some polymorphisms. These results suggest that in ISS patients, short stature does not appear to be frequently caused by abnormalities in ghrelin signaling. Copyright © 2010 S. Karger AG, Basel.

  15. Regulation of ghrelin secretion and action.

    Science.gov (United States)

    Camiña, Jesus P; Carreira, Marcos C; Micic, Dragan; Pombo, Manuel; Kelestimur, Fahrettin; Dieguez, Carlos; Casanueva, Felipe F

    2003-10-01

    The pulsatile release of growth hormone (GH) from anterior pituitary gland is regulated by the interplay of at least two hypothalamic hormones, GH-releasing hormone (GHRH) and somatostatin, via their engagement with specific cell surface receptors on the anterior pituitary somatotroph. Furthermore, release of GH in vivo may also be controlled by a third type of receptor, the growth hormone secretagogue receptor, a G-protein-coupled receptor, called GHS receptor type 1a (GHSR1a), which was identified in the pituitary and the hypothalamus in humans using a nonpeptidyl growth hormone secretagogue (MK-0677). Ghrelin, the endogenous ligand for the GHS-R1a, is a 28-amino-acid peptide isolated from human stomach that is modified by a straight chain octanoyl group covalently linked to Ser3, which is essential for its endocrine activity. This hormone, predominantly expressed and secreted by the stomach, has a dual action on GH secretion and food intake, showing interdependency between these actions. The finding that fasting and food intake, respectively, increase and decrease the secretion of ghrelin suggests that this hormone may be the bridge connecting somatic growth and body composition with energy metabolism, and appears to play a role in the alteration of energy homeostasis and body weight in pathophysiological states such as hypothyroidism and hyperthyroidism. Despite this, little is known about the intracellular signaling through which ghrelin exerts its regulatory actions. Activation of intracellular calcium mobilization is one of the earliest known cellular signals elicited by ghrelin. In HEK- 293 cells expressing the GHS-R1a, ghrelin induces a biphasic cytosolic calcium elevation characterized by a spike phase of the response, which reflects Ins(1,4,5)P3- dependent calcium mobilization of intracellular stores, and a sustained phase of the response, which is due to calcium influx across the plasma membrane triggered by aperture of capacitative calcium channels

  16. Ghrelin; The Renown Hormone

    Directory of Open Access Journals (Sweden)

    H. Murat Bilgin

    2006-01-01

    Full Text Available Ghrelin , a 28 amino acid gastric peptide, was found to be a potent releaser of GH and in addition, actively participate in controlling energy balance and the regulation of food intake. Specifically, plasma ghrelin originates in the oxyntic gland where A-like cells exist and is secreted into the bloodstream. Lower concentrations have also been reported at various regions in the body. It is well known that ghrelin participates in the regulation of many functions in the body.

  17. A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear.

    Science.gov (United States)

    Meyer, R M; Burgos-Robles, A; Liu, E; Correia, S S; Goosens, K A

    2014-12-01

    Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to stressors, yet there is no clear relationship between the levels of these hormones and stress-associated mental illnesses such as posttraumatic stress disorder (PTSD). Therefore, other hormones are likely to be involved in this effect of stress. Here we used a rodent model of PTSD in which rats repeatedly exposed to a stressor display heightened fear learning following auditory Pavlovian fear conditioning. Our results show that stress-related increases in circulating ghrelin, a peptide hormone, are necessary and sufficient for stress-associated vulnerability to exacerbated fear learning and these actions of ghrelin occur in the amygdala. Importantly, these actions are also independent of the classic HPA stress axis. Repeated systemic administration of a ghrelin receptor agonist enhanced fear memory but did not increase either corticotropin-releasing factor (CRF) or corticosterone. Repeated intraamygdala infusion of a ghrelin receptor agonist produced a similar enhancement of fear memory. Ghrelin receptor antagonism during repeated stress abolished stress-related enhancement of fear memory without blunting stress-induced corticosterone release. We also examined links between ghrelin and growth hormone (GH), a major downstream effector of the ghrelin receptor. GH protein was upregulated in the amygdala following chronic stress, and its release from amygdala neurons was enhanced by ghrelin receptor stimulation. Virus-mediated overexpression of GH in the amygdala was also sufficient to increase fear. Finally, virus-mediated overexpression of a GH receptor antagonist was sufficient to block the fear-enhancing effects of repeated ghrelin receptor stimulation. Thus, ghrelin requires GH in the amygdala to exert fear-enhancing effects. These results suggest that ghrelin mediates a novel branch of the stress response and highlight a previously unrecognized role for ghrelin and

  18. Ghrelin knockout mice show decreased voluntary alcohol consumption and reduced ethanol-induced conditioned place preference.

    Science.gov (United States)

    Bahi, Amine; Tolle, Virginie; Fehrentz, Jean-Alain; Brunel, Luc; Martinez, Jean; Tomasetto, Catherine-Laure; Karam, Sherif M

    2013-05-01

    Recent work suggests that stomach-derived hormone ghrelin receptor (GHS-R1A) antagonism may reduce motivational aspects of ethanol intake. In the current study we hypothesized that the endogenous GHS-R1A agonist ghrelin modulates alcohol reward mechanisms. For this purpose ethanol-induced conditioned place preference (CPP), ethanol-induced locomotor stimulation and voluntary ethanol consumption in a two-bottle choice drinking paradigm were examined under conditions where ghrelin and its receptor were blocked, either using ghrelin knockout (KO) mice or the specific ghrelin receptor (GHS-R1A) antagonist "JMV2959". We showed that ghrelin KO mice displayed lower ethanol-induced CPP than their wild-type (WT) littermates. Consistently, when injected during CPP-acquisition, JMV2959 reduced CPP-expression in C57BL/6 mice. In addition, ethanol-induced locomotor stimulation was lower in ghrelin KO mice. Moreover, GHS-R1A blockade, using JMV2959, reduced alcohol-stimulated locomotion only in WT but not in ghrelin KO mice. When alcohol consumption and preference were assessed using the two-bottle choice test, both genetic deletion of ghrelin and pharmacological antagonism of the GHS-R1A (JMV2959) reduced voluntary alcohol consumption and preference. Finally, JMV2959-induced reduction of alcohol intake was only observed in WT but not in ghrelin KO mice. Taken together, these results suggest that ghrelin neurotransmission is necessary for the stimulatory effect of ethanol to occur, whereas lack of ghrelin leads to changes that reduce the voluntary intake as well as conditioned reward by ethanol. Our findings reveal a major, novel role for ghrelin in mediating ethanol behavior, and add to growing evidence that ghrelin is a key mediator of the effects of multiple abused drugs. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Ghrelin, food intake, and botanical extracts: A Review.

    Science.gov (United States)

    Rezaie, Peyman; Mazidi, Mohsen; Nematy, Mohsen

    2015-01-01

    A kind of growth hormone secretagogue (GHS), ghrelin, was first isolated from the rat stomach and plays a major role in the activation of the growth hormone secretagogue receptor 1a (GHS-R1a) resulting the release of growth hormone (GH). The preproghrelin gene is placed on chromosome 3, at locus 3p25 -2 in humans and constitutes five exons and three introns. Ghrelin is most plentifully expressed in particular cells in the oxyntic glands of the gastric epithelium, initially named X/A-like cells. Almost 60-70% of circulating ghrelin is secreted by the stomach. Plasma ghrelin concentration alters throughout the day. Ghrelin has been suggested to act as a meal initiator because of its appetite-stimulating influences in free feeding rats in short period. In addition to ghrelin's function as a meal motivator, it seems to contribute in long-term energy balance and nutritional status. In addition, many studies have been carried out in order to investigate the effects of natural and medicinal plants and botanical extracts on appetite, food intake, energy hemostasis, and the level of related hormones including ghrelin. Due to the importance of ghrelin in nutritional and medical sciences, this review was performed to understand new aspects of this hormone's function.

  20. Desacyl Ghrelin Decreases Anxiety-like Behavior in Male Mice.

    Science.gov (United States)

    Mahbod, Parinaz; Smith, Eric P; Fitzgerald, Maureen E; Morano, Rachel L; Packard, Benjamin A; Ghosal, Sriparna; Scheimann, Jessie R; Perez-Tilve, Diego; Herman, James P; Tong, Jenny

    2018-01-01

    Ghrelin is a 28-amino acid polypeptide that regulates feeding, glucose metabolism, and emotionality (stress, anxiety, and depression). Plasma ghrelin circulates as desacyl ghrelin (DAG) or, in an acylated form, acyl ghrelin (AG), through the actions of ghrelin O-acyltransferase (GOAT), exhibiting low or high affinity, respectively, for the growth hormone secretagogue receptor (GHSR) 1a. We investigated the role of endogenous AG, DAG, and GHSR1a signaling on anxiety and stress responses using ghrelin knockout (Ghr KO), GOAT KO, and Ghsr stop-floxed (Ghsr null) mice. Behavioral and hormonal responses were tested in the elevated plus maze and light/dark (LD) box. Mice lacking both AG and DAG (Ghr KO) increased anxiety-like behaviors across tests, whereas anxiety reactions were attenuated in DAG-treated Ghr KO mice and in mice lacking AG (GOAT KO). Notably, loss of GHSR1a (Ghsr null) did not affect anxiety-like behavior in any test. Administration of AG and DAG to Ghr KO mice with lifelong ghrelin deficiency reduced anxiety-like behavior and decreased phospho-extracellular signal-regulated kinase phosphorylation in the Edinger-Westphal nucleus in wild-type mice, a site normally expressing GHSR1a and involved in stress- and anxiety-related behavior. Collectively, our data demonstrate distinct roles for endogenous AG and DAG in regulation of anxiety responses and suggest that the behavioral impact of ghrelin may be context dependent. Copyright © 2018 Endocrine Society.

  1. Ghrelin in eating disorders

    NARCIS (Netherlands)

    Yi, Chun-Xia; Heppner, Kristy; Tschöp, Matthias H.

    2011-01-01

    Ghrelin is the only known circulating hormone that acts on peripheral and central targets to increase food intake and promote adiposity. The present review focuses on the possible clinical relevance of ghrelin in the regulation of human feeding behavior in individuals with obesity and other eating

  2. The suppression of ghrelin signaling mitigates age-associated thermogenic impairment

    Science.gov (United States)

    Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age-associated obesity and insulin resistance. Ghrelin and obestatin are ...

  3. Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner.

    Science.gov (United States)

    Perello, Mario; Sakata, Ichiro; Birnbaum, Shari; Chuang, Jen-Chieh; Osborne-Lawrence, Sherri; Rovinsky, Sherry A; Woloszyn, Jakub; Yanagisawa, Masashi; Lutter, Michael; Zigman, Jeffrey M

    2010-05-01

    Ghrelin is a potent orexigenic hormone that likely impacts eating via several mechanisms. Here, we hypothesized that ghrelin can regulate extra homeostatic, hedonic aspects of eating behavior. In the current study, we assessed the effects of different pharmacological, physiological, and genetic models of increased ghrelin and/or ghrelin-signaling blockade on two classic behavioral tests of reward behavior: conditioned place preference (CPP) and operant conditioning. Using both CPP and operant conditioning, we found that ghrelin enhanced the rewarding value of high-fat diet (HFD) when administered to ad lib-fed mice. Conversely, wild-type mice treated with ghrelin receptor antagonist and ghrelin receptor-null mice both failed to show CPP to HFD normally observed under calorie restriction. Interestingly, neither pharmacologic nor genetic blockade of ghrelin signaling inhibited the body weight homeostasis-related, compensatory hyperphagia associated with chronic calorie restriction. Also, ghrelin's effects on HFD reward were blocked in orexin-deficient mice and wild-type mice treated with an orexin 1 receptor antagonist. Our results demonstrate an obligatory role for ghrelin in certain rewarding aspects of eating that is separate from eating associated with body weight homeostasis and that requires the presence of intact orexin signaling. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  4. Receptor oligomerization in family B1 of G-protein-coupled receptors

    DEFF Research Database (Denmark)

    Roed, Sarah Norklit; Ørgaard, Anne; Jørgensen, Rasmus

    2012-01-01

    , the glucagon receptor, and the receptors for parathyroid hormone (PTHR1 and PTHR2). The dysregulation of several family B1 receptors is involved in diseases, such as diabetes, chronic inflammation, and osteoporosis which underlines the pathophysiological importance of this GPCR subfamily. In spite of this......, investigation of family B1 receptor oligomerization and especially its pharmacological importance is still at an early stage. Even though GPCR oligomerization is a well-established phenomenon, there is a need for more investigations providing a direct link between these interactions and receptor functionality......The superfamily of the seven transmembrane G-protein-coupled receptors (7TM/GPCRs) is the largest family of membrane-associated receptors. GPCRs are involved in the pathophysiology of numerous human diseases, and they constitute an estimated 30-40% of all drug targets. During the last two decades...

  5. Increased plasma ghrelin suppresses insulin release in wethers fed with a high-protein diet.

    Science.gov (United States)

    Takahashi, T; Sato, K; Kato, S; Yonezawa, T; Kobayashi, Y; Ohtani, Y; Ohwada, S; Aso, H; Yamaguchi, T; Roh, S G; Katoh, K

    2014-06-01

    Ghrelin is a multifunctional peptide that promotes an increase of food intake and stimulates GH secretion. Ghrelin secretion is regulated by nutritional status and nutrients. Although a high-protein (HP) diet increases plasma ghrelin secretion in mammals, the mechanisms and the roles of the elevated ghrelin concentrations due to a HP diet have not been fully established. To clarify the roles of elevated acylated ghrelin upon intake of a HP diet, we investigated the regulation of ghrelin concentrations in plasma and tissues in wethers fed with either the HP diet or the control (CNT) diet for 14 days, and examined the action of the elevated plasma ghrelin by using a ghrelin-receptor antagonist. The HP diet gradually increased the plasma acylated-ghrelin concentrations, but the CNT diet did not. Although the GH concentrations did not vary significantly across the groups, an injection of ghrelin-receptor antagonist enhanced insulin levels in circulation in the HP diet group. In the fundus region of the stomach, the ghrelin levels did not differ between the HP and CNT diet groups, whereas ghrelin O-acyltransferase mRNA levels were higher in the group fed with HP diet than those of the CNT diet group were. These results indicate that the HP diet elevated the plasma ghrelin levels by increasing its synthesis; this elevation strongly suppresses the appearance of insulin in the circulation of wethers, but it is not involved in GH secretion. Overall, our findings indicate a role of endogenous ghrelin action in secretion of insulin, which acts as a regulator after the consumption of a HP diet. © 2014 Society for Endocrinology.

  6. Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs?

    Science.gov (United States)

    Barwell, James; Gingell, Joseph J; Watkins, Harriet A; Archbold, Julia K; Poyner, David R; Hay, Debbie L

    2012-05-01

    The calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR) are two of the 15 human family B (or Secretin-like) GPCRs. CTR and CLR are of considerable biological interest as their pharmacology is moulded by interactions with receptor activity-modifying proteins. They also have therapeutic relevance for many conditions, such as osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine and cardiovascular disease. In light of recent advances in understanding ligand docking and receptor activation in both the family as a whole and in CLR and CTR specifically, this review reflects how applicable general family B GPCR themes are to these two idiosyncratic receptors. We review the main functional domains of the receptors; the N-terminal extracellular domain, the juxtamembrane domain and ligand interface, the transmembrane domain and the intracellular C-terminal domain. Structural and functional findings from the CLR and CTR along with other family B GPCRs are critically appraised to gain insight into how these domains may function. The ability for CTR and CLR to interact with receptor activity-modifying proteins adds another level of sophistication to these receptor systems but means careful consideration is needed when trying to apply generic GPCR principles. This review encapsulates current thinking in the realm of family B GPCR research by highlighting both conflicting and recurring themes and how such findings relate to two unusual but important receptors, CTR and CLR. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  7. In1-ghrelin splicing variant is overexpressed in pituitary adenomas and increases their aggressive features

    Science.gov (United States)

    Ibáñez-Costa, Alejandro; Gahete, Manuel D.; Rivero-Cortés, Esther; Rincón-Fernández, David; Nelson, Richard; Beltrán, Manuel; de la Riva, Andrés; Japón, Miguel A.; Venegas-Moreno, Eva; Gálvez, Ma Ángeles; García-Arnés, Juan A.; Soto-Moreno, Alfonso; Morgan, Jennifer; Tsomaia, Natia; Culler, Michael D.; Dieguez, Carlos; Castaño, Justo P.; Luque, Raúl M.

    2015-01-01

    Pituitary adenomas comprise a heterogeneous subset of pathologies causing serious comorbidities, which would benefit from identification of novel, common molecular/cellular biomarkers and therapeutic targets. The ghrelin system has been linked to development of certain endocrine-related cancers. Systematic analysis of the presence and functional implications of some components of the ghrelin system, including native ghrelin, receptors and the recently discovered splicing variant In1-ghrelin, in human normal pituitaries (n = 11) and pituitary adenomas (n = 169) revealed that expression pattern of ghrelin system suffers a clear alteration in pituitary adenomasas comparedwith normal pituitary, where In1-ghrelin is markedly overexpressed. Interestingly, in cultured pituitary adenoma cells In1-ghrelin treatment (acylated peptides at 100 nM; 24–72 h) increased GH and ACTH secretion, Ca2+ and ERK1/2 signaling and cell viability, whereas In1-ghrelin silencing (using a specific siRNA; 100 nM) reduced cell viability. These results indicate that an alteration of the ghrelin system, specially its In1-ghrelin variant, could contribute to pathogenesis of different pituitary adenomas types, and suggest that this variant and its related ghrelin system could provide new tools to identify novel, more general diagnostic, prognostic and potential therapeutic targets in pituitary tumors. PMID:25737012

  8. Modulation of ingestive behavior and gastrointestinal motility by ghrelin in diabetic animals and humans.

    Science.gov (United States)

    Chen, Chih-Yen; Fujimiya, Mineko; Laviano, Alessandro; Chang, Full-Young; Lin, Han-Chieh; Lee, Shou-Dong

    2010-05-01

    Acyl ghrelin, a 28-amino acid peptide hormone, is the endogenous cognate ligand for the growth hormone secretagogue receptor. Ghrelin is involved in stimulating growth hormone release, eliciting feeding behavior, inducing adiposity and stimulating gastrointestinal motility. Ghrelin is unique for its post-translational modification of O-n-octanoylation at serine 3 through ghrelin O-acyltransferase, and is the only peripheral signal to enhance food intake. Plasma ghrelin levels manifest "biphasic changes" in diabetes mellitus (DM). In the early stage of DM, the stomach significantly increases the secretion of ghrelin into the plasma, and elevated plasma ghrelin levels are correlated with diabetic hyperphagic feeding and accelerated gastrointestinal motility. In the late stage of DM, plasma ghrelin levels may be lower, which might be linked with anorexia/muscle wasting, delayed gastrointestinal transit, and even gastroparesis. Therefore, the unique ghrelin system may be the most important player compared to the other hindgut hormones participating in the "entero-insular axis". Further studies using either knockdown or knockout of ghrelin gene products and ghrelin O-acyltransferase may unravel the pathogenesis of DM, and show benefits in combating this disease and metabolic syndrome. Copyright 2010 Elsevier. Published by Elsevier B.V. All rights reserved.

  9. Modulation of Ingestive Behavior and Gastrointestinal Motility by Ghrelin in Diabetic Animals and Humans

    Directory of Open Access Journals (Sweden)

    Chih-Yen Chen

    2010-05-01

    Full Text Available Acyl ghrelin, a 28-amino acid peptide hormone, is the endogenous cognate ligand for the growth hormone secretagogue receptor. Ghrelin is involved in stimulating growth hormone release, eliciting feeding behavior, inducing adiposity and stimulating gastrointestinal motility. Ghrelin is unique for its post-translational modification of O-n-octanoylation at serine 3 through ghrelin O-acyltransferase, and is the only peripheral signal to enhance food intake. Plasma ghrelin levels manifest “biphasic changes” in diabetes mellitus (DM. In the early stage of DM, the stomach significantly increases the secretion of ghrelin into the plasma, and elevated plasma ghrelin levels are correlated with diabetic hyperphagic feeding and accelerated gastrointestinal motility. In the late stage of DM, plasma ghrelin levels may be lower, which might be linked with anorexia/muscle wasting, delayed gastrointestinal transit, and even gastroparesis. Therefore, the unique ghrelin system may be the most important player compared to the other hindgut hormones participating in the “entero-insular axis”. Further studies using either knockdown or knockout of ghrelin gene products and ghrelin O-acyltransferase may unravel the pathogenesis of DM, and show benefits in combating this disease and metabolic syndrome.

  10. Neonatal overfeeding disrupts pituitary ghrelin signalling in female rats long-term; Implications for the stress response.

    Science.gov (United States)

    Sominsky, Luba; Ziko, Ilvana; Spencer, Sarah J

    2017-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis responses to psychological stress are exacerbated in adult female but not male rats made obese due to overfeeding in early life. Ghrelin, traditionally known for its role in energy homeostasis, has been recently recognised for its role in coordinating the HPA responses to stress, particularly by acting directly at the anterior pituitary where the growth hormone secretagogue receptor (GHSR), the receptor for acyl ghrelin, is abundantly expressed. We therefore hypothesised that neonatal overfeeding in female rats would compromise pituitary responsiveness to ghrelin, contributing to a hyperactive central stress responsiveness. Unlike in males where hypothalamic ghrelin signalling is compromised by neonatal overfeeding, there was no effect of early life diet on circulating ghrelin or hypothalamic ghrelin signalling in females, indicating hypothalamic feeding and metabolic ghrelin circuitry remains intact. However, neonatal overfeeding did lead to long-term alterations in the pituitary ghrelin system. The neonatally overfed females had increased neonatal and reduced adult expression of GHSR and ghrelin-O-acyl transferase (GOAT) in the pituitary as well as reduced pituitary responsiveness to exogenous acyl ghrelin-induced adrenocorticotropic hormone (ACTH) release in vitro. These data suggest that neonatal overfeeding dysregulates pituitary ghrelin signalling long-term in females, potentially accounting for the hyper-responsive HPA axis in these animals. These findings have implications for how females may respond to stress throughout life, suggesting the way ghrelin modifies the stress response at the level of the pituitary may be less efficient in the neonatally overfed.

  11. Focus on the short- and long-term effects of ghrelin on energy homeostasis.

    Science.gov (United States)

    De Vriese, Carine; Perret, Jason; Delporte, Christine

    2010-06-01

    The endogenous ligand for the growth hormone secretagogue receptor, ghrelin, is a 28-amino-acid peptide acylated with an octanoyl group at the serine in position 3. Most of the circulating ghrelin results from its synthesis and secretion by the X/A-like endocrine cells from the stomach and proximal small intestine. Besides its potent growth hormone secretory action, ghrelin is a highly pleiotropic hormone, contributing significantly to the regulation of appetite and food intake control, gastrointestinal motility, gastric acid secretion, endocrine and exocrine pancreatic secretions, cell proliferation, glucose and lipid metabolism, and cardiovascular and immunologic processes. The purpose of this review is to consider the orexigenic effects of ghrelin on short-term regulation of food intake and long-term regulation of body weight, the implications of genetic ghrelin and growth hormone secretagogue receptor polymorphism, and the use of antagonists and agonists of ghrelin in pathophysiological conditions. Copyright 2010 Elsevier Inc. All rights reserved.

  12. Ghrelin: an emerging player in the regulation of reproduction in non-mammalian vertebrates.

    Science.gov (United States)

    Unniappan, Suraj

    2010-07-01

    The endocrine regulation of vertebrate reproduction is achieved by the coordinated actions of multiple endocrine factors mainly produced from the brain, pituitary, and gonads. In addition to these, several other tissues including the fat and gut produce factors that have reproductive effects. Ghrelin is one such gut/brain hormone with species-specific effects in the regulation of mammalian reproduction. Recent studies have shown that ghrelin and ghrelin receptor mRNAs, and protein are expressed in the ovary and testis of mammals, indicating a direct effect for ghrelin in the control of reproduction. Ghrelin regulates mammalian reproduction by modulating hormone secretion from the brain and pituitary, and by acting directly on the gonads to influence reproductive tissue development and steroid hormone release. Based on the studies reported so far, ghrelin seems to have a predominantly inhibitory role on mammalian reproduction. The presence of ghrelin and ghrelin receptor has been found in the brain, pituitary and gonads of several non-mammalian vertebrates. In contrast to mammals, ghrelin seems to have a stimulatory role in the regulation of non-mammalian reproduction. The main objective of this review is to do a perspective analysis of the comparative aspects of ghrelin regulation of reproduction. (c) 2009 Elsevier Inc. All rights reserved.

  13. Fasting up-regulates ferroportin 1 expression via a Ghrelin/GHSR/MAPK signaling pathway.

    Science.gov (United States)

    Luo, Qian-Qian; Zhou, Yu-Fu; Chen, Mesona Yung-Jin; Liu, Li; Ma, Juan; Zhang, Meng-Wan; Zhang, Fa-Li; Ke, Ya; Qian, Zhong-Ming

    2018-01-01

    The significant positive correlation between ghrelin and iron and hepcidin levels in the plasma of children with iron deficiency anemia prompted us to hypothesize that ghrelin may affect iron metabolism. Here, we investigated the effects of fasting or ghrelin on the expression of hepcidin, ferroportin 1 (Fpn1), transferrin receptor 1 (TfR1), ferritin light chain (Ft-L) proteins, and ghrelin, and also hormone secretagogue receptor 1 alpha (GHSR1α) and ghrelin O-acyltransferase (GOAT) mRNAs in the spleen and/or macrophage. We demonstrated that fasting induces a significant increase in the expression of ghrelin, GHSR1α, GOAT, and hepcidin mRNAs, as well as Ft-L and Fpn1 but not TfR1 proteins in the spleens of mice in vivo. Similar to the effects of fasting on the spleen, ghrelin induced a significant increase in the expression of Ft-L and Fpn1 but not TfR1 proteins in macrophages in vitro. In addition, ghrelin was found to induce a significant enhancement in phosphorylation of ERK as well as translocation of pERK from the cytosol to nuclei. Furthermore, the increased pERK and Fpn1 induced by ghrelin was demonstrated to be preventable by pre-treatment with either GHSR1α antagonist or pERK inhibitor. Our findings support the hypothesis that fasting upregulates Fpn1 expression, probably via a ghrelin/GHSR/MAPK signaling pathway. © 2017 Wiley Periodicals, Inc.

  14. Ghrelin stimulates angiogenesis in human microvascular endothelial cells: Implications beyond GH release

    International Nuclear Information System (INIS)

    Li Aihua; Cheng Guangli; Zhu Genghui; Tarnawski, Andrzej S.

    2007-01-01

    Ghrelin, a peptide hormone isolated from the stomach, releases growth hormone and stimulates appetite. Ghrelin is also expressed in pancreas, kidneys, cardiovascular system and in endothelial cells. The precise role of ghrelin in endothelial cell functions remains unknown. We examined the expression of ghrelin and its receptor (GHSR1) mRNAs and proteins in human microvascular endothelial cells (HMVEC) and determined whether ghrelin affects in these cells proliferation, migration and in vitro angiogenesis; and whether MAPK/ERK2 signaling is important for the latter action. We found that ghrelin and GHSR1 are constitutively expressed in HMVEC. Treatment of HMVEC with exogenous ghrelin significantly increased in these cells proliferation, migration, in vitro angiogenesis and ERK2 phosphorylation. MEK/ERK2 inhibitor, PD 98059 abolished ghrelin-induced in vitro angiogenesis. This is First demonstration that ghrelin and its receptor are expressed in human microvascular endothelial cells and that ghrelin stimulates HMVEC proliferation, migration, and angiogenesis through activation of ERK2 signaling

  15. Transitional change in rat fetal cell proliferation in response to ghrelin and des-acyl ghrelin during the last stage of pregnancy

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Yoshiyuki; Nakahara, Keiko [Department of Veterinary Physiology, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192 (Japan); Kangawa, Kenji [Department of Biochemistry, National Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565 (Japan); Murakami, Noboru, E-mail: a0d201u@cc.miyazaki-u.ac.jp [Department of Veterinary Physiology, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192 (Japan)

    2010-03-12

    Expression of mRNA for the ghrelin receptor, GHS-R1a, was detected in various peripheral and central tissues of fetal rats, including skin, bone, heart, liver, gut, brain and spinal cord, on embryonic day (ED)15 and ED17. However, its expression in skin, bone, heart and liver, but not in gut, brain and spinal cord, became relatively weak on ED19 and disappeared after birth (ND2). Ghrelin and des-acyl ghrelin facilitated the proliferation of cultured fetal (ED17, 19), but not neonatal (ND2), skin cells. On the other hand, with regard to cells from the spinal cord and hypothalamus, the proliferative effect of ghrelin continued after birth, whereas the effect of des-acyl ghrelin on neurogenesis in these tissues was lost at the ED19 fetal and ND2 neonatal stages. Immunohistochemistry revealed that the cells in the hypothalamus induced to proliferate by ghrelin at the ND2 stage were positive for nestin and glial fibrillary acidic protein. These results suggest that in the period immediately prior to, and after birth, rat fetal cells showing proliferation in response to ghrelin and des-acyl ghrelin are at a transitional stage characterized by alteration of the expression of GHS-R1a and an undefined des-acyl ghrelin receptor, their responsiveness varying among different tissues.

  16. Transitional change in rat fetal cell proliferation in response to ghrelin and des-acyl ghrelin during the last stage of pregnancy

    International Nuclear Information System (INIS)

    Inoue, Yoshiyuki; Nakahara, Keiko; Kangawa, Kenji; Murakami, Noboru

    2010-01-01

    Expression of mRNA for the ghrelin receptor, GHS-R1a, was detected in various peripheral and central tissues of fetal rats, including skin, bone, heart, liver, gut, brain and spinal cord, on embryonic day (ED)15 and ED17. However, its expression in skin, bone, heart and liver, but not in gut, brain and spinal cord, became relatively weak on ED19 and disappeared after birth (ND2). Ghrelin and des-acyl ghrelin facilitated the proliferation of cultured fetal (ED17, 19), but not neonatal (ND2), skin cells. On the other hand, with regard to cells from the spinal cord and hypothalamus, the proliferative effect of ghrelin continued after birth, whereas the effect of des-acyl ghrelin on neurogenesis in these tissues was lost at the ED19 fetal and ND2 neonatal stages. Immunohistochemistry revealed that the cells in the hypothalamus induced to proliferate by ghrelin at the ND2 stage were positive for nestin and glial fibrillary acidic protein. These results suggest that in the period immediately prior to, and after birth, rat fetal cells showing proliferation in response to ghrelin and des-acyl ghrelin are at a transitional stage characterized by alteration of the expression of GHS-R1a and an undefined des-acyl ghrelin receptor, their responsiveness varying among different tissues.

  17. Ghrelin Signalling on Food Reward: A Salient Link Between the Gut and the Mesolimbic System

    OpenAIRE

    Perello, M.; Dickson, S. L.

    2015-01-01

    ?Hunger is the best spice? is an old and wise saying that acknowledges the fact that almost any food tastes better when we are hungry. The neurobiological underpinnings of this lore include activation of the brain's reward system and the stimulation of this system by the hunger?promoting hormone ghrelin. Ghrelin is produced largely from the stomach and levels are higher preprandially. The ghrelin receptor is expressed in many brain areas important for feeding control, including not only the h...

  18. Abalation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues

    Science.gov (United States)

    Aging is associated with increased adiposity in white adipose tissues and impaired thermogenesis in brown adipose tissues; both contribute to increased incidences of obesity and type 2 diabetes. Ghrelin is the only known circulating orexigenic hormone that promotes adiposity. In this study, we show ...

  19. Polymorphisms for ghrelin with consequences on satiety and metabolic alterations.

    Science.gov (United States)

    Perret, Jason; De Vriese, Carine; Delporte, Christine

    2014-07-01

    To understand the current trend of ghrelin genetic variations on the control of satiety, eating behaviours, obesity, and metabolic alterations, and its development over the last 18 months. Several polymorphisms of the ghrelin gene, its receptor gene and ghrelin's acylating enzyme, ghrelin O-acyl transferase, have been identified and studied over the last decade in relation to control of satiety, obesity, eating behaviours, metabolic syndrome, glucose homeostasis, and type 2 diabetes. However, the effects described are either small or nonsignificant and often subjected to contradictory conclusions between studies. In the last 18 months, several of these areas of investigations have been revisited under more controlled conditions or have been subjected to meta-analysis. The effects of ghrelin gene polymorphism, is a complex area of investigation, due to ghrelin's interplay with a host of various factors part of an integrative network. However, taken together, results suggest that there are no or nonsignificant effects of the common genetic variants. A better understanding of the network, probably by a systems biology type approach, will be necessary to assign the exact role played by gene polymorphism of the component of the ghrelin axis.

  20. Ghrelin and eating disorders

    OpenAIRE

    Fabbri,Alessandra Donzelli; Deram,Sophie; Kerr,Daniel Shikanai; Cordás,Táki Athanássios

    2015-01-01

    Background Ghrelin is a potent hormone with central and peripheral action. This hormone plays an important role in the regulation of appetite, food intake, and energy balance. Studies have suggested that ghrelin is involved with eating disorders (ED), particularly bingeing and purging. Genetic variants have also been studied to explain changes in eating behavior. Methods We conducted a literature review; we searched PubMed, Scientific Electronic Library Online (SciELO), and LILACS databases u...

  1. [Ghrelin: beyond hunger regulation].

    Science.gov (United States)

    Milke García, Maria del Pilar

    2005-01-01

    Man ingests food to mitigate hunger (mediated by physiological and biochemical signals), satisfy appetite (subjective sensation) and because of psychosocial reasons. Satiation biomarkers (stop feeding) are gastric distention and hormones (CCK, GLP-1) and satiety biomarkers (induce feeding) are food-induced thermogenesis, body temperature, glycaemia and also hormones (insulin, leptin and ghrelin). Oxidative metabolism/body composition, tryptophan/serotonin and proinflammatory cytokines are also implicated on hunger physiology. At the present time, ghrelin is the only known circulating orexigenic with potential on hunger/body weight regulation. It is a neuropeptide (endogenous ligand for the GH secretagogue) recently isolated from the oxyntic mucosa and synthesized mainly in the stomach. Its blood concentration depends on diet, hyperglucemia and adiposity/leptin. It is secreted 1-2 hours preprandially and its concentration decreases drastically during the postprandium. Ghrelin acts on the lateral hypothalamus and theoretically inhibits proinflammatory cytokine secretion and antagonizes leptin. Ghrelin physiologically increases food intake and stimulates adipogenesis, gastrointestinal motility and gastric acid secretion, and has other hormonal and cardiovascular functions. Ghrelin blood concentration is reduced in massive obesity, non-alcoholic steatohepatitis, polycystic ovary syndrome, acromegaly, hypogonadism, ageing, short bowel syndrome and rheumatoid arthritis; and increased in primary or secondary anorexia, starvation, chronic liver disease and celiac disease. Cerebral and peritoneal ghrelin administration (rats) and systemic administration (rats and healthy volunteers, cancer patients or patients on peritoneal dialysis) promotes food consumption and increases adiposity, of utmost importance in the treatment of patients with anorexia.

  2. Divergent circuitry underlying food reward and intake effects of ghrelin: dopaminergic VTA-accumbens projection mediates ghrelin's effect on food reward but not food intake.

    Science.gov (United States)

    Skibicka, Karolina P; Shirazi, Rozita H; Rabasa-Papio, Cristina; Alvarez-Crespo, Mayte; Neuber, Corinna; Vogel, Heike; Dickson, Suzanne L

    2013-10-01

    Obesity has reached global epidemic proportions and creating an urgent need to understand mechanisms underlying excessive and uncontrolled food intake. Ghrelin, the only known circulating orexigenic hormone, potently increases food reward behavior. The neurochemical circuitry that links ghrelin to the mesolimbic reward system and to the increased food reward behavior remains unclear. Here we examine whether VTA-NAc dopaminergic signaling is required for the effects of ghrelin on food reward and intake. In addition, we examine the possibility of endogenous ghrelin acting on the VTA-NAc dopamine neurons. A D1-like or a D2 receptor antagonist was injected into the NAc in combination with ghrelin microinjection into the VTA to investigate whether this blockade attenuates ghrelin-induced food reward behavior. VTA injections of ghrelin produced a significant increase in food motivation/reward behavior, as measured by sucrose-induced progressive ratio operant conditioning, and chow intake. Pretreatment with either a D1-like or D2 receptor antagonist into the NAc, completely blocked the reward effect of ghrelin, leaving chow intake intact. We also found that this circuit is potentially relevant for the effects of endogenously released ghrelin as both antagonists reduced fasting (a state of high circulating levels of ghrelin) elevated sucrose-motivated behavior but not chow hyperphagia. Taken together our data identify the VTA to NAc dopaminergic projections, along with D1-like and D2 receptors in the NAc, as essential elements of the ghrelin responsive circuits controlling food reward behavior. Interestingly results also suggest that food reward behavior and simple intake of chow are controlled by divergent circuitry, where NAc dopamine plays an important role in food reward but not in food intake. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  3. Direct versus indirect actions of ghrelin on hypothalamic NPY neurons.

    Science.gov (United States)

    Hashiguchi, Hiroshi; Sheng, Zhenyu; Routh, Vanessa; Gerzanich, Volodymyr; Simard, J Marc; Bryan, Joseph

    2017-01-01

    Assess direct versus indirect action(s) of ghrelin on hypothalamic NPY neurons. Electrophysiology was used to measure ion channel activity in NPY-GFP neurons in slice preparations. Ca2+ imaging was used to monitor ghrelin activation of isolated NPY GFP-labeled neurons. Immunohistochemistry was used to localize Trpm4, SUR1 and Kir6.2 in the hypothalamus. Acylated ghrelin depolarized the membrane potential (MP) of NPY-GFP neurons in brain slices. Depolarization resulted from a decreased input resistance (IR) in ~70% of neurons (15/22) or an increased IR in the remainder (7/22), consistent with the opening or closing of ion channels, respectively. Although tetrodotoxin (TTX) blockade of presynaptic action potentials reduced ghrelin-induced changes in MP and IR, ghrelin still significantly depolarized the MP and decreased IR in TTX-treated neurons, suggesting that ghrelin directly opens cation channel(s) in NPY neurons. In isolated NPY-GFP neurons, ghrelin produced a sustained rise of [Ca2+]c, with an EC50 ~110 pM. Pharmacologic studies confirmed that the direct action of ghrelin was through occupation of the growth hormone secretagogue receptor, GHS-R, and demonstrated the importance of the adenylate cyclase/cAMP/protein kinase A (PKA) and phospholipase C/inositol triphosphate (PLC/IP3) pathways as activators of 5' AMP-activated protein kinase (AMPK). Activation of isolated neurons was not affected by CNQX or TTX, but reducing [Na+]o suppressed activation, suggesting a role for Na+-permeable cation channels. SUR1 and two channel partners, Kir6.2 and Trpm4, were identified immunologically in NPY-GFP neurons in situ. The actions of SUR1 and Trpm4 modulators were informative: like ghrelin, diazoxide, a SUR1 agonist, elevated [Ca2+]c and glibenclamide, a SUR1 antagonist, partially suppressed ghrelin action, while 9-phenanthrol and flufenamic acid, selective Trpm4 antagonists, blocked ghrelin actions on isolated neurons. Ghrelin activation was unaffected by nifedipine and

  4. Functional group and stereochemical requirements for substrate binding by ghrelin O-acyltransferase revealed by unnatural amino acid incorporation.

    Science.gov (United States)

    Cleverdon, Elizabeth R; Davis, Tasha R; Hougland, James L

    2018-04-21

    Ghrelin is a small peptide hormone that undergoes a unique posttranslational modification, serine octanoylation, to play its physiological roles in processes including hunger signaling and glucose metabolism. Ghrelin O-acyltransferase (GOAT) catalyzes this posttranslational modification, which is essential for ghrelin to bind and activate its cognate GHS-R1a receptor. Inhibition of GOAT offers a potential avenue for modulating ghrelin signaling for therapeutic effect. Defining the molecular characteristics of ghrelin that lead to binding and recognition by GOAT will facilitate the development and optimization of GOAT inhibitors. We show that small peptide mimics of ghrelin substituted with 2,3-diaminopropanoic acid in place of the serine at the site of octanoylation act as submicromolar inhibitors of GOAT. Using these chemically modified analogs of desacyl ghrelin, we define key functional groups within the N-terminal sequence of ghrelin essential for binding to GOAT and determine GOAT's tolerance to backbone methylations and altered amino acid stereochemistry within ghrelin. Our study provides a structure-activity analysis of ghrelin binding to GOAT that expands upon activity-based investigations of ghrelin recognition and establishes a new class of potent substrate-mimetic GOAT inhibitors for further investigation and therapeutic interventions targeting ghrelin signaling. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. A family of photoswitchable NMDA receptors

    Science.gov (United States)

    Berlin, Shai; Szobota, Stephanie; Reiner, Andreas; Carroll, Elizabeth C; Kienzler, Michael A; Guyon, Alice; Xiao, Tong; Trauner, Dirk; Isacoff, Ehud Y

    2016-01-01

    NMDA receptors, which regulate synaptic strength and are implicated in learning and memory, consist of several subtypes with distinct subunit compositions and functional properties. To enable spatiotemporally defined, rapid and reproducible manipulation of function of specific subtypes, we engineered a set of photoswitchable GluN subunits ('LiGluNs'). Photo-agonism of GluN2A or GluN2B elicits an excitatory drive to hippocampal neurons that can be shaped in time to mimic synaptic activation. Photo-agonism of GluN2A at single dendritic spines evokes spine-specific calcium elevation and expansion, the morphological correlate of LTP. Photo-antagonism of GluN2A alone, or in combination with photo-antagonism of GluN1a, reversibly blocks excitatory synaptic currents, prevents the induction of long-term potentiation and prevents spine expansion. In addition, photo-antagonism in vivo disrupts synaptic pruning of developing retino-tectal projections in larval zebrafish. By providing precise and rapidly reversible optical control of NMDA receptor subtypes, LiGluNs should help unravel the contribution of specific NMDA receptors to synaptic transmission, integration and plasticity. DOI: http://dx.doi.org/10.7554/eLife.12040.001 PMID:26929991

  6. Ghrelin and leptin interplay in prevention of testicular damage due to cryptochidism

    Science.gov (United States)

    Ghrelin, the endogenous ligand to the growth hormone secretagogue receptor (ghsr), is centrally implicated in body weight homeostasis. A novel murine model for ghrelin and its physiologic antagonist, leptin, was developed at this institution. Mice with a deletion of ghsr (ghsr -/-) or a targeted dis...

  7. Anti-ghrelin Spiegelmer inhibits exogenous ghrelin-induced increases in food intake, hoarding, and neural activation, but not food deprivation-induced increases

    Science.gov (United States)

    Teubner, Brett J. W.

    2013-01-01

    Circulating concentrations of the stomach-derived “hunger-peptide” ghrelin increase in direct proportion to the time since the last meal. Exogenous ghrelin also increases food intake in rodents and humans, suggesting ghrelin may increase post-fast ingestive behaviors. Food intake after food deprivation is increased by laboratory rats and mice, but not by humans (despite dogma to the contrary) or by Siberian hamsters; instead, humans and Siberian hamsters increase food hoarding, suggesting the latter as a model of fasting-induced changes in human ingestive behavior. Exogenous ghrelin markedly increases food hoarding by ad libitum-fed Siberian hamsters similarly to that after food deprivation, indicating sufficiency. Here, we tested the necessity of ghrelin to increase food foraging, food hoarding, and food intake, and neural activation [c-Fos immunoreactivity (c-Fos-ir)] using anti-ghrelin Spiegelmer NOX-B11–2 (SPM), an l-oligonucleotide that specifically binds active ghrelin, inhibiting peptide-receptor interaction. SPM blocked exogenous ghrelin-induced increases in food hoarding the first 2 days after injection, and foraging and food intake at 1–2 h and 2–4 h, respectively, and inhibited hypothalamic c-Fos-ir. SPM given every 24 h across 48-h food deprivation inconsistently inhibited food hoarding after refeeding and c-Fos-ir, similarly to inabilities to do so in laboratory rats and mice. These results suggest that ghrelin may not be necessary for food deprivation-induced foraging and hoarding and neural activation. A possible compensatory response, however, may underlie these findings because SPM treatment led to marked increases in circulating ghrelin concentrations. Collectively, these results show that SPM can block exogenous ghrelin-induced ingestive behaviors, but the necessity of ghrelin for food deprivation-induced ingestive behaviors remains unclear. PMID:23804279

  8. The Role of Ghrelin and Ghrelin Signaling in Aging.

    Science.gov (United States)

    Amitani, Marie; Amitani, Haruka; Cheng, Kai-Chun; Kairupan, Timothy Sean; Sameshima, Nanami; Shimoshikiryo, Ippei; Mizuma, Kimiko; Rokot, Natasya Trivena; Nerome, Yasuhito; Owaki, Tetsuhiro; Asakawa, Akihiro; Inui, Akio

    2017-07-12

    With our aging society, more people hope for a long and healthy life. In recent years, researchers have focused on healthy longevity factors. In particular, calorie restriction delays aging, reduces mortality, and extends life. Ghrelin, which is secreted during fasting, is well known as an orexigenic peptide. Because ghrelin is increased by caloric restriction, ghrelin may play an important role in the mechanism of longevity mediated by calorie restriction. In this review, we will discuss the role of orexigenic peptides with a particular focus on ghrelin. We conclude that the ghrelin-growth hormone secretagogue-R signaling pathway may play an important role in the anti-aging mechanism.

  9. Ghrelin influences novelty seeking behavior in rodents and men.

    Science.gov (United States)

    Hansson, Caroline; Shirazi, Rozita H; Näslund, Jakob; Vogel, Heike; Neuber, Corinna; Holm, Göran; Anckarsäter, Henrik; Dickson, Suzanne L; Eriksson, Elias; Skibicka, Karolina P

    2012-01-01

    Recent discoveries indicate an important role for ghrelin in drug and alcohol reward and an ability of ghrelin to regulate mesolimbic dopamine activity. The role of dopamine in novelty seeking, and the association between this trait and drug and alcohol abuse, led us to hypothesize that ghrelin may influence novelty seeking behavior. To test this possibility we applied several complementary rodent models of novelty seeking behavior, i.e. inescapable novelty-induced locomotor activity (NILA), novelty-induced place preference and novel object exploration, in rats subjected to acute ghrelin receptor (growth hormone secretagogue receptor; GHSR) stimulation or blockade. Furthermore we assessed the possible association between polymorphisms in the genes encoding ghrelin and GHSR and novelty seeking behavior in humans. The rodent studies indicate an important role for ghrelin in a wide range of novelty seeking behaviors. Ghrelin-injected rats exhibited a higher preference for a novel environment and increased novel object exploration. Conversely, those with GHSR blockade drastically reduced their preference for a novel environment and displayed decreased NILA. Importantly, the mesolimbic ventral tegmental area selective GHSR blockade was sufficient to reduce the NILA response indicating that the mesolimbic GHSRs might play an important role in the observed novelty responses. Moreover, in untreated animals, a striking positive correlation between NILA and sucrose reward behavior was detected. Two GHSR single nucleotide polymorphisms (SNPs), rs2948694 and rs495225, were significantly associated with the personality trait novelty seeking, as assessed using the Temperament and Character Inventory (TCI), in human subjects. This study provides the first evidence for a role of ghrelin in novelty seeking behavior in animals and humans, and also points to an association between food reward and novelty seeking in rodents.

  10. Maturing of the nuclear receptor family.

    Science.gov (United States)

    Lazar, Mitchell A

    2017-04-03

    Members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors play important roles in reproduction, development, and physiology. In humans, genetic mutations in NRs are causes of rare diseases, while hormones and drugs that target NRs are in widespread therapeutic use. The present issue of the JCI includes a series of Review articles focused on specific NRs and their wide range of biological functions. Here I reflect on the past, present, and potential future highlights of research on the NR superfamily.

  11. Gastrointestinal Spatiotemporal mRNA Expression of Ghrelin vs Growth Hormone Receptor and New Growth Yield Machine Learning Model Based on Perturbation Theory.

    Science.gov (United States)

    Ran, Tao; Liu, Yong; Li, Hengzhi; Tang, Shaoxun; He, Zhixiong; Munteanu, Cristian R; González-Díaz, Humberto; Tan, Zhiliang; Zhou, Chuanshe

    2016-07-27

    The management of ruminant growth yield has economic importance. The current work presents a study of the spatiotemporal dynamic expression of Ghrelin and GHR at mRNA levels throughout the gastrointestinal tract (GIT) of kid goats under housing and grazing systems. The experiments show that the feeding system and age affected the expression of either Ghrelin or GHR with different mechanisms. Furthermore, the experimental data are used to build new Machine Learning models based on the Perturbation Theory, which can predict the effects of perturbations of Ghrelin and GHR mRNA expression on the growth yield. The models consider eight longitudinal GIT segments (rumen, abomasum, duodenum, jejunum, ileum, cecum, colon and rectum), seven time points (0, 7, 14, 28, 42, 56 and 70 d) and two feeding systems (Supplemental and Grazing feeding) as perturbations from the expected values of the growth yield. The best regression model was obtained using Random Forest, with the coefficient of determination R(2) of 0.781 for the test subset. The current results indicate that the non-linear regression model can accurately predict the growth yield and the key nodes during gastrointestinal development, which is helpful to optimize the feeding management strategies in ruminant production system.

  12. Ghrelin and eating disorders

    Directory of Open Access Journals (Sweden)

    Alessandra Donzelli Fabbri

    2015-04-01

    Full Text Available Background Ghrelin is a potent hormone with central and peripheral action. This hormone plays an important role in the regulation of appetite, food intake, and energy balance. Studies have suggested that ghrelin is involved with eating disorders (ED, particularly bingeing and purging. Genetic variants have also been studied to explain changes in eating behavior. Methods We conducted a literature review; we searched PubMed, Scientific Electronic Library Online (SciELO, and LILACS databases using the keywords “eating disorder”, “ghrelin”, “polymorphism”, “anorexia nervosa”, “bulimia nervosa”, “binge eating disorder”, and their combinations. We found 319 articles. Thirty-nine articles met the inclusion criteria. Results High levels of ghrelin were found in patients with anorexia nervosa (AN, especially in the purging subtype (AN-P. There was also a positive correlation between fasting ghrelin level and frequency of episodes of bingeing/purging in bulimia nervosa (BN and the frequency of bingeing in periodic binge eating disorder (BED. Some polymorphisms were associated with AN and BN. Conclusion Changes in ghrelin levels and its polymorphism may be involved in the pathogenesis of EDs; however, further studies should be conducted to clarify the associations.

  13. Ghrelin as a Survival Hormone.

    Science.gov (United States)

    Mani, Bharath K; Zigman, Jeffrey M

    2017-12-01

    Ghrelin administration induces food intake and body weight gain. Based on these actions, the ghrelin system was initially proposed as an antiobesity target. Subsequent studies using genetic mouse models have raised doubts about the role of the endogenous ghrelin system in mediating body weight homeostasis or obesity. However, this is not to say that the endogenous ghrelin system is not important metabolically or otherwise. Here we review an emerging concept in which the endogenous ghrelin system serves an essential function during extreme nutritional and psychological challenges to defend blood glucose, protect body weight, avoid exaggerated depression, and ultimately allow survival. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Multiple Receptor Subtypes for the CGRP Super-Family

    Directory of Open Access Journals (Sweden)

    R. Quirion

    2001-01-01

    Full Text Available Molecular evidence for the existence of multiple receptors for CGRP has been rather difficult to obtain. Over 10 years after suggesting the existence of at least two classes (CGRP1 and CGRP2 of CGRP receptors on the basis of pharmacological data[1], molecular data on the CGRP2 receptor subtype are still lacking as well as potent and selective antagonists. The situation is somewhat different for the functional CGRP1 subtype which is likely composed of diverse subunits CRLR, RAMP1 and possibly RCP[2]. Moreover, BIBN 4096BS was recently reported as the first nonpeptide highly potent CGRP1 receptor antagonist[3]. However, in situ hybridization and receptor autoradiographic data have clearly shown the existence of major mismatches (e.g., cerebellum between the discrete localization of CRLR, RAMP1, and specific CGRP binding sites supporting the existence of CGRP receptor subtypes. Functional studies have also provided evidence in that regard (for a recent review: [4]. Accordingly, additional studies aiming at cloning additional CGRP receptors are certainly warranted. Similarly, recent evidence from various laboratories including ours suggests the existence of more than one class (CRLR and RAMP2 of adrenomedullin receptors at least in the rat brain. In contrast, most evidence suggests the existence of a single class of amylin receptors. In brief, it appears that multiple receptors or receptor complexes do exist for CGRP and related peptides but their composition is apparently unique among the GPCR super-family and additional data are needed to fully establish the molecular organization of each subtype. Supported by CIHR of Canada.

  15. Ghrelin O-acyltransferase (GOAT) is expressed in prostate cancer tissues and cell lines and expression is differentially regulated in vitro by ghrelin

    Science.gov (United States)

    2013-01-01

    Background Ghrelin is a 28 amino acid peptide hormone that is expressed in the stomach and a range of peripheral tissues, where it frequently acts as an autocrine/paracrine growth factor. Ghrelin is modified by a unique acylation required for it to activate its cognate receptor, the growth hormone secretagogue receptor (GHSR), which mediates many of the actions of ghrelin. Recently, the enzyme responsible for adding the fatty acid residue (octanoyl/acyl group) to the third amino acid of ghrelin, GOAT (ghrelin O-acyltransferase), was identified. Methods We used cell culture, quantitative real-time reverse transcription (RT)-PCR and immunohistochemistry to demonstrate the expression of GOAT in prostate cancer cell lines and tissues from patients. Real-time RT-PCR was used to demonstrate the expression of prohormone convertase (PC)1/3, PC2 and furin in prostate cancer cell lines. Prostate-derived cell lines were treated with ghrelin and desacyl ghrelin and the effect on GOAT expression was measured using quantitative RT-PCR. Results We have demonstrated that GOAT mRNA and protein are expressed in the normal prostate and human prostate cancer tissue samples. The RWPE-1 and RWPE-2 normal prostate-derived cell lines and the LNCaP, DU145, and PC3 prostate cancer cell lines express GOAT and at least one other enzyme that is necessary to produce mature, acylated ghrelin from proghrelin (PC1/3, PC2 or furin). Finally, ghrelin, but not desacyl ghrelin (unacylated ghrelin), can directly regulate the expression of GOAT in the RWPE-1 normal prostate derived cell line and the PC3 prostate cancer cell line. Ghrelin treatment (100nM) for 6 hours significantly decreased GOAT mRNA expression two-fold (P ghrelin did not regulate GOAT expression in the DU145 and LNCaP prostate cancer cell lines. Conclusions This study demonstrates that GOAT is expressed in prostate cancer specimens and cell lines. Ghrelin regulates GOAT expression, however, this is likely to be cell-type specific

  16. Genetic diversity of bitter taste receptor gene family in Sichuan

    Indian Academy of Sciences (India)

    Genetic diversity of bitter taste receptor gene family in Sichuan domestic and Tibetan chicken populations. YUAN SU DIYAN LI UMA GAUR YAN WANG NAN WU BINLONG CHEN HONGXIAN XU HUADONG YIN YAODONG HU QING ZHU. RESEARCH ARTICLE Volume 95 Issue 3 September 2016 pp 675-681 ...

  17. Ghrelin potentiates cardiac reactivity to stress by modulating sympathetic control and beta-adrenergic response.

    Science.gov (United States)

    Camargo-Silva, Gabriel; Turones, Larissa Córdova; da Cruz, Kellen Rosa; Gomes, Karina Pereira; Mendonça, Michelle Mendanha; Nunes, Allancer; de Jesus, Itamar Guedes; Colugnati, Diego Basile; Pansani, Aline Priscila; Pobbe, Roger Luis Henschel; Santos, Robson; Fontes, Marco Antônio Peliky; Guatimosim, Silvia; de Castro, Carlos Henrique; Ianzer, Danielle; Ferreira, Reginaldo Nassar; Xavier, Carlos Henrique

    2018-03-01

    Prior evidence indicates that ghrelin is involved in the integration of cardiovascular functions and behavioral responses. Ghrelin actions are mediated by the growth hormone secretagogue receptor subtype 1a (GHS-R1a), which is expressed in peripheral tissues and central areas involved in the control of cardiovascular responses to stress. In the present study, we assessed the role of ghrelin - GHS-R1a axis in the cardiovascular reactivity to acute emotional stress in rats. Ghrelin potentiated the tachycardia evoked by restraint and air jet stresses, which was reverted by GHS-R1a blockade. Evaluation of the autonomic balance revealed that the sympathetic branch modulates the ghrelin-evoked positive chronotropy. In isolated hearts, the perfusion with ghrelin potentiated the contractile responses caused by stimulation of the beta-adrenergic receptor, without altering the amplitude of the responses evoked by acetylcholine. Experiments in isolated cardiomyocytes revealed that ghrelin amplified the increases in calcium transient changes evoked by isoproterenol. Taken together, our results indicate that the Ghrelin-GHS-R1a axis potentiates the magnitude of stress-evoked tachycardia by modulating the autonomic nervous system and peripheral mechanisms, strongly relying on the activation of cardiac calcium transient and beta-adrenergic receptors. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. Ghrelin and Eating Disorders

    Science.gov (United States)

    Atalayer, Deniz; Gibson, Charlisa; Konopacka, Alexandra; Geliebter, Allan

    2012-01-01

    There is growing evidence supporting a multifactorial etiology that includes genetic, neurochemical, and physiological components for eating disorders above and beyond the more conventional theories based on psychological and sociocultural factors. Ghrelin is one of the key gut signals associated with appetite, and the only known circulating hormone that triggers a positive energy balance by stimulating food intake. This review summarizes recent findings and several conflicting reports on ghrelin in eating disorders. Understanding these findings and inconsistencies may help in developing new methods to prevent and treat patients with these disorders. PMID:22960103

  19. Signal transduction through the IL-4 and insulin receptor families.

    Science.gov (United States)

    Wang, L M; Keegan, A; Frankel, M; Paul, W E; Pierce, J H

    1995-07-01

    Activation of tyrosine kinase-containing receptors and intracellular tyrosine kinases by ligand stimulation is known to be crucial for mediating initial and subsequent events involved in mitogenic signal transduction. Receptors for insulin and insulin-like growth factor 1 (IGF-1) contain cytoplasmic tyrosine kinase domains that undergo autophosphorylation upon ligand stimulation. Activation of these receptors also leads to pronounced and rapid tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells of connective tissue origin. A related substrate, designated 4PS, is similarly phosphorylated by insulin and IGF-1 stimulation in many hematopoietic cell types. IRS-1 and 4PS possess a number of tyrosine phosphorylation sites that are within motifs that bind specific SH2-containing molecules known to be involved in mitogenic signaling such as PI-3 kinase, SHPTP-2 (Syp) and Grb-2. Thus, they appear to act as docking substrates for a variety of signaling molecules. The majority of hematopoietic cytokines bind to receptors that do not possess intrinsic kinase activity, and these receptors have been collectively termed as members of the hematopoietin receptor superfamily. Despite their lack of tyrosine kinase domains, stimulation of these receptors has been demonstrated to activate intracellular kinases leading to tyrosine phosphorylation of multiple substrates. Recent evidence has demonstrated that activation of different members of the Janus family of tyrosine kinases is involved in mediating tyrosine phosphorylation events by specific cytokines. Stimulation of the interleukin 4 (IL-4) receptor, a member of the hematopoietin receptor superfamily, is thought to result in activation of Jak1, Jak3, and/or Fes tyrosine kinases.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Genetic variation of the ghrelin activator gene ghrelin O-acyltransferase (GOAT) is associated with anorexia nervosa.

    Science.gov (United States)

    Müller, Timo D; Tschöp, Matthias H; Jarick, Ivonne; Ehrlich, Stefan; Scherag, Susann; Herpertz-Dahlmann, Beate; Zipfel, Stefan; Herzog, Wolfgang; de Zwaan, Martina; Burghardt, Roland; Fleischhaker, Christian; Klampfl, Karin; Wewetzer, Christoph; Herpertz, Stephan; Zeeck, Almut; Tagay, Sefik; Burgmer, Markus; Pfluger, Paul T; Scherag, André; Hebebrand, Johannes; Hinney, Anke

    2011-05-01

    The gastrointestinal peptide hormone ghrelin promotes food intake and increases body weight and adiposity through activation of the growth hormone secretagogue receptor (GHSR1a). To promote its biological action ghrelin is acylated at its serine 3 residue by the recently discovered ghrelin O-acyltransferase (GOAT, a.k.a. membrane-bound O-acyltransferase 4, MBOAT4). Plasma levels of total and acyl-ghrelin are negatively correlated with body-mass-index (BMI); as lower the BMI as higher plasma levels of total and acylated ghrelin and vice versa. Accordingly, plasma levels of total and acyl-ghrelin are elevated in patients with anorexia nervosa (AN) and decline upon weight regain. The importance of the endogenous Goat/ghrelin system in the neuroendocrine adaptation to fasting was recently highlighted by the observation that acyl-ghrelin mediated elevation of growth hormone (GH) release prevents starvation induced hypoglycemia in Goat(-/-) mice. The aim of this study was to test if genetic variation of GOAT is implicated in the etiology of AN. We therefore assessed association of 6 tagging single nucleotide polymorphisms (tagSNPs), which were predicted to cover 96% the common genetic variability of GOAT plus 50 kb of the 5' and 3' flanking region, in 543 German patients with AN and 612 German normal and underweight healthy controls. Based on a recessive mode of inheritance we observed some evidence for association of the G/G genotype at SNP rs10096097 with AN (nominal two-sided p = 0.031). Based on our results we conclude that genetic variation in GOAT might be implicated in the etiology of AN. Copyright © 2010 Elsevier Ltd. All rights reserved.

  1. Ghrelin attenuates vascular calcification in diabetic patients with amputation.

    Science.gov (United States)

    Xu, Suining; Ye, Fei; Li, Lihua; Yan, Jinchuan; Bao, Zhengyang; Sun, Zhen; Xu, Liangjie; Zhu, Jie; Wang, Zhongqun

    2017-07-01

    Vascular calcification is established to be a critical factor in diabetes mellitus, which causes cardiovascular and amputation complication of diabetic patients. OPG/RANKL/RANK axis serves as a regulatory role in vascular calcification. Ghrelin, an endogenous ligand of growth hormone secretagogue receptor (GHSR), has been reported to exhibit potent cardiovascular protective effects. However, the role of ghrelin in the regulation of diabetic vascular calcification is still elusive. Here, we reported the role of ghrelin and its relationship with OPG/RANKL/RANK system in patients with diabetic foot amputation. In vivo and in vitro investigations were performed. Sixty type 2 diabetic patients with foot amputation were enrolled in vivo investigation, and they were divided into three groups through Doppler ultrasound: mild stenosis group (n=20), moderate stenosis group (n=20), and severe stenosis/occlusion group (n=20). Morphological analysis results showed diffused calcium depositions in the anterior tibial artery of diabetic amputees. Compared with the mild and moderate stenosis group, the severe stenosis/occlusion group had more spotty calcium depositions in atherosclerotic plaques. Western blot analysis indicated the expressions of osteoprotegerin (OPG) and ghrelin were downregulated, while the expression of receptor activator of nuclear factor kappa B ligand (RANKL) was upregulated with the vascular stenosis aggravation. Pearson correlation analysis revealed a negative correlation between calcium content and ghrelin levels (r=-0.58, Pghrelin levels and sRANKL levels (r=-0.57, Pghrelin levels (r=0.63, PGhrelin blunted calcification in a dose-dependent manner. In addition, ghrelin upregulated OPG expression and downregulated RANKL expression in VSMC calcification when anti-OPG antibody and RANKL were performed. Collectively, we therefore conclude serum ghrelin level may be a predictor of diabetic vascular calcification. The possible mechanism may be related with OPG

  2. Metabolic Benefit of Chronic Caloric Restriction and Activation of Hypothalamic AGRP/NPY Neurons in Male Mice Is Independent of Ghrelin

    Science.gov (United States)

    Rogers, Nicole H.; Walsh, Heidi; Alvarez-Garcia, Oscar; Park, Seongjoon; Gaylinn, Bruce; Thorner, Michael O.

    2016-01-01

    Aging is associated with attenuated ghrelin signaling. During aging, chronic caloric restriction (CR) produces health benefits accompanied by enhanced ghrelin production. Ghrelin receptor (GH secretagogue receptor 1a) agonists administered to aging rodents and humans restore the young adult phenotype; therefore, we tested the hypothesis that the metabolic benefits of CR are mediated by endogenous ghrelin. Three month-old male mice lacking ghrelin (Ghrelin−/−) or ghrelin receptor (Ghsr−/−), and their wild-type (WT) littermates were randomly assigned to 2 groups: ad libitum (AL) fed and CR, where 40% food restriction was introduced gradually to allow Ghrelin−/− and Ghsr−/− mice to metabolically adapt and avoid severe hypoglycemia. Twelve months later, plasma ghrelin, metabolic parameters, ambulatory activity, hypothalamic and liver gene expression, as well as body composition were measured. CR increased plasma ghrelin and des-acyl ghrelin concentrations in WT and Ghsr−/− mice. CR of WT, Ghsr−/−, and Ghrelin−/− mice markedly improved metabolic flexibility, enhanced ambulatory activity, and reduced adiposity. Inactivation of Ghrelin or Ghsr had no effect on AL food intake or food anticipatory behavior. In contrast to the widely held belief that endogenous ghrelin regulates food intake, CR increased expression of hypothalamic Agrp and Npy, with reduced expression of Pomc across genotypes. In the AL context, ablation of ghrelin signaling markedly inhibited liver steatosis, which correlated with reduced Pparγ expression and enhanced Irs2 expression. Although CR and administration of GH secretagogue receptor 1a agonists both benefit the aging phenotype, we conclude the benefits of chronic CR are a consequence of enhanced metabolic flexibility independent of endogenous ghrelin or des-acyl ghrelin signaling. PMID:26812158

  3. MTA family of coregulators in nuclear receptor biology and pathology

    Science.gov (United States)

    Manavathi, Bramanandam; Singh, Kamini; Kumar, Rakesh

    2007-01-01

    Nuclear receptors (NRs) rely on coregulators (coactivators and corepressors) to modulate the transcription of target genes. By interacting with nucleosome remodeling complexes, NR coactivators potentiate transcription, whereas corepressors inhibit transcription of the target genes. Metastasis-associated proteins (MTA) represent an emerging family of novel NR coregulators. In general, MTA family members form independent nucleosome remodeling and deacetylation (NuRD) complexes and repress the transcription of different genes by recruiting histone deacetylases onto their target genes. However, MTA1 also acts as a coactivator in a promoter-context dependent manner. Recent findings that repression of estrogen receptor transactivation functions by MTA1, MTA1s, and MTA2 and regulation of MTA3 by estrogen signaling have indicated the significance of these proteins in NR signaling. Here, we highlight the action of MTA proteins on NR signaling and their roles in pathophysiological conditions. PMID:18174918

  4. Peripherally Circulating Ghrelin Does Not Mediate Alcohol‐Induced Reward and Alcohol Intake in Rodents

    OpenAIRE

    Jerlhag, Elisabet; Ivanoff, Lisa; Vater, Axel; Engel, Jörgen A.

    2014-01-01

    Background Development of alcohol dependence, a chronic and relapsing disease, largely depends on the effects of alcohol on the brain reward systems. By elucidating the mechanisms involved in alcohol use disorder, novel treatment strategies may be developed. Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor 1A, acts as an important regulator of energy balance. Recently ghrelin and its receptor were shown to mediate alcohol reward and to control alcohol consumption in...

  5. The amygdala as a neurobiological target for ghrelin in rats: neuroanatomical, electrophysiological and behavioral evidence.

    Directory of Open Access Journals (Sweden)

    Mayte Alvarez-Crespo

    Full Text Available Here, we sought to demonstrate that the orexigenic circulating hormone, ghrelin, is able to exert neurobiological effects (including those linked to feeding control at the level of the amygdala, involving neuroanatomical, electrophysiological and behavioural studies. We found that ghrelin receptors (GHS-R are densely expressed in several subnuclei of the amygdala, notably in ventrolateral (LaVL and ventromedial (LaVM parts of the lateral amygdaloid nucleus. Using whole-cell patch clamp electrophysiology to record from cells in the lateral amygdaloid nucleus, we found that ghrelin reduced the frequency of mEPSCs recorded from large pyramidal-like neurons, an effect that could be blocked by co-application of a ghrelin receptor antagonist. In ad libitum fed rats, intra-amygdala administration of ghrelin produced a large orexigenic response that lasted throughout the 4 hr of testing. Conversely, in hungry, fasted rats ghrelin receptor blockade in the amygdala significantly reduced food intake. Finally, we investigated a possible interaction between ghrelin's effects on feeding control and emotional reactivity exerted at the level of the amygdala. In rats allowed to feed during a 1-hour period between ghrelin injection and anxiety testing (elevated plus maze and open field, intra-amygdala ghrelin had no effect on anxiety-like behavior. By contrast, if the rats were not given access to food during this 1-hour period, a decrease in anxiety-like behavior was observed in both tests. Collectively, these data indicate that the amygdala is a valid target brain area for ghrelin where its neurobiological effects are important for food intake and for the suppression of emotional (anxiety-like behaviors if food is not available.

  6. Evolution of the vertebrate insulin receptor substrate (Irs) gene family.

    Science.gov (United States)

    Al-Salam, Ahmad; Irwin, David M

    2017-06-23

    Insulin receptor substrate (Irs) proteins are essential for insulin signaling as they allow downstream effectors to dock with, and be activated by, the insulin receptor. A family of four Irs proteins have been identified in mice, however the gene for one of these, IRS3, has been pseudogenized in humans. While it is known that the Irs gene family originated in vertebrates, it is not known when it originated and which members are most closely related to each other. A better understanding of the evolution of Irs genes and proteins should provide insight into the regulation of metabolism by insulin. Multiple genes for Irs proteins were identified in a wide variety of vertebrate species. Phylogenetic and genomic neighborhood analyses indicate that this gene family originated very early in vertebrae evolution. Most Irs genes were duplicated and retained in fish after the fish-specific genome duplication. Irs genes have been lost of various lineages, including Irs3 in primates and birds and Irs1 in most fish. Irs3 and Irs4 experienced an episode of more rapid protein sequence evolution on the ancestral mammalian lineage. Comparisons of the conservation of the proteins sequences among Irs paralogs show that domains involved in binding to the plasma membrane and insulin receptors are most strongly conserved, while divergence has occurred in sequences involved in interacting with downstream effector proteins. The Irs gene family originated very early in vertebrate evolution, likely through genome duplications, and in parallel with duplications of other components of the insulin signaling pathway, including insulin and the insulin receptor. While the N-terminal sequences of these proteins are conserved among the paralogs, changes in the C-terminal sequences likely allowed changes in biological function.

  7. Trace amine-associated receptor 1-Family archetype or iconoclast?

    Science.gov (United States)

    Grandy, David K

    2007-12-01

    Interest has recently been rekindled in receptors that are activated by low molecular weight, noncatecholic, biogenic amines that are typically found as trace constituents of various vertebrate and invertebrate tissues and fluids. The timing of this resurgent focus on receptors activated by the "trace amines" (TA) beta-phenylethylamine (PEA), tyramine (TYR), octopamine (OCT), synephrine (SYN), and tryptamine (TRYP) is the direct result of 2 publications that appeared in 2001 describing the cloning of a novel G protein-coupled receptor (GPCR) referred to by their discoverers Borowsky et al. as TA1 and Bunzow et al. as TA receptor 1 (TAR1). When heterologously expressed in Xenopus laevis oocytes and various eukaryotic cell lines, recombinant rodent and human TAR dose-dependently couple to the stimulation of adenosine 3',5'-monophosphate (cAMP) production. Structure-activity profiling based on this functional response has revealed that in addition to the TA, other biologically active compounds containing a 2-carbon aliphatic side chain linking an amino group to at least 1 benzene ring are potent and efficacious TA receptor agonists with amphetamine (AMPH), methamphetamine, 3-iodothyronamine, thyronamine, and dopamine (DA) among the most notable. Almost 100 years after the search for TAR began, numerous TA1/TAR1-related sequences, now called TA-associated receptors (TAAR), have been identified in the genome of every species of vertebrate examined to date. Consequently, even though heterologously expressed TAAR1 fits the pharmacological criteria established for a bona fide TAR, a major challenge for those working in the field is to discern the in vivo pharmacology and physiology of each purported member of this extended family of GPCR. Only then will it be possible to establish whether TAAR1 is the family archetype or an iconoclast.

  8. Immunohistochemical evidence for an endocrine/paracrine role for ghrelin in the reproductive tissues of sheep

    Directory of Open Access Journals (Sweden)

    Brown Yvonne A

    2005-10-01

    Full Text Available Abstract Background The gut hormone, ghrelin, is involved in the neuroendocrine and metabolic responses to hunger. In monogastric species, circulating ghrelin levels show clear meal-related and body weight-related changes. The pattern of secretion and its role in ruminant species is less clear. Ghrelin acts via growth hormone secretagogue receptors (GHSR-1a to alter food intake, fat utilization, and cellular proliferation. There is also evidence that ghrelin is involved in reproductive function. In the present study we used immunohistochemistry to investigate the presence of ghrelin and GHSR-1a in sheep reproductive tissues. In addition, we examined whether ghrelin and GHSR-1a protein expression is developmentally regulated in the adult and fetal ovine testis, and whether there is an association with markers of cellular proliferation, i.e. stem cell factor (SCF and proliferating cell nuclear antigen (PCNA. Methods Antibodies raised against ghrelin and its functional receptor, GHSR-type 1a, were used in standard immunohistochemical protocols on various reproductive tissues collected from adult and fetal sheep. GHSR-1a mRNA presence was also confirmed by in situ hybridisation. SCF and PCNA immunoexpression was investigated in fetal testicular samples. Adult and fetal testicular immunostaining for ghrelin, GHSR-1a, SCF and PCNA was analysed using computer-aided image analysis. Image analysis data were subjected to one-way ANOVA, with differences in immunostaining between time-points determined by Fisher's least significant difference. Results In adult sheep tissue, ghrelin and GHSR-1a immunostaining was detected in the stomach (abomasum, anterior pituitary gland, testis, ovary, and hypothalamic and hindbrain regions of the brain. In the adult testis, there was a significant effect of season (photoperiod on the level of immunostaining for ghrelin (p Conclusion Evidence is presented for the presence of ghrelin and its receptor in various reproductive

  9. Distribution and developmental changes of ghrelin-immunopositive cells in the pancreas of African ostrich chicks (Struthio camelus).

    Science.gov (United States)

    Wang, J X; Li, P; Zhang, X T; Ye, L X

    2017-09-01

    Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by multiple cell types and affects feeding behavior, metabolic regulation, and energy balance. In the mammalian pancreas, the types of endocrine cells that are immunoreactive to ghrelin vary. However, little was known about its distribution and developmental changes in the pancreas of African ostrich chicks (Struthio camelus). In the present study, the distribution, morphological characteristics, and developmental changes of ghrelin-immunopositive (ghrelin-ip) cells in the pancreas of African ostrich chicks were investigated using immunohistochemistry. Ghrelin-ip cells were found in both the pancreatic islets and acinar cell regions. The greatest number of ghrelin-ip cells were found in the pancreatic islets, and were primarily observed at the periphery of the islets; some ghrelin-ip cells were also located in the central portion of the pancreatic islets. Interestingly, from postnatal d 1 to d 90, there was a steady decrease in the number of ghrelin-ip cells in the pancreatic islets and acinar cell regions. These results clearly demonstrated that ghrelin-ip cells exist and decreased with age in the African ostrich pancreas from postnatal d 1 to d90. Thus, these findings indicated that ghrelin may be involved in the development of the pancreas in the African ostrich. © 2017 Poultry Science Association Inc.

  10. The repertoire of olfactory C family G protein-coupled receptors in zebrafish: candidate chemosensory receptors for amino acids

    Directory of Open Access Journals (Sweden)

    Ngai John

    2006-12-01

    Full Text Available Abstract Background Vertebrate odorant receptors comprise at least three types of G protein-coupled receptors (GPCRs: the OR, V1R, and V2R/V2R-like receptors, the latter group belonging to the C family of GPCRs. These receptor families are thought to receive chemosensory information from a wide spectrum of odorant and pheromonal cues that influence critical animal behaviors such as feeding, reproduction and other social interactions. Results Using genome database mining and other informatics approaches, we identified and characterized the repertoire of 54 intact "V2R-like" olfactory C family GPCRs in the zebrafish. Phylogenetic analysis – which also included a set of 34 C family GPCRs from fugu – places the fish olfactory receptors in three major groups, which are related to but clearly distinct from other C family GPCRs, including the calcium sensing receptor, metabotropic glutamate receptors, GABA-B receptor, T1R taste receptors, and the major group of V2R vomeronasal receptor families. Interestingly, an analysis of sequence conservation and selective pressure in the zebrafish receptors revealed the retention of a conserved sequence motif previously shown to be required for ligand binding in other amino acid receptors. Conclusion Based on our findings, we propose that the repertoire of zebrafish olfactory C family GPCRs has evolved to allow the detection and discrimination of a spectrum of amino acid and/or amino acid-based compounds, which are potent olfactory cues in fish. Furthermore, as the major groups of fish receptors and mammalian V2R receptors appear to have diverged significantly from a common ancestral gene(s, these receptors likely mediate chemosensation of different classes of chemical structures by their respective organisms.

  11. Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle.

    Science.gov (United States)

    Cervone, Daniel T; Dyck, David J

    2017-07-01

    Emerging evidence implicates ghrelin, a gut-derived, orexigenic hormone, as a potential mediator of insulin-responsive peripheral tissue metabolism. However, in vitro and in vivo studies assessing ghrelin's direct influence on metabolism have been controversial, particularly due to confounding factors such as the secondary rise in growth hormone (GH) after ghrelin injection. Skeletal muscle is important in the insulin-stimulated clearance of glucose, and ghrelin's exponential rise prior to a meal could potentially facilitate this. This study was aimed at elucidating any direct stimulatory action that ghrelin may have on glucose transport and insulin signaling in isolated rat skeletal muscle, in the absence of confounding secondary factors. Oxidative soleus and glycolytic extensor digitorum longus skeletal muscles were isolated from male Sprague Dawley rats in the fed state and incubated with various concentrations of acylated and unacylated ghrelin in the presence or absence of insulin. Ghrelin did not stimulate glucose transport in either muscle type, with or without insulin. Moreover, GH had no acute, direct stimulatory effect on either basal or insulin-stimulated muscle glucose transport. In agreement with the lack of observed effect on glucose transport, ghrelin and GH also had no stimulatory effect on Ser 473 AKT or Thr 172 AMPK phosphorylation, two key signaling proteins involved in glucose transport. Furthermore, to our knowledge, we are among the first to show that ghrelin can act independent of its receptor and cause an increase in calmodulin-dependent protein kinase 2 (CaMKII) phosphorylation in glycolytic muscle, although this was not associated with an increase in glucose transport. We conclude that both acylated and unacylated ghrelin have no direct, acute influence on skeletal muscle glucose transport. Furthermore, the immediate rise in GH in response to ghrelin also does not appear to directly stimulate glucose transport in muscle. © 2017 The

  12. The effect of ghrelin upon the early immune response in lean and obese mice during sepsis.

    Directory of Open Access Journals (Sweden)

    Daniel Siegl

    Full Text Available It is well established that obesity-related hormones can have modulatory effects associated with the immune response. Ghrelin, a hormone mainly derived from endocrine cells of the gastric mucosa, regulates appetite, energy expenditure and body weight counteracting leptin, a hormone mainly derived from adipocytes. Additionally, receptors of both have been detected on immune cells and demonstrated an immune regulatory function during sepsis.In the present study, the effect of peripheral ghrelin administration on early immune response and survival was investigated with lean mice and mice with diet-induced obesity using cecal ligation and puncture to induce sepsis.In the obese group, we found that ghrelin treatment improved survival, ameliorated hypothermia, and increased hyperleptinemia as compared to the lean controls. We also observed that ghrelin treatment divergently regulated serum IL-1ß and TNF-α concentrations in both lean and obese septic mice. Ghrelin treatment initially decreased but later resulted in increased bacteriaemia in lean mice while having no impact upon obese mice. Similarly, ghrelin treatment increased early neutrophil oxidative burst while causing a decrease 48 hours after sepsis inducement.In conclusion, as the immune response to sepsis temporally changes, ghrelin treatment differentially mediates this response. Specifically, we observed that ghrelin conferred protective effects during the early phase of sepsis, but during the later phase deteriorated immune response and outcome. These adverse effects were more pronounced upon lean mice as compared to obese mice.

  13. Exogenous ghrelin regulates proliferation and apoptosis in the hypotrophic gut mucosa of the rat.

    Science.gov (United States)

    de Segura, Ignacio A Gómez; Vallejo-Cremades, María Teresa; Lomas, Jesús; Sánchez, Miriam F; Caballero, María Isabel; Largo, Carlota; De Miguel, Enrique

    2010-04-01

    Ghrelin is the natural endogenous ligand for growth hormone secretagogue receptors. This peptide regulates energy homeostasis and expenditure and is a potential link between gut absorptive function and growth. We hypothesized that ghrelin may induce a proliferative and antiapoptotic action promoting the recovery of the hypotrophic gut mucosa. Therefore, the aim of the study was to determine the action of exogenous ghrelin following gut mucosal hypotrophia in rats fed an elemental diet. An elemental diet provides readily absorbable simple nutrients and is usually given to patients with absorptive dysfunction. Male Wistar rats (n = 48) were fed the elemental diet for one week to induce mucosal hypotrophy and then treated for another week with systemic ghrelin and pair-fed with either a normoproteic or hyperproteic isocaloric liquid diet. Another group received a standard diet instead of the elemental diet and served as control (normotrophy). The elemental diet induced intestinal hypotrophia characterized by decreased proliferation in the ileum and increased apoptosis in jejunum and ileum. Ghrelin administration restored normal levels of proliferation in the ileum and apoptosis in the jejunum, with partial apoptosis restoration in the ileum. Ghrelin levels in plasma and fundus were increased in all groups, although the highest levels were found in rats treated with exogenous ghrelin. Ghrelin administration has a positive effect in the hypotrophic gut, regulating both proliferation and apoptosis towards a physiological balance counteracting the negative changes induced by an elemental diet in the intestines.

  14. Fasting levels of ghrelin covary with the brain response to food pictures.

    Science.gov (United States)

    Kroemer, Nils B; Krebs, Lena; Kobiella, Andrea; Grimm, Oliver; Pilhatsch, Maximilian; Bidlingmaier, Martin; Zimmermann, Ulrich S; Smolka, Michael N

    2013-09-01

    Ghrelin figures prominently in the regulation of appetite in normal-weighed individuals. The apparent failure of this mechanism in eating disorders and the connection to addictive behavior in general demand a deeper understanding of the endogenous central-nervous processes related to ghrelin. Thus, we investigated processing of pictures showing palatable food after overnight fasting and following a standardized caloric intake (i.e. a 75-g oral glucose tolerance test) using functional magnetic resonance imaging and correlated it with blood plasma levels of ghrelin. Twenty-six healthy female and male volunteers viewed food and control pictures in a block design and rated their appetite after each block. Fasting levels of ghrelin correlated positively with food-cue reactivity in a bilateral network of visual processing-, reward- and taste-related regions, including limbic and paralimbic regions. Notably, among those regions were the hypothalamus and the midbrain where ghrelin receptors are densely concentrated. In addition, high fasting ghrelin levels were associated with stronger increases of subjective appetite during the food-cue-reactivity task. In conclusion, brain activation and subjective appetite ratings suggest that ghrelin elevates the hedonic effects of food pictures. Thereby, fasting ghrelin levels may generally enhance subjective craving when confronted with reward cues. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

  15. Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin.

    Science.gov (United States)

    Wang, Qian; Liu, Chen; Uchida, Aki; Chuang, Jen-Chieh; Walker, Angela; Liu, Tiemin; Osborne-Lawrence, Sherri; Mason, Brittany L; Mosher, Christina; Berglund, Eric D; Elmquist, Joel K; Zigman, Jeffrey M

    2014-02-01

    The hormone ghrelin stimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreER(T2) transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelin receptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenic response to administered ghrelin and fully restored the lowered blood glucose levels observed upon caloric restriction. The normalizing glucoregulatory effect of AgRP neuron-selective GHSR expression was linked to glucagon rises and hepatic gluconeogenesis induction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigenic effects but are sufficient to mediate ghrelin's effects on glycemia.

  16. Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis by inhibiting the activation of nuclear factor-kappa B

    International Nuclear Information System (INIS)

    Cheng, Jian; Zhang, Lin; Dai, Weiqi; Mao, Yuqing; Li, Sainan; Wang, Jingjie; Li, Huanqing; Guo, Chuanyong; Fan, Xiaoming

    2015-01-01

    Aim: This study aimed to investigate the effect and underlying mechanism of ghrelin on intestinal barrier dysfunction in dextran sulfate sodium (DSS)-induced colitis. Methods and results: Acute colitis was induced in C57BL/6J mice by administering 2.5% DSS. Saline or 25, 125, 250 μg/kg ghrelin was administrated intraperitoneally (IP) to mice 1 day before colitis induction and on days 4, 5, and 6 after DSS administration. IP injection of a ghrelin receptor antagonist, [D-lys 3 ]-GHRP-6, was performed immediately prior to ghrelin injection. Ghrelin (125 or 250 μg/kg) could reduce the disease activity index, histological score, and myeloperoxidase activities in experimental colitis, and also prevented shortening of the colon. Ghrelin could prevent the reduction of transepithelial electrical resistance and tight junction expression, and bolstered tight junction structural integrity and regulated cytokine secretion. Ultimately, ghrelin inhibited nuclear factor kappa B (NF-κB), inhibitory κB-α, myosin light chain kinase, and phosphorylated myosin light chain 2 activation. Conclusions: Ghrelin prevented the breakdown of intestinal barrier function in DSS-induced colitis. The protective effects of ghrelin on intestinal barrier function were mediated by its receptor GHSR-1a. The inhibition of NF-κB activation might be part of the mechanism underlying the effects of ghrelin that protect against barrier dysfunction. - Highlights: • Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis. • The effect of ghrelin is mediated by GHSR-1a. • Inhibition of NF-κB activation

  17. Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis by inhibiting the activation of nuclear factor-kappa B

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Jian; Zhang, Lin [Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai (China); Dai, Weiqi [Department of Gastroenterology, Shanghai Tenth People' s Hospital, Tongji University, Shanghai (China); Mao, Yuqing [Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai (China); Li, Sainan [Department of Gastroenterology, Shanghai Tenth People' s Hospital, Tongji University, Shanghai (China); Wang, Jingjie; Li, Huanqing [Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai (China); Guo, Chuanyong [Department of Gastroenterology, Shanghai Tenth People' s Hospital, Tongji University, Shanghai (China); Fan, Xiaoming, E-mail: xiaomingfan57@sina.com [Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai (China)

    2015-02-27

    Aim: This study aimed to investigate the effect and underlying mechanism of ghrelin on intestinal barrier dysfunction in dextran sulfate sodium (DSS)-induced colitis. Methods and results: Acute colitis was induced in C57BL/6J mice by administering 2.5% DSS. Saline or 25, 125, 250 μg/kg ghrelin was administrated intraperitoneally (IP) to mice 1 day before colitis induction and on days 4, 5, and 6 after DSS administration. IP injection of a ghrelin receptor antagonist, [D-lys{sup 3}]-GHRP-6, was performed immediately prior to ghrelin injection. Ghrelin (125 or 250 μg/kg) could reduce the disease activity index, histological score, and myeloperoxidase activities in experimental colitis, and also prevented shortening of the colon. Ghrelin could prevent the reduction of transepithelial electrical resistance and tight junction expression, and bolstered tight junction structural integrity and regulated cytokine secretion. Ultimately, ghrelin inhibited nuclear factor kappa B (NF-κB), inhibitory κB-α, myosin light chain kinase, and phosphorylated myosin light chain 2 activation. Conclusions: Ghrelin prevented the breakdown of intestinal barrier function in DSS-induced colitis. The protective effects of ghrelin on intestinal barrier function were mediated by its receptor GHSR-1a. The inhibition of NF-κB activation might be part of the mechanism underlying the effects of ghrelin that protect against barrier dysfunction. - Highlights: • Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis. • The effect of ghrelin is mediated by GHSR-1a. • Inhibition of NF-κB activation.

  18. Ghrelin reverses experimental diabetic neuropathy in mice

    Energy Technology Data Exchange (ETDEWEB)

    Kyoraku, Itaru; Shiomi, Kazutaka [Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692 (Japan); Kangawa, Kenji [Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565 (Japan); Nakazato, Masamitsu, E-mail: nakazato@med.miyazaki-u.ac.jp [Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692 (Japan)

    2009-11-20

    Ghrelin, an acylated peptide produced in the stomach, increases food intake and growth hormone secretion, suppresses inflammation and oxidative stress, and promotes cell survival and proliferation. We investigated the pharmacological potential of ghrelin in the treatment of polyneuropathy in uncontrolled streptozotocin (STZ)-induced diabetes in mice. Ghrelin or desacyl-ghrelin was administered daily for 4 weeks after STZ-induced diabetic polyneuropathy had developed. Ghrelin administration did not alter food intake, body weight gain, blood glucose levels, or plasma insulin levels when compared with mice given saline or desacyl-ghrelin administration. Ghrelin administration ameliorated reductions in motor and sensory nerve conduction velocities in diabetic mice and normalized their temperature sensation and plasma concentrations of 8-isoprostaglandin {alpha}, an oxidative stress marker. Desacyl-ghrelin failed to have any effect. Ghrelin administration in a mouse model of diabetes ameliorated polyneuropathy. Thus, ghrelin's effects represent a novel therapeutic paradigm for the treatment of this otherwise intractable disorder.

  19. Ghrelin reverses experimental diabetic neuropathy in mice

    International Nuclear Information System (INIS)

    Kyoraku, Itaru; Shiomi, Kazutaka; Kangawa, Kenji; Nakazato, Masamitsu

    2009-01-01

    Ghrelin, an acylated peptide produced in the stomach, increases food intake and growth hormone secretion, suppresses inflammation and oxidative stress, and promotes cell survival and proliferation. We investigated the pharmacological potential of ghrelin in the treatment of polyneuropathy in uncontrolled streptozotocin (STZ)-induced diabetes in mice. Ghrelin or desacyl-ghrelin was administered daily for 4 weeks after STZ-induced diabetic polyneuropathy had developed. Ghrelin administration did not alter food intake, body weight gain, blood glucose levels, or plasma insulin levels when compared with mice given saline or desacyl-ghrelin administration. Ghrelin administration ameliorated reductions in motor and sensory nerve conduction velocities in diabetic mice and normalized their temperature sensation and plasma concentrations of 8-isoprostaglandin α, an oxidative stress marker. Desacyl-ghrelin failed to have any effect. Ghrelin administration in a mouse model of diabetes ameliorated polyneuropathy. Thus, ghrelin's effects represent a novel therapeutic paradigm for the treatment of this otherwise intractable disorder.

  20. The Neurobiological Impact of Ghrelin Suppression after Oesophagectomy

    Directory of Open Access Journals (Sweden)

    Conor F. Murphy

    2016-12-01

    Full Text Available Ghrelin, discovered in 1999, is a 28-amino-acid hormone, best recognized as a stimulator of growth hormone secretion, but with pleiotropic functions in the area of energy homeostasis, such as appetite stimulation and energy expenditure regulation. As the intrinsic ligand of the growth hormone secretagogue receptor (GHS-R, ghrelin appears to have a broad array of effects, but its primary role is still an area of debate. Produced mainly from oxyntic glands in the stomach, but with a multitude of extra-metabolic roles, ghrelin is implicated in complex neurobiological processes. Comprehensive studies within the areas of obesity and metabolic surgery have clarified the mechanism of these operations. As a stimulator of growth hormone (GH, and an apparent inducer of positive energy balance, other areas of interest include its impact on carcinogenesis and tumour proliferation and its role in the cancer cachexia syndrome. This has led several authors to study the hormone in the cancer setting. Ghrelin levels are acutely reduced following an oesophagectomy, a primary treatment modality for oesophageal cancer. We sought to investigate the nature of this postoperative ghrelin suppression, and its neurobiological implications.

  1. Polymorphisms of genes coding for ghrelin and its receptor in relation to anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer risk: a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC).

    Science.gov (United States)

    Dossus, Laure; McKay, James D; Canzian, Federico; Wilkening, Stefan; Rinaldi, Sabina; Biessy, Carine; Olsen, Anja; Tjønneland, Anne; Jakobsen, Marianne U; Overvad, Kim; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie-Christine; Fournier, Agnes; Linseisen, Jakob; Lukanova, Annekatrin; Boeing, Heiner; Fisher, Eva; Trichopoulou, Antonia; Georgila, Christina; Trichopoulos, Dimitrios; Palli, Domenico; Krogh, Vittorio; Tumino, Rosario; Vineis, Paolo; Quirós, José Ramon; Sala, Núria; Martínez-García, Carmen; Dorronsoro, Miren; Chirlaque, Maria-Dolores; Barricarte, Aurelio; van Duijnhoven, Fränzel J B; Bueno-de-Mesquita, H B; van Gils, Carla H; Peeters, Petra H M; Hallmans, Göran; Lenner, Per; Bingham, Sheila; Khaw, Kay Tee; Key, Tim J; Travis, Ruth C; Ferrari, Pietro; Jenab, Mazda; Riboli, Elio; Kaaks, Rudolf

    2008-07-01

    Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also suggests a role of ghrelin in cancer development. We conducted a case-control study on 1359 breast cancer cases and 2389 matched controls, nested within the European Prospective Investigation into Cancer and Nutrition, to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with anthropometric measures, circulating insulin growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 and breast cancer risk. Pair-wise tagging was used to select the 15 polymorphisms that represent the majority of common genetic variants across the GHRL and GHSR genes. A significant increase in breast cancer risk was observed in carriers of the GHRL rs171407-G allele (odds ratio: 1.2; 95% confidence interval: 1.0-1.4; P = 0.02). The GHRL single-nucleotide polymorphism rs375577 was associated with a 5% increase in IGF-I levels (P = 0.01). A number of GHRL and GHSR polymorphisms were associated with body mass index (BMI) and height (P between GHRL variations are associated with BMI. Furthermore, we have observed evidence for association of GHRL polymorphisms with circulating IGF-I levels and with breast cancer risk. These associations, however, might also be due to chance findings and further large studies are needed to confirm our results.

  2. Concomitant release of ventral tegmental acetylcholine and accumbal dopamine by ghrelin in rats.

    Directory of Open Access Journals (Sweden)

    Elisabet Jerlhag

    Full Text Available Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg to the dopaminergic cells of the ventral tegmental area (VTA and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.. Ghrelin receptors (GHS-R1A are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating.

  3. DESACYL GHRELIN INHIBITS THE OREXIGENIC EFFECT OF PERIPHERALLY INJECTED GHRELIN IN RATS

    OpenAIRE

    Inhoff, Tobias; Mönnikes, Hubert; Noetzel, Steffen; Stengel, Andreas; Goebel, Miriam; Dinh, Q. Thai; Riedl, Andrea; Bannert, Norbert; Wisser, Anna-Sophia; Wiedenmann, Bertram; Klapp, Burghard F.; Taché, Yvette; Kobelt, Peter

    2008-01-01

    Studies showed that the metabolic unlike the neuroendocrine effects of ghrelin could be abrogated by co-administered unacylated ghrelin. The aim was to investigate the interaction between ghrelin and desacyl ghrelin administered intraperitoneally on food intake and neuronal activity (c-Fos) in the arcuate nucleus in non-fasted rats. Ghrelin (13 μg/kg) significantly increased food intake within the first 30 min post injection. Desacyl ghrelin at 64 and 127 μg/kg injected simultaneously with gh...

  4. Ghrelin Partially Protects Against Cisplatin-Induced Male Murine Gonadal Toxicity in a GHSR-1a-Dependent Manner1

    Science.gov (United States)

    Whirledge, Shannon D.; Garcia, Jose M.; Smith, Roy G.; Lamb, Dolores J.

    2015-01-01

    ABSTRACT The chemotherapeutic drug cisplatin causes a number of dose-dependent side effects, including cachexia and testicular damage. Patients receiving a high cumulative dose of cisplatin may develop permanent azoospermia and subsequent infertility. Thus, the development of chemotherapeutic regimens with the optimal postsurvival quality of life (fertility) is of high importance. This study tested the hypothesis that ghrelin administration can prevent or minimize cisplatin-induced testicular damage and cachexia. Ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR-1a), are expressed and function in the testis. Targeted deletion of ghrelin, or its receptor, significantly increases the rate of cell death in the testis, suggesting a protective role. Intraperitoneal administration of vehicle, ghrelin, or cisplatin alone or in combination with ghrelin, in cycles of 9 or 18 days, to adult male C57Bl/6 mice was performed. Body weight was measured daily and testicular and epididymal weight, sperm density and motility, testicular histology, and testicular cell death were analyzed at the time of euthanization. Ghrelin coadministration decreased the severity of cisplatin-induced cachexia and gonadal toxicity. Body, testicular, and epididymal weights significantly increased as testicular cell death decreased with ghrelin coadministration. The widespread damage to the seminiferous epithelium induced by cisplatin administration was less severe in mice simultaneously treated with ghrelin. Furthermore, ghrelin diminished the deleterious effects of cisplatin on testis and body weight homeostasis in wild-type but not Ghsr−/− mice, showing that ghrelin's actions are mediated via GHSR. Ghrelin or more stable GHSR agonists potentially offer a novel therapeutic approach to minimize the testicular damage that occurs after gonadotoxin exposure. PMID:25631345

  5. GHRELIN ACTIVATES HYPOPHYSIOTROPIC CORTICOTROPIN-RELEASING FACTOR NEURONS INDEPENDENTLY OF THE ARCUATE NUCLEUS

    Science.gov (United States)

    Cabral, Agustina; Portiansky, Enrique; Sánchez-Jaramillo, Edith; Zigman, Jeffrey M.; Perello, Mario

    2016-01-01

    Previous work has established that the hormone ghrelin engages the hypothalamic-pituitary-adrenal neuroendocrine axis via activation of corticotropin-releasing factor (CRF) neurons of the hypothalamic paraventricular nucleus (PVN). The neuronal circuitry that mediates this effect of ghrelin is currently unknown. Here, we show that ghrelin-induced activation of PVN CRF neurons involved inhibition of γ-aminobutyric acid (GABA) inputs, likely via ghrelin binding sites that were localized at GABAergic terminals within the PVN. While ghrelin activated PVN CRF neurons in the presence of neuropeptide Y (NPY) receptor antagonists or in arcuate nucleus (ARC)-ablated mice, it failed to do it so in mice with ghrelin receptor expression limited to ARC agouti gene related protein (AgRP)/NPY neurons. These data support the notion that ghrelin activates PVN CRF neurons via inhibition of local GABAergic tone, in an ARC-independent manner. Furthermore, these data suggest that the neuronal circuits mediating ghrelin’s orexigenic action vs. its role as a stress signal are anatomically dissociated. PMID:26874559

  6. Central and peripheral des-acyl ghrelin regulates body temperature in rats.

    Science.gov (United States)

    Inoue, Yoshiyuki; Nakahara, Keiko; Maruyama, Keisuke; Suzuki, Yoshiharu; Hayashi, Yujiro; Kangawa, Kenji; Murakami, Noboru

    2013-01-04

    In the present study using rats, we demonstrated that central and peripheral administration of des-acyl ghrelin induced a decrease in the surface temperature of the back, and an increase in the surface temperature of the tail, although the effect of peripheral administration was less marked than that of central administration. Furthermore, these effects of centrally administered des-acyl ghrelin could not be prevented by pretreatment with [D-Lys3]-GHRP-6 GH secretagogue receptor 1a (GHS-R1a) antagonists. Moreover, these actions of des-acyl ghrelin on body temperature were inhibited by the parasympathetic nerve blocker methylscopolamine but not by the sympathetic nerve blocker timolol. Using immunohistochemistry, we confirmed that des-acyl ghrelin induced an increase of cFos expression in the median preoptic nucleus (MnPO). Additionally, we found that des-acyl ghrelin dilated the aorta and tail artery in vitro. These results indicate that centrally administered des-acyl ghrelin regulates body temperature via the parasympathetic nervous system by activating neurons in the MnPO through interactions with a specific receptor distinct from the GHS-R1a, and that peripherally administered des-acyl ghrelin acts on the central nervous system by passing through the blood-brain barrier, whereas it exerts a direct action on the peripheral vascular system. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. The Central Nervous System Sites Mediating the Orexigenic Actions of Ghrelin

    Science.gov (United States)

    Mason, B.L.; Wang, Q.; Zigman, J.M.

    2014-01-01

    The peptide hormone ghrelin is important for both homeostatic and hedonic eating behaviors, and its orexigenic actions occur mainly via binding to the only known ghrelin receptor, the growth hormone secretagogue receptor (GHSR). GHSRs are located in several distinct regions of the central nervous system. This review discusses those central nervous system sites that have been found to play critical roles in the orexigenic actions of ghrelin, including hypothalamic nuclei, the hippocampus, the amygdala, the caudal brain stem, and midbrain dopaminergic neurons. Hopefully, this review can be used as a stepping stone for the reader wanting to gain a clearer understanding of the central nervous system sites of direct ghrelin action on feeding behavior, and as inspiration for future studies to provide an even-more-detailed map of the neurocircuitry controlling eating and body weight. PMID:24111557

  8. Ghrelin alleviates anxiety- and depression-like behaviors induced by chronic unpredictable mild stress in rodents.

    Science.gov (United States)

    Huang, Hui-Jie; Zhu, Xiao-Cang; Han, Qiu-Qin; Wang, Ya-Lin; Yue, Na; Wang, Jing; Yu, Rui; Li, Bing; Wu, Gen-Cheng; Liu, Qiong; Yu, Jin

    2017-05-30

    As a regulator of food intake, ghrelin also plays a key role in mood disorders. Previous studies reported that acute ghrelin administration defends against depressive symptoms of chronic stress. However, the effects of long-term ghrelin on rodents under chronic stress hasn't been revealed. In this study, we found chronic peripheral administration of ghrelin (5nmol/kg/day for 2 weeks, i.p.) could alleviate anxiety- and depression-like behaviors induced by chronic unpredictable mild stress (CUMS). The depression-like behaviors were assessed by the forced swimming test (FST), and anxiety-like behaviors were assessed by the open field test (OFT) and the elevated plus maze test (EPM). Meanwhile, we observed that peripheral acylated ghrelin, together with gastral and hippocampal ghrelin prepropeptide mRNA level, were significantly up-regulated in CUMS mice. Besides, the increased protein level of growth hormone secretagogue receptor (GHSR) in hippocampus were also detected. These results suggested that the endogenous ghrelin/GHSR pathway activated by CUMS plays a role in homeostasis. Further results showed that central treatment of ghrelin (10μg/rat/day for 2 weeks, i.c.v.) or GHRP-6 (the agonist of GHSR, 10μg/rat/day for 2 weeks, i.c.v.) significantly alleviated the depression-like behaviors induced by CUMS in FST and sucrose preference test (SPT). Based on these results, we concluded that central GHSR is involved in the antidepressant-like effect of exogenous ghrelin treatment, and ghrelin/GHSR may have the inherent neuromodulatory properties against depressive symptoms. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular nuclei.

    Science.gov (United States)

    Currie, Paul J; Mirza, Aaisha; Fuld, Rebecca; Park, Diana; Vasselli, Joseph R

    2005-08-01

    Ghrelin is a 28-amino acid acylated peptide and is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). The GHS-R is expressed in hypothalamic nuclei, including the arcuate nucleus (Arc) where it is colocalized with neuropeptide Y (NPY) neurons. In the present study, we examined the effects of ghrelin on feeding and energy substrate utilization (respiratory quotient; RQ) following direct injections into either the arcuate or the paraventricular nucleus (PVN) of the hypothalamus. Ghrelin was administered at the beginning of the dark cycle at doses of 15-60 pmol to male and female rats. In feeding studies, food intake was measured 2 and 4 h postinjection. Separate groups of rats were injected with ghrelin, and the RQ (VCO(2)/VO(2)) was measured using an open circuit calorimeter over a 4-h period. Both Arc and PVN injections of ghrelin increased food intake in male and female rats. Ghrelin also increased RQ, reflecting a shift in energy substrate utilization in favor of carbohydrate oxidation. Because these effects are similar to those observed after PVN injection of NPY, we then assessed the impact of coinjecting ghrelin with NPY into the PVN. When rats were pretreated with very low doses of ghrelin (2.5-10 pmol), NPY's (50 pmol) effects on eating and RQ were potentiated. Overall, these data are in agreement with evidence suggesting that ghrelin functions as a gut-brain endocrine hormone implicated in the regulation of food intake and energy metabolism. Our findings are also consistent with a possible interactive role of hypothalamic ghrelin and NPY systems.

  10. Changes in Subcellular Distribution of n-Octanoyl or n-Decanoyl Ghrelin in Ghrelin-Producing Cells

    OpenAIRE

    Nishi, Yoshihiro; Mifune, Hiroharu; Yabuki, Akira; Tajiri, Yuji; Hirata, Rumiko; Tanaka, Eiichiro; Hosoda, Hiroshi; Kangawa, Kenji; Kojima, Masayasu

    2013-01-01

    Background: The enzyme ghrelin O-acyltransferase (GOAT) catalyzes the acylation of ghrelin. The molecular form of GOAT, together with its reaction in vitro, has been reported previously. However, the sub-cellular processes governing the acylation of ghrelin remain to be elucidated.Methods: Double immunoelectron microscopy was used to examine changes in the relative proportions of secretory granules containing n-octanoyl ghrelin (C8-ghrelin) or n-decanoyl ghrelin (C10-ghrelin) in ghrelin-pro...

  11. Role of ghrelin in drug abuse and reward-relevant behaviors: a burgeoning field and gaps in the literature.

    Science.gov (United States)

    Revitsky, A R; Klein, L C

    2013-09-01

    Ghrelin is a gut-brain hormone that regulates energy balance through food consumption. While ghrelin is well known for its role in hypothalamic activation and homeostatic feeding, more recent evidence suggests that ghrelin also is involved in hedonic feeding through the dopaminergic reward pathway. This paper investigated how ghrelin administration (intraperitoneal, intracerebroventricular, or directly into dopaminergic reward-relevant brain regions) activates the dopaminergic reward pathway and associated reward-relevant behavioral responses in rodents. A total of 19 empirical publications that examined one or more of these variables were included in this review. Overall, ghrelin administration increases dopamine levels in the nucleus accumbens, as well as reward-relevant behaviors such as food (both standard chow and palatable foods) and alcohol consumption. Ghrelin administration also increases operant responding for sucrose, and conditioned place preference. Following a review of the small body of literature examining the effects of ghrelin administration on the dopamine reward pathway, we present a model of the relationship between ghrelin and dopaminergic reward activation. Specifically, ghrelin acts on ghrelin receptors (GHS-R1A) in the ventral tegmental area (VTA) and lateral dorsal tegmental nucleus (LDTg) to stimulate the mesolimbic dopamine reward pathway, which results in increased rewarding behaviors in rodents. Results from this review suggest that selective antagonism of the ghrelin system may serve as potential treatment for addictive drug use. This review highlights gaps in the literature, including a lack of examination of sex- or age-related differences in the effects of ghrelin on dopamine reward processes. In light of vulnerability to drug abuse among female and adolescent populations, future studies should target these individual difference factors.

  12. A concerted kinase interplay identifies PPARgamma as a molecular target of ghrelin signaling in macrophages.

    Directory of Open Access Journals (Sweden)

    Annie Demers

    2009-11-01

    Full Text Available The peroxisome proliferator-activator receptor PPARgamma plays an essential role in vascular biology, modulating macrophage function and atherosclerosis progression. Recently, we have described the beneficial effect of combined activation of the ghrelin/GHS-R1a receptor and the scavenger receptor CD36 to induce macrophage cholesterol release through transcriptional activation of PPARgamma. Although the interplay between CD36 and PPARgamma in atherogenesis is well recognized, the contribution of the ghrelin receptor to regulate PPARgamma remains unknown. Here, we demonstrate that ghrelin triggers PPARgamma activation through a concerted signaling cascade involving Erk1/2 and Akt kinases, resulting in enhanced expression of downstream effectors LXRalpha and ABC sterol transporters in human macrophages. These effects were associated with enhanced PPARgamma phosphorylation independently of the inhibitory conserved serine-84. Src tyrosine kinase Fyn was identified as being recruited to GHS-R1a in response to ghrelin, but failure of activated Fyn to enhance PPARgamma Ser-84 specific phosphorylation relied on the concomitant recruitment of docking protein Dok-1, which prevented optimal activation of the Erk1/2 pathway. Also, substitution of Ser-84 preserved the ghrelin-induced PPARgamma activity and responsiveness to Src inhibition, supporting a mechanism independent of Ser-84 in PPARgamma response to ghrelin. Consistent with this, we found that ghrelin promoted the PI3-K/Akt pathway in a Galphaq-dependent manner, resulting in Akt recruitment to PPARgamma, enhanced PPARgamma phosphorylation and activation independently of Ser-84, and increased expression of LXRalpha and ABCA1/G1. Collectively, these results illustrate a complex interplay involving Fyn/Dok-1/Erk and Galphaq/PI3-K/Akt pathways to transduce in a concerted manner responsiveness of PPARgamma to ghrelin in macrophages.

  13. Ghrelin increases the motivation to eat, but does not alter food palatability

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    Overduin, Joost; Figlewicz, Dianne P.; Bennett-Jay, Jennifer; Kittleson, Sepideh

    2012-01-01

    Homeostatic eating cannot explain overconsumption of food and pathological weight gain. A more likely factor promoting excessive eating is food reward and its representation in the central nervous system (CNS). The anorectic hormones leptin and insulin reduce food reward and inhibit related CNS reward pathways. Conversely, the orexigenic gastrointestinal hormone ghrelin activates both homeostatic and reward-related neurocircuits. The current studies were conducted to identify in rats the effects of intracerebroventricular ghrelin infusions on two distinct aspects of food reward: hedonic valuation (i.e., “liking”) and the motivation to self-administer (i.e., “wanting”) food. To assess hedonic valuation of liquid food, lick motor patterns were recorded using lickometry. Although ghrelin administration increased energy intake, it did not alter the avidity of licking (initial lick rates or lick-cluster size). Several positive-control conditions ruled out lick-rate ceiling effects. Similarly, when the liquid diet was hedonically devalued with quinine supplementation, ghrelin failed to reverse the quinine-associated reduction of energy intake and avidity of licking. The effects of ghrelin on rats' motivation to eat were assessed using lever pressing to self-administer food in a progressive-ratio paradigm. Ghrelin markedly increased motivation to eat, to levels comparable to or greater than those seen following 24 h of food deprivation. Pretreatment with the dopamine D1 receptor antagonist SCH-23390 eliminated ghrelin-induced increases in lever pressing, without compromising generalized licking motor control, indicating a role for D1 signaling in ghrelin's motivational feeding effects. These results indicate that ghrelin increases the motivation to eat via D1 receptor-dependent mechanisms, without affecting perceived food palatability. PMID:22673784

  14. Clarifying the Ghrelin System’s Ability to Regulate Feeding Behaviours Despite Enigmatic Spatial Separation of the GHSR and Its Endogenous Ligand

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    Alexander Edwards

    2017-04-01

    Full Text Available Ghrelin is a hormone predominantly produced in and secreted from the stomach. Ghrelin is involved in many physiological processes including feeding, the stress response, and in modulating learning, memory and motivational processes. Ghrelin does this by binding to its receptor, the growth hormone secretagogue receptor (GHSR, a receptor found in relatively high concentrations in hypothalamic and mesolimbic brain regions. While the feeding and metabolic effects of ghrelin can be explained by the effects of this hormone on regions of the brain that have a more permeable blood brain barrier (BBB, ghrelin produced within the periphery demonstrates a limited ability to reach extrahypothalamic regions where GHSRs are expressed. Therefore, one of the most pressing unanswered questions plaguing ghrelin research is how GHSRs, distributed in brain regions protected by the BBB, are activated despite ghrelin’s predominant peripheral production and poor ability to transverse the BBB. This manuscript will describe how peripheral ghrelin activates central GHSRs to encourage feeding, and how central ghrelin synthesis and ghrelin independent activation of GHSRs may also contribute to the modulation of feeding behaviours.

  15. The role of GABAergic system on the inhibitory effect of ghrelin on food intake in neonatal chicks.

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    Jonaidi, H; Abbassi, L; Yaghoobi, M M; Kaiya, H; Denbow, D M; Kamali, Y; Shojaei, B

    2012-06-27

    Ghrelin is a gut-brain peptide that has a stimulatory effect on food intake in mammals. In contrast, this peptide decreases food intake in neonatal chicks when injected intracerebroventricularly (ICV). In mammals, neuropeptide Y (NPY) mediates the orexigenic effect of ghrelin whereas in chicks it appears that corticotrophin releasing factor (CRF) is partially involved in the inhibitory effect of ghrelin on food intake. Gamma aminobutyric acid (GABA) has a stimulatory effect on food intake in mammals and birds. In this study we investigated whether the anorectic effect of ghrelin is mediated by the GABAergic system. In Experiment 1, 3h-fasted chicks were given an ICV injection of chicken ghrelin and picrotoxin, a GABA(A) receptors antagonist. Picrotoxin decreased food intake compared to the control chicks indicating a stimulatory effect of GABA(A) receptors on food intake. However, picrotoxin did not alter the inhibitory effect of ghrelin on food intake. In Experiment 2, THIP hydrochloride, a GABA(A) receptor agonist, was used in place of picrotoxin. THIP hydrochloride appeared to partially attenuate the decrease in food intake induced by ghrelin at 30 min postinjection. In Experiment 3, the effect of ICV injection of chicken ghrelin on gene expression of glutamate decarboxylase (GAD)(1) and GAD(2), GABA synthesis enzymes in the brain stem including hypothalamus, was investigated. The ICV injection of chicken ghrelin significantly reduced GAD(2) gene expression. These findings suggest that ghrelin may decrease food intake in neonatal chicks by reducing GABA synthesis and thereby GABA release within brain feeding centers. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  16. Ghrelin inhibits the apoptosis of MC3T3-E1 cells through ERK and AKT signaling pathway

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    Liang, Qiu-Hua; Liu, Yuan; Wu, Shan-Shan; Cui, Rong-Rong; Yuan, Ling-Qing, E-mail: allenylq@hotmail.com; Liao, Er-Yuan, E-mail: eyliao@21cn.com

    2013-11-01

    Ghrelin is a 28-amino-acid peptide that acts as a natural endogenous ligand of the growth hormone secretagogue receptor (GHSR) and strongly stimulates the release of growth hormone from the hypothalamus–pituitary axis. Previous studies have identified the important physiological effects of ghrelin on bone metabolism, such as regulating proliferation and differentiation of osteoblasts, independent of GH/IGF-1 axis. However, research on effects and mechanisms of ghrelin on osteoblast apoptosis is still rare. In this study, we identified expression of GHSR in MC3T3-E1 cells and determined the effects of ghrelin on the apoptosis of osteoblastic MC3T3-E1 cells and the mechanism involved. Our data demonstrated that ghrelin inhibited the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, as determined by terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate nick end-labeling (TUNEL) and ELISA assays. Moreover, ghrelin upregulated Bcl-2 expression and downregulated Bax expression in a dose-dependent manner. Our study also showed decreased activated caspase-3 activity under the treatment of ghrelin. Further study suggested that ghrelin stimulated the phosphorylation of ERK and AKT. Pretreatment of cells with the ERK inhibitor PD98059, PI3K inhibitor LY294002, and GHSR-siRNA blocked the ghrelin-induced activation of ERK and AKT, respectively; however, ghrelin did not stimulate the phosphorylation of p38 or JNK. PD90859, LY294002 and GHSR-siRNA attenuated the anti-apoptosis effect of ghrelin in MC3T3-E1 cells. In conclusion, ghrelin inhibits the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, which may be mediated by activating the GHSR/ERK and GHSR/PI3K/AKT signaling pathways. - Highlights: • We explored the effects of ghrelin on serum deprivation-induced MC3T3-E1 cells apoptosis. • Both ELISA and TUNEL were used to detect the apoptosis. • The receptor of ghrelin, GHSR, was expressed in MC3T3-E1

  17. Ghrelin inhibits the apoptosis of MC3T3-E1 cells through ERK and AKT signaling pathway

    International Nuclear Information System (INIS)

    Liang, Qiu-Hua; Liu, Yuan; Wu, Shan-Shan; Cui, Rong-Rong; Yuan, Ling-Qing; Liao, Er-Yuan

    2013-01-01

    Ghrelin is a 28-amino-acid peptide that acts as a natural endogenous ligand of the growth hormone secretagogue receptor (GHSR) and strongly stimulates the release of growth hormone from the hypothalamus–pituitary axis. Previous studies have identified the important physiological effects of ghrelin on bone metabolism, such as regulating proliferation and differentiation of osteoblasts, independent of GH/IGF-1 axis. However, research on effects and mechanisms of ghrelin on osteoblast apoptosis is still rare. In this study, we identified expression of GHSR in MC3T3-E1 cells and determined the effects of ghrelin on the apoptosis of osteoblastic MC3T3-E1 cells and the mechanism involved. Our data demonstrated that ghrelin inhibited the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, as determined by terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate nick end-labeling (TUNEL) and ELISA assays. Moreover, ghrelin upregulated Bcl-2 expression and downregulated Bax expression in a dose-dependent manner. Our study also showed decreased activated caspase-3 activity under the treatment of ghrelin. Further study suggested that ghrelin stimulated the phosphorylation of ERK and AKT. Pretreatment of cells with the ERK inhibitor PD98059, PI3K inhibitor LY294002, and GHSR-siRNA blocked the ghrelin-induced activation of ERK and AKT, respectively; however, ghrelin did not stimulate the phosphorylation of p38 or JNK. PD90859, LY294002 and GHSR-siRNA attenuated the anti-apoptosis effect of ghrelin in MC3T3-E1 cells. In conclusion, ghrelin inhibits the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, which may be mediated by activating the GHSR/ERK and GHSR/PI3K/AKT signaling pathways. - Highlights: • We explored the effects of ghrelin on serum deprivation-induced MC3T3-E1 cells apoptosis. • Both ELISA and TUNEL were used to detect the apoptosis. • The receptor of ghrelin, GHSR, was expressed in MC3T3-E1

  18. Purification of family B G protein-coupled receptors using nanodiscs: Application to human glucagon-like peptide-1 receptor.

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    Yingying Cai

    Full Text Available Family B G protein-coupled receptors (GPCRs play vital roles in hormone-regulated homeostasis. They are drug targets for metabolic diseases, including type 2 diabetes and osteoporosis. Despite their importance, the signaling mechanisms for family B GPCRs at the molecular level remain largely unexplored due to the challenges in purification of functional receptors in sufficient amount for biophysical characterization. Here, we purified the family B GPCR human glucagon-like peptide-1 (GLP-1 receptor (GLP1R, whose agonists, e.g. exendin-4, are used for the treatment of type 2 diabetes mellitus. The receptor was expressed in HEK293S GnTl- cells using our recently developed protocol. The protocol incorporates the receptor into the native-like lipid environment of reconstituted high density lipoprotein (rHDL particles, also known as nanodiscs, immediately after the membrane solubilization step followed by chromatographic purification, minimizing detergent contact with the target receptor to reduce denaturation and prolonging stabilization of receptor in lipid bilayers without extra steps of reconstitution. This method yielded purified GLP1R in nanodiscs that could bind to GLP-1 and exendin-4 and activate Gs protein. This nanodisc purification method can potentially be a general strategy to routinely obtain purified family B GPCRs in the 10s of microgram amounts useful for spectroscopic analysis of receptor functions and activation mechanisms.

  19. Purification of family B G protein-coupled receptors using nanodiscs: Application to human glucagon-like peptide-1 receptor.

    Science.gov (United States)

    Cai, Yingying; Liu, Yuting; Culhane, Kelly J; DeVree, Brian T; Yang, Yang; Sunahara, Roger K; Yan, Elsa C Y

    2017-01-01

    Family B G protein-coupled receptors (GPCRs) play vital roles in hormone-regulated homeostasis. They are drug targets for metabolic diseases, including type 2 diabetes and osteoporosis. Despite their importance, the signaling mechanisms for family B GPCRs at the molecular level remain largely unexplored due to the challenges in purification of functional receptors in sufficient amount for biophysical characterization. Here, we purified the family B GPCR human glucagon-like peptide-1 (GLP-1) receptor (GLP1R), whose agonists, e.g. exendin-4, are used for the treatment of type 2 diabetes mellitus. The receptor was expressed in HEK293S GnTl- cells using our recently developed protocol. The protocol incorporates the receptor into the native-like lipid environment of reconstituted high density lipoprotein (rHDL) particles, also known as nanodiscs, immediately after the membrane solubilization step followed by chromatographic purification, minimizing detergent contact with the target receptor to reduce denaturation and prolonging stabilization of receptor in lipid bilayers without extra steps of reconstitution. This method yielded purified GLP1R in nanodiscs that could bind to GLP-1 and exendin-4 and activate Gs protein. This nanodisc purification method can potentially be a general strategy to routinely obtain purified family B GPCRs in the 10s of microgram amounts useful for spectroscopic analysis of receptor functions and activation mechanisms.

  20. KATP channels in the nodose ganglia mediate the orexigenic actions of ghrelin

    Science.gov (United States)

    Grabauskas, Gintautas; Wu, Xiaoyin; Lu, Yuanxu; Heldsinger, Andrea; Song, Il; Zhou, Shi-Yi; Owyang, Chung

    2015-01-01

    Abstract Ghrelin is the only known hunger signal derived from the peripheral tissues. Ghrelin overcomes the satiety signals evoked by anorexigenic molecules, such as cholecystokinin (CCK) and leptin, to stimulate feeding. The mechanisms by which ghrelin reduces the sensory signals evoked by anorexigenic hormones, which act via the vagus nerve to stimulate feeding, are unknown. Patch clamp recordings of isolated rat vagal neurons show that ghrelin hyperpolarizes neurons by activating K+ conductance. Administering a KATP channel antagonist or silencing Kir6.2, a major subunit of the KATP channel, abolished ghrelin inhibition in vitro and in vivo. Patch clamp studies show that ghrelin inhibits currents evoked by leptin and CCK-8, which operate through independent ionic channels. The inhibitory actions of ghrelin were abolished by treating the vagal ganglia neurons with pertussis toxin, as well as phosphatidylinositol 3-kinase (PI3K) or extracellular signal-regulated kinase 1 and 2 (Erk1/2) small interfering RNA. In vivo gene silencing of PI3K and Erk1/2 in the nodose ganglia prevented ghrelin inhibition of leptin- or CCK-8-evoked vagal firing. Feeding experiments showed that silencing Kir6.2 in the vagal ganglia abolished the orexigenic actions of ghrelin. These data indicate that ghrelin modulates vagal ganglia neuron excitability by activating KATP conductance via the growth hormone secretagogue receptor subtype 1a–Gαi–PI3K–Erk1/2–KATP pathway. The resulting hyperpolarization renders the neurons less responsive to signals evoked by anorexigenic hormones. This provides a mechanism to explain the actions of ghrelin with respect to overcoming anorexigenic signals that act via the vagal afferent pathways. Key points Ghrelin, a hunger signalling peptide derived from the peripheral tissues, overcomes the satiety signals evoked by anorexigenic molecules, such as cholecystokinin (CCK) and leptin, to stimulate feeding. Using in vivo and in vitro electrophysiological

  1. Potentiation of ghrelin signaling attenuates cancer anorexia–cachexia and prolongs survival

    Science.gov (United States)

    Fujitsuka, N; Asakawa, A; Uezono, Y; Minami, K; Yamaguchi, T; Niijima, A; Yada, T; Maejima, Y; Sedbazar, U; Sakai, T; Hattori, T; Kase, Y; Inui, A

    2011-01-01

    Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut–brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia–cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia–cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia–cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia–cachexia. PMID:22832525

  2. The GOAT-ghrelin system is not essential for hypoglycemia prevention during prolonged calorie restriction.

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    Chun-Xia Yi

    Full Text Available Ghrelin acylation by ghrelin O-acyltransferase (GOAT has recently been reported to be essential for the prevention of hypoglycemia during prolonged negative energy balance. Using a unique set of four different genetic loss-of-function models for the GOAT/ghrelin/growth hormone secretagogue receptor (GHSR system, we thoroughly tested the hypothesis that lack-of-ghrelin activation or signaling would lead to hypoglycemia during caloric deprivation.Male and female knockout (KO mice for GOAT, ghrelin, GHSR, or both ghrelin and GHSR (dKO were subjected to prolonged calorie restriction (40% of ad libitum chow intake. Body weight, fat mass, and glucose levels were recorded daily and compared to wildtype (WT controls. Forty-eight hour blood glucose profiles were generated for each individual mouse when 2% or less body fat mass was reached. Blood samples were obtained for analysis of circulating levels of acyl- and desacyl-ghrelin, IGF-1, and insulin.Chronic calorie restriction progressively decreased body weight and body fat mass in all mice regardless of genotype. When fat mass was depleted to 2% or less of body weight for 2 consecutive days, random hypoglycemic events occurred in some mice across all genotypes. There was no increase in the incidence of hypoglycemia in any of the four loss-of-function models for ghrelin signaling including GOAT KO mice. Furthermore, no differences in insulin or IGF-1 levels were observed between genotypes.The endogenous GOAT-ghrelin-GHSR system is not essential for the maintenance of euglycemia during prolonged calorie restriction.

  3. Ghrelin in the CNS: from hunger to a rewarding and memorable meal?

    Science.gov (United States)

    Olszewski, Pawel K; Schiöth, Helgi B; Levine, Allen S

    2008-06-01

    Ghrelin, the endogenous agonist of the growth hormone secretagogue receptor, has been shown to induce robust feeding responses in numerous experimental models. Although ghrelin comes from both peripheral and central sources, its hyperphagic properties, to a large extent, arise from activity at the brain level. The current review focuses on describing central mechanisms through which this peptide affects consumption. We address the issue of whether ghrelin serves just as a signal of energy needs of the organism or - as suggested by the most recent findings - also affects food intake via other feeding-related mechanisms, including reward and memory. Complexity of ghrelin's role in the regulation of ingestive behavior is discussed by characterizing its influence on consumption, reward and memory as well as by defining its function within the brain circuitry and interplay with other neuropeptides.

  4. Neuroprotective Actions of Ghrelin and Growth Hormone Secretagogues

    Science.gov (United States)

    Frago, Laura M.; Baquedano, Eva; Argente, Jesús; Chowen, Julie A.

    2011-01-01

    The brain incorporates and coordinates information based on the hormonal environment, receiving information from peripheral tissues through the circulation. Although it was initially thought that hormones only acted on the hypothalamus to perform endocrine functions, it is now known that they in fact exert diverse actions on many different brain regions including the hypothalamus. Ghrelin is a gastric hormone that stimulates growth hormone secretion and food intake to regulate energy homeostasis and body weight by binding to its receptor, growth hormone secretagogues–GH secretagogue-receptor, which is most highly expressed in the pituitary and hypothalamus. In addition, ghrelin has effects on learning and memory, reward and motivation, anxiety, and depression, and could be a potential therapeutic agent in neurodegenerative disorders where excitotoxic neuronal cell death and inflammatory processes are involved. PMID:21994488

  5. Ghrelin modulates the fMRI BOLD response of homeostatic and hedonic brain centers regulating energy balance in the rat.

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    Miklós Sárvári

    Full Text Available The orexigenic gut-brain peptide, ghrelin and its G-protein coupled receptor, the growth hormone secretagogue receptor 1a (GHS-R1A are pivotal regulators of hypothalamic feeding centers and reward processing neuronal circuits of the brain. These systems operate in a cooperative manner and receive a wide array of neuronal hormone/transmitter messages and metabolic signals. Functional magnetic resonance imaging was employed in the current study to map BOLD responses to ghrelin in different brain regions with special reference on homeostatic and hedonic regulatory centers of energy balance. Experimental groups involved male, ovariectomized female and ovariectomized estradiol-replaced rats. Putative modulation of ghrelin signaling by endocannabinoids was also studied. Ghrelin-evoked effects were calculated as mean of the BOLD responses 30 minutes after administration. In the male rat, ghrelin evoked a slowly decreasing BOLD response in all studied regions of interest (ROI within the limbic system. This effect was antagonized by pretreatment with GHS-R1A antagonist JMV2959. The comparison of ghrelin effects in the presence or absence of JMV2959 in individual ROIs revealed significant changes in the prefrontal cortex, nucleus accumbens of the telencephalon, and also within hypothalamic centers like the lateral hypothalamus, ventromedial nucleus, paraventricular nucleus and suprachiasmatic nucleus. In the female rat, the ghrelin effects were almost identical to those observed in males. Ovariectomy and chronic estradiol replacement had no effect on the BOLD response. Inhibition of the endocannabinoid signaling by rimonabant significantly attenuated the response of the nucleus accumbens and septum. In summary, ghrelin can modulate hypothalamic and mesolimbic structures controlling energy balance in both sexes. The endocannabinoid signaling system contributes to the manifestation of ghrelin's BOLD effect in a region specific manner. In females, the

  6. Development of ghrelin transgenic mice for elucidation of clinical implication of ghrelin.

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    Aotani, Daisuke; Ariyasu, Hiroyuki; Shimazu-Kuwahara, Satoko; Shimizu, Yoshiyuki; Nomura, Hidenari; Murofushi, Yoshiteru; Kaneko, Kentaro; Izumi, Ryota; Matsubara, Masaki; Kanda, Hajime; Noguchi, Michio; Tanaka, Tomohiro; Kusakabe, Toru; Miyazawa, Takashi; Nakao, Kazuwa

    2017-01-01

    To elucidate the clinical implication of ghrelin, we have been trying to generate variable models of transgenic (Tg) mice overexpressing ghrelin. We generated Tg mice overexpressing des-acyl ghrelin in a wide variety of tissues under the control of β-actin promoter. While plasma des-acyl ghrelin level in the Tg mice was 44-fold greater than that of control mice, there was no differences in the plasma ghrelin level between des-acyl ghrelin Tg and the control mice. The des-acyl ghrelin Tg mice exhibited the lower body weight and the shorter body length due to modulation of GH-IGF-1 axis. We tried to generate Tg mice expressing a ghrelin analog, which possessed ghrelin-like activity (Trp 3 -ghrelin Tg mice). The plasma Trp 3 -ghrelin concentration in Trp 3 -ghrelin Tg mice was approximately 85-fold higher than plasma ghrelin (acylated ghrelin) concentration seen in the control mice. Because Trp 3 -ghrelin is approximately 24-fold less potent than ghrelin, the plasma Trp 3 -ghrelin concentration in Trp 3 -ghrelin Tg mice was calculated to have approximately 3.5-fold biological activity greater than that of ghrelin (acylated ghrelin) in the control mice. Trp 3 -ghrelin Tg mice did not show any phenotypes except for reduced insulin sensitivity in 1-year old. After the identification of ghrelin O-acyltransferase (GOAT), we generated doubly Tg mice overexpressing both mouse des-acyl ghrelin and mouse GOAT in the liver by cross-mating the two kinds of Tg mice. The plasma ghrelin concentration of doubly Tg mice was approximately 2-fold higher than that of the control mice. No apparent phenotypic changes in body weight and food intake were observed in doubly Tg mice. Further studies are ongoing in our laboratory to generate Tg mice with the increased plasma ghrelin level to a greater extent. The better understanding of physiological and pathophysiological significance of ghrelin from experiments using an excellent animal model may provide a new therapeutic approach for human

  7. Antinociceptive Effect of Ghrelin in a Rat Model of Irritable Bowel Syndrome Involves TRPV1/Opioid Systems

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    Yuqing Mao

    2017-09-01

    Full Text Available Background/Aims: Irritable bowel syndrome (IBS, defined as recurrent abdominal pain and changes in bowel habits, seriously affects quality of life and ability to work. Ghrelin is a brain-gut hormone, which has been reported to show antinociceptive effects in peripheral pain. We investigated the effect of ghrelin on visceral hypersensitivity and pain in a rat model of IBS. Methods: Maternal deprivation (MD was used to provide a stress-induced model of IBS in Wistar rats. Colorectal distension (CRD was used to detect visceral sensitivity, which was evaluated by abdominal withdrawal reflex (AWR scores. Rats that were confirmed to have visceral hypersensitivity after MD were injected with ghrelin (10 µg/kg subcutaneously twice a week from weeks 7 to 8. [D-Lys3]-GHRP-6 (100 nmol/L and naloxone (100 nmol/L were administered subcutaneously to block growth hormone secretagogue receptor 1α (GHS-R1α and opioid receptors, respectively. Expression of transient receptor potential vanilloid type 1 (TRPV1 and µ and κ opioid receptors (MOR and KOR in colon, dorsal root ganglion (DRG and cerebral cortex tissues were detected by western blotting, quantitative real-time polymerase chain reaction (qRT-PCR, immunohistochemical analyses and immunofluorescence. Results: Ghrelin treatment increased expression of opioid receptors and inhibited expression of TRPV1 in colon, dorsal root ganglion (DRG and cerebral cortex. The antinociceptive effect of ghrelin in the rat model of IBS was partly blocked by both the ghrelin antagonist [D-Lys3]-GHRP-6 and the opioid receptor antagonist naloxone. Conclusion: The results indicate that ghrelin exerted an antinociceptive effect, which was mediated via TRPV1/opioid systems, in IBS-induced visceral hypersensitivity. Ghrelin might potentially be used as a new treatment for IBS.

  8. Ghrelin at the interface of obesity and reward.

    Science.gov (United States)

    Schellekens, Harriët; Dinan, Timothy G; Cryan, John F

    2013-01-01

    The prevalence of obesity continues to increase and has reached epidemic proportions. Accumulating data over the past few decades have given us key insights and broadened our understanding of the peripheral and central regulation of energy homeostasis. Despite this, the currently available pharmacological treatments, reducing body weight, remain limited due to poor efficacy and side effects. The gastric peptide ghrelin has been identified as the only orexigenic hormone from the periphery to act in the hypothalamus to stimulate food intake. Recently, a role for ghrelin and its receptor at the interface between homeostatic control of appetite and reward circuitries modulating the hedonic aspects of food has also emerged. Nonhomeostatic factors such as the rewarding and motivational value of food, which increase with food palatability and caloric content, can override homeostatic control of food intake. This nonhomeostatic decision to eat leads to overconsumption beyond nutritional needs and is being recognized as a key component in the underlying causes for the increase in obesity incidence worldwide. In addition, the hedonic feeding behavior has been linked to food addiction and an important role for ghrelin in the development of addiction has been suggested. Moreover, plasma ghrelin levels are responsive to conditions of stress, and recent evidence has implicated ghrelin in stress-induced food-reward behavior. The prominent role of the ghrelinergic system in the regulation of feeding gives rise to it as an effective target for the development of successful antiobesity pharmacotherapies that not only affect satiety but also selectively modulate the rewarding properties of food and reduce the desire to eat. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexia.

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    DeBoer, Mark D; Zhu, Xin Xia; Levasseur, Peter; Meguid, Michael M; Suzuki, Susumu; Inui, Akio; Taylor, John E; Halem, Heather A; Dong, Jesse Z; Datta, Rakesh; Culler, Michael D; Marks, Daniel L

    2007-06-01

    Cancer cachexia is a debilitating syndrome of anorexia and loss of lean body mass that accompanies many malignancies. Ghrelin is an orexigenic hormone with a short half-life that has been shown to improve food intake and weight gain in human and animal subjects with cancer cachexia. We used a rat model of cancer cachexia and administered human ghrelin and a synthetic ghrelin analog BIM-28131 via continuous infusion using sc osmotic minipumps. Tumor-implanted rats receiving human ghrelin or BIM-28131 exhibited a significant increase in food consumption and weight gain vs. saline-treated animals. We used dual-energy x-ray absorptiometry scans to show that the increased weight was due to maintenance of lean mass vs. a loss of lean mass in saline-treated animals. Also, BIM-28131 significantly limited the loss of fat mass normally observed in tumor-implanted rats. We further performed real-time PCR analysis of the hypothalami and brainstems and found that ghrelin-treated animals exhibited a significant increase in expression of orexigenic peptides agouti-related peptide and neuropeptide Y in the hypothalamus and a significant decrease in the expression of IL-1 receptor-I transcript in the hypothalamus and brainstem. We conclude that ghrelin and a synthetic ghrelin receptor agonist improve weight gain and lean body mass retention via effects involving orexigenic neuropeptides and antiinflammatory changes.

  10. Integrating Solid-State NMR and Computational Modeling to Investigate the Structure and Dynamics of Membrane-Associated Ghrelin

    Science.gov (United States)

    Els-Heindl, Sylvia; Chollet, Constance; Scheidt, Holger A.; Beck-Sickinger, Annette G.; Meiler, Jens; Huster, Daniel

    2015-01-01

    The peptide hormone ghrelin activates the growth hormone secretagogue receptor 1a, also known as the ghrelin receptor. This 28-residue peptide is acylated at Ser3 and is the only peptide hormone in the human body that is lipid-modified by an octanoyl group. Little is known about the structure and dynamics of membrane-associated ghrelin. We carried out solid-state NMR studies of ghrelin in lipid vesicles, followed by computational modeling of the peptide using Rosetta. Isotropic chemical shift data of isotopically labeled ghrelin provide information about the peptide’s secondary structure. Spin diffusion experiments indicate that ghrelin binds to membranes via its lipidated Ser3. Further, Phe4, as well as electrostatics involving the peptide’s positively charged residues and lipid polar headgroups, contribute to the binding energy. Other than the lipid anchor, ghrelin is highly flexible and mobile at the membrane surface. This observation is supported by our predicted model ensemble, which is in good agreement with experimentally determined chemical shifts. In the final ensemble of models, residues 8–17 form an α-helix, while residues 21–23 and 26–27 often adopt a polyproline II helical conformation. These helices appear to assist the peptide in forming an amphipathic conformation so that it can bind to the membrane. PMID:25803439

  11. Integrating solid-state NMR and computational modeling to investigate the structure and dynamics of membrane-associated ghrelin.

    Directory of Open Access Journals (Sweden)

    Gerrit Vortmeier

    Full Text Available The peptide hormone ghrelin activates the growth hormone secretagogue receptor 1a, also known as the ghrelin receptor. This 28-residue peptide is acylated at Ser3 and is the only peptide hormone in the human body that is lipid-modified by an octanoyl group. Little is known about the structure and dynamics of membrane-associated ghrelin. We carried out solid-state NMR studies of ghrelin in lipid vesicles, followed by computational modeling of the peptide using Rosetta. Isotropic chemical shift data of isotopically labeled ghrelin provide information about the peptide's secondary structure. Spin diffusion experiments indicate that ghrelin binds to membranes via its lipidated Ser3. Further, Phe4, as well as electrostatics involving the peptide's positively charged residues and lipid polar headgroups, contribute to the binding energy. Other than the lipid anchor, ghrelin is highly flexible and mobile at the membrane surface. This observation is supported by our predicted model ensemble, which is in good agreement with experimentally determined chemical shifts. In the final ensemble of models, residues 8-17 form an α-helix, while residues 21-23 and 26-27 often adopt a polyproline II helical conformation. These helices appear to assist the peptide in forming an amphipathic conformation so that it can bind to the membrane.

  12. Ghrelin enhances cue-induced bar pressing for high fat food.

    Science.gov (United States)

    St-Onge, Veronique; Watts, Alexander; Abizaid, Alfonso

    2016-02-01

    Ghrelin is an orexigenic hormone produced by the stomach that acts on growth hormone secretagogue receptors (GHSRs) both peripherally and centrally. The presence of GHSRs in the ventral tegmental area (VTA) suggests that ghrelin signaling at this level may increase the incentive value of palatable foods as well as other natural and artificial rewards. The present investigation sought to determine if ghrelin plays a role in relapse to such foods following a period of abstinence. To achieve this, thirty-six male Long Evans rats were trained to press a lever to obtain a high fat chocolate food reward on a fixed ratio schedule of 1. Following an extinction period during which lever presses were not reinforced, rats were implanted with a cannula connected to a minipump that continuously delivered ghrelin, a GHSR antagonist ([d-Lys-3]-GHRP-6), or saline in the VTA for 14days. One week later, food reward-associated cues, food reward priming, and an overnight fast were used to induce reinstatement of the lever pressing response. Our results indicate that intra-VTA ghrelin enhances cue-induced reinstatement of responses for palatable food pellets. To the extent that the reinstatement paradigm is considered a valid model of relapse in humans, this suggests that ghrelin signaling facilitates relapse to preferred foods in response to food cues through GHSR signaling in the VTA. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. The role of the central ghrelin system in reward from food and chemical drugs.

    Science.gov (United States)

    Dickson, Suzanne L; Egecioglu, Emil; Landgren, Sara; Skibicka, Karolina P; Engel, Jörgen A; Jerlhag, Elisabet

    2011-06-20

    Here we review recent advances that identify a role for the central ghrelin signalling system in reward from both natural rewards (such as food) and artificial rewards (that include alcohol and drugs of abuse). Whereas ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called "cholinergic-dopaminergic reward link". This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. Ghrelin administration into the VTA or LDTg activates the "cholinergic-dopaminergic" reward link, suggesting that ghrelin may increase the incentive value of motivated behaviours such as reward-seeking behaviour ("wanting" or "incentive motivation"). Further, direct injection of ghrelin into the brain ventricles or into the VTA increases the consumption of rewarding foods as well as alcohol in mice and rats. Studies in rodents show beneficial effects of ghrelin receptor (GHS-R1A) antagonists to suppress the intake of palatable food, to reduce preference for caloric foods, to suppress food reward and motivated behaviour for food. They have also been shown to reduce alcohol consumption, suppress reward induced by alcohol, cocaine and amphetamine. Furthermore, variations in the GHS-R1A and pro-ghrelin genes have been associated with high alcohol consumption, smoking and increased weight gain in alcohol dependent individuals as well as with bulimia nervosa and obesity. Thus, the central ghrelin signalling system interfaces neurobiological circuits involved in reward from food as well as chemical drugs; agents that directly or indirectly suppress this system emerge as potential candidate drugs for suppressing problematic over-eating that leads to obesity as well as for the

  14. Ghrelin Attenuates Retinal Neuronal Autophagy and Apoptosis in an Experimental Rat Glaucoma Model.

    Science.gov (United States)

    Zhu, Ke; Zhang, Meng-Lu; Liu, Shu-Ting; Li, Xue-Yan; Zhong, Shu-Min; Li, Fang; Xu, Ge-Zhi; Wang, Zhongfeng; Miao, Yanying

    2017-12-01

    Ghrelin, a natural ligand for the growth hormone secretagogue receptor type 1a (GHSR-1a), may protect retinal neurons against glaucomatous injury. We therefore characterized the underlying mechanism of the ghrelin/GHSR-1a-mediated neuroprotection with a rat chronic intraocular hypertension (COH) model. The rat COH model was produced by blocking episcleral veins. A combination of immunohistochemistry, Western blot, TUNEL assay, and retrograde labeling of retinal ganglion cells (RGCs) was used. Elevation of intraocular pressure induced a significant increase in ghrelin and GHSR-1a expression in retinal cells, including RGCs and Müller cells. Western blot confirmed that the protein levels of ghrelin exhibited a transient upregulation at week 2 after surgery (G2w), while the GHSR-1a protein levels were maintained at high levels from G2w to G4w. In COH retinas, the ratio of LC3-II/LC-I and beclin1, two autophagy-related proteins, were increased from G1w to G4w, and the cleavage product of caspase3, an apoptotic executioner, was detected from G2w to G4w. Intraperitoneal injection of ghrelin significantly increased the number of surviving RGCs; inhibited the changes of LC3-II/LC-I, beclin1, and the cleavage products of caspase3; and reduced the number of TUNEL-positive cells in COH retinas. Ghrelin treatment also reversed the decreased levels of p-Akt and p-mTOR, upregulated GHSR-1a protein levels, and attenuated glial fibrillary acidic protein levels in COH retinas. All these results suggest that ghrelin may provide neuroprotective effect in COH retinas through activating ghrelin/GHSR-1a system, which was mediated by inhibiting retinal autophagy, ganglion cell apoptosis, and Müller cell gliosis.

  15. Ghrelin did not change coronary angiogenesis in diet-induced obese mice.

    Science.gov (United States)

    Khazaei, M; Tahergorabi, Z

    2017-02-28

    Ghrelin is a 28 amino acids peptide that initially was recognized as an endogenous ligand for growth hormone secretagogue receptor (GHSR). Recently, a number of studies demonstrated that ghrelin is a cardiovascular hormone with a series cardiovascular effect. The main objective of this study was to investigate the effect of systemic ghrelin administration on angiogenesis in the heart and its correlation with serum leptin levels in normal and diet-induced obese mice. 24 male C57BL/6 mice were randomly divided into four groups: normal diet (ND) or control, ND+ghrelin, high-fat-diet (HFD) or obese and HFD+ghrelin (n=6/group). Obese and control groups received HFD or ND, respectively, for 14 weeks. Then, the ghrelin was injected subcutaneously 100µg/kg twice daily. After 10 days, the animals were sacrificed, blood samples were taken and the hearts were removed. The angiogenic response in the heart was assessed by immunohisochemical staining. HFD significantly increased angiogenesis in the heart expressed as the number of CD31 positive cells than standard diet. Ghrelin did not alter angiogenesis in the heart in both obese and control groups, however, it reduced serum nitric oxide (NO) and leptin levels in obese mice. There was a strong positive correlation between the number of CD31 positive cells and serum leptin concentration (r=0.74). Leptin as an angiogenic factor has a positive correlation with angiogenesis in the heart. Although systemic administration of ghrelin reduced serum leptin and NO levels in obese mice, however, it could not alter coronary angiogenesis.

  16. Genetic variation of the ghrelin signaling system in females with severe alcohol dependence.

    Science.gov (United States)

    Landgren, Sara; Jerlhag, Elisabet; Hallman, Jarmila; Oreland, Lars; Lissner, Lauren; Strandhagen, Elisabeth; Thelle, Dag S; Zetterberg, Henrik; Blennow, Kaj; Engel, Jörgen A

    2010-09-01

    Central ghrelin signaling is required for the rewarding effects of alcohol in mice. Because ghrelin is implied in other addictive behaviors such as eating disorders and smoking, and because there is co-morbidity between these disorders and alcohol dependence, the ghrelin signaling system could be involved in mediating reward in general. Furthermore, in humans, single nucleotide polymorphisms (SNPs) and haplotypes of the pro-ghrelin gene (GHRL) and the ghrelin receptor gene (GHSR) have previously been associated with increased alcohol consumption and increased body weight. Known gender differences in plasma ghrelin levels prompted us to investigate genetic variation of the ghrelin signaling system in females with severe alcohol dependence (n = 113) and in a selected control sample of female low-consumers of alcohol from a large cohort study in southwest Sweden (n = 212). Six tag SNPs in the GHRL (rs696217, rs3491141, rs4684677, rs35680, rs42451, and rs26802) and four tag SNPs in the GHSR (rs495225, rs2232165, rs572169, and rs2948694) were genotyped in all individuals. We found that one GHRL haplotype was associated with reports of paternal alcohol dependence as well as with reports of withdrawal symptoms in the female alcohol-dependent group. Associations with 2 GHSR haplotypes and smoking were also shown. One of these haplotypes was also negatively associated with BMI in controls, while another haplotype was associated with having the early-onset, more heredity-driven, type 2 form of alcohol dependence in the patient group. Taken together, the genes encoding the ghrelin signaling system cannot be regarded as major susceptibility genes for female alcohol dependence, but is, however, involved in paternal heritability and may affect other reward- and energy-related factors such as smoking and BMI.

  17. Neuroprotective actions of ghrelin and growth hormone secretagogues

    Directory of Open Access Journals (Sweden)

    Laura M. Frago

    2011-09-01

    Full Text Available The brain incorporates and coordinates information based on the hormonal environment, receiving information from peripheral tissues through the circulation. Although it was initially thought that hormones only acted on the hypothalamus to perform endocrine functions, it is now known that they in fact exert diverse actions on many different brain regions including the hypothalamus. Ghrelin is a gastric hormone that stimulates growth hormone (GH secretion and food intake to regulate energy homeostasis and body weight by binding to its receptor, GHS-R1a, which is most highly expressed in the pituitary and hypothalamus. In addition, ghrelin has effects on learning and memory, reward and motivation, anxiety and depression, and could be a potential therapeutic agent in neurodegenerative disorders where excitotoxic neuronal cell death and inflammatory processes are involved.

  18. Ghrelin-related peptides do not modulate vasodilator nitric oxide production or superoxide levels in mouse systemic arteries.

    Science.gov (United States)

    Ku, Jacqueline M; Sleeman, Mark W; Sobey, Christopher G; Andrews, Zane B; Miller, Alyson A

    2016-04-01

    The ghrelin gene is expressed in the stomach where it ultimately encodes up to three peptides, namely, acylated ghrelin, des-acylated ghrelin and obestatin, which all have neuroendocrine roles. Recently, the authors' reported that these peptides have important physiological roles in positively regulating vasodilator nitric oxide (NO) production in the cerebral circulation, and may normally suppress superoxide production by the pro-oxidant enzyme, Nox2-NADPH oxidase. To date, the majority of studies using exogenous peptides infer that they may have similar roles in the systemic circulation. Therefore, this study examined whether exogenous and endogenous ghrelin-related peptides modulate NO production and superoxide levels in mouse mesenteric arteries and/or thoracic aorta. Using wire myography, it was found that application of exogenous acylated ghrelin, des-acylated ghrelin or obestatin to mouse thoracic aorta or mesenteric arteries failed to elicit a vasorelaxation response, whereas all three peptides elicited vasorelaxation responses of rat thoracic aorta. Also, none of the peptides modulated mouse aortic superoxide levels as measured by L-012-enhanced chemiluminescence. Next, it was found that NO bioactivity and superoxide levels were unaffected in the thoracic aorta from ghrelin-deficient mice when compared with wild-type mice. Lastly, using novel GHSR-eGFP reporter mice in combination with double-labelled immunofluorescence, no evidence was found for the growth hormone secretagogue receptor (GHSR1a) in the throracic aorta, which is the only functional ghrelin receptor identified to date. Collectively these findings demonstrate that, in contrast to systemic vessels of other species (e.g. rat and human) and mouse cerebral vessels, ghrelin-related peptides do not modulate vasodilator NO production or superoxide levels in mouse systemic arteries. © 2016 John Wiley & Sons Australia, Ltd.

  19. Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets

    DEFF Research Database (Denmark)

    Adriaenssens, Alice E; Svendsen, Berit; Lam, Brian Y H

    2016-01-01

    cytometry and analysed by RNA sequencing. The role of the ghrelin receptor was validated by imaging delta cell calcium concentrations using islets with delta cell restricted expression of the calcium reporter GCaMP3, and in perfused mouse pancreases. RESULTS: A database was constructed of all genes...... expressed in alpha, beta and delta cells. The gene encoding the ghrelin receptor, Ghsr, was highlighted as being highly expressed and enriched in delta cells. Activation of the ghrelin receptor raised cytosolic calcium levels in primary pancreatic delta cells and enhanced somatostatin secretion in perfused...... pancreases, correlating with a decrease in insulin and glucagon release. The inhibition of insulin secretion by ghrelin was prevented by somatostatin receptor antagonism. CONCLUSIONS/INTERPRETATION: Our transcriptomic database of genes expressed in the principal islet cell populations will facilitate...

  20. Theoretical and Computational Studies of Peptides and Receptors of the Insulin Family

    Directory of Open Access Journals (Sweden)

    Harish Vashisth

    2015-02-01

    Full Text Available Synergistic interactions among peptides and receptors of the insulin family are required for glucose homeostasis, normal cellular growth and development, proliferation, differentiation and other metabolic processes. The peptides of the insulin family are disulfide-linked single or dual-chain proteins, while receptors are ligand-activated transmembrane glycoproteins of the receptor tyrosine kinase (RTK superfamily. Binding of ligands to the extracellular domains of receptors is known to initiate signaling via activation of intracellular kinase domains. While the structure of insulin has been known since 1969, recent decades have seen remarkable progress on the structural biology of apo and liganded receptor fragments. Here, we review how this useful structural information (on ligands and receptors has enabled large-scale atomically-resolved simulations to elucidate the conformational dynamics of these biomolecules. Particularly, applications of molecular dynamics (MD and Monte Carlo (MC simulation methods are discussed in various contexts, including studies of isolated ligands, apo-receptors, ligand/receptor complexes and intracellular kinase domains. The review concludes with a brief overview and future outlook for modeling and computational studies in this family of proteins.

  1. Ghrelin- and GH-induced insulin resistance

    DEFF Research Database (Denmark)

    Vestergaard, Esben Thyssen; Krag, Morten B; Poulsen, Morten M

    2013-01-01

    Supraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects.......Supraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects....

  2. The Human Experience With Ghrelin Administration

    Science.gov (United States)

    Garin, Margaret C.; Burns, Carrie M.; Kaul, Shailja

    2013-01-01

    Context: Ghrelin is an endogenous stimulator of GH and is implicated in a number of physiological processes. Clinical trials have been performed in a variety of patient populations, but there is no comprehensive review of the beneficial and adverse consequences of ghrelin administration to humans. Evidence Acquisition: PubMed was utilized, and the reference list of each article was screened. We included 121 published articles in which ghrelin was administered to humans. Evidence Synthesis: Ghrelin has been administered as an infusion or a bolus in a variety of doses to 1850 study participants, including healthy participants and patients with obesity, prior gastrectomy, cancer, pituitary disease, diabetes mellitus, eating disorders, and other conditions. There is strong evidence that ghrelin stimulates appetite and increases circulating GH, ACTH, cortisol, prolactin, and glucose across varied patient populations. There is a paucity of evidence regarding the effects of ghrelin on LH, FSH, TSH, insulin, lipolysis, body composition, cardiac function, pulmonary function, the vasculature, and sleep. Adverse effects occurred in 20% of participants, with a predominance of flushing and gastric rumbles and a mild degree of severity. The few serious adverse events occurred in patients with advanced illness and were not clearly attributable to ghrelin. Route of administration may affect the pattern of adverse effects. Conclusions: Existing literature supports the short-term safety of ghrelin administration and its efficacy as an appetite stimulant in diverse patient populations. There is some evidence to suggest that ghrelin has wider ranging therapeutic effects, although these areas require further investigation. PMID:23533240

  3. Ghrelin and obestatin levels in rheumatoid arthritis.

    Science.gov (United States)

    Koca, Suleyman Serdar; Ozgen, Metin; Aydin, Suleyman; Dag, Sait; Evren, Bahri; Isik, Ahmet

    2008-10-01

    Ghrelin is a powerful, endogenous orexigenic peptide. In addition, ghrelin has anti-inflammatory effects, and it has been reported that ghrelin down-regulates pro-inflammatory cytokines, including interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. Obestatin appears to decrease food intake and appetite, and its potential role in inflammation is not yet clear. The aims of this study were to assess total and acylated (active) ghrelin and obestatin serum levels and their relations with inflammatory status in rheumatoid arthritis (RA) patients. Fasting blood samples were obtained from 37 patients with RA, 29 patients with Behçet's disease (BD) and 28 healthy controls (HC). Total ghrelin and obestatin levels were measured by radioimmunoassay and acylated ghrelin was quantified by enzyme-linked immunosorbent assay. Patients with RA had lower total ghrelin, but higher obestatin levels than patients with BD (pghrelin. Total ghrelin level was not correlated with any study parameters in the all groups. Obestatin level correlated with erythrocyte sedimentation rate and DAS-28 in the RA group, the level of IL-6 in the BD group, and with the level of TNF-alpha in the HC group (r=0.400, pghrelin and clinical or laboratory markers of disease activity in RA. Surprisingly, obestatin correlated with some inflammatory markers. So, obestatin seems to be more valuable than ghrelin in the pathogenesis of RA.

  4. Molecular evolution of a chordate specific family of G protein-coupled receptors

    Directory of Open Access Journals (Sweden)

    Leese Florian

    2011-08-01

    Full Text Available Abstract Background Chordate evolution is a history of innovations that is marked by physical and behavioral specializations, which led to the development of a variety of forms from a single ancestral group. Among other important characteristics, vertebrates obtained a well developed brain, anterior sensory structures, a closed circulatory system and gills or lungs as blood oxygenation systems. The duplication of pre-existing genes had profound evolutionary implications for the developmental complexity in vertebrates, since mutations modifying the function of a duplicated protein can lead to novel functions, improving the evolutionary success. Results We analyzed here the evolution of the GPRC5 family of G protein-coupled receptors by comprehensive similarity searches and found that the receptors are only present in chordates and that the size of the receptor family expanded, likely due to genome duplication events in the early history of vertebrate evolution. We propose that a single GPRC5 receptor coding gene originated in a stem chordate ancestor and gave rise by duplication events to a gene family comprising three receptor types (GPRC5A-C in vertebrates, and a fourth homologue present only in mammals (GPRC5D. Additional duplications of GPRC5B and GPRC5C sequences occurred in teleost fishes. The finding that the expression patterns of the receptors are evolutionarily conserved indicates an important biological function of these receptors. Moreover, we found that expression of GPRC5B is regulated by vitamin A in vivo, confirming previous findings that linked receptor expression to retinoic acid levels in tumor cell lines and strengthening the link between the receptor expression and the development of a complex nervous system in chordates, known to be dependent on retinoic acid signaling. Conclusions GPRC5 receptors, a class of G protein-coupled receptors with unique sequence characteristics, may represent a molecular novelty that helped non

  5. Ghrelin and food reward: the story of potential underlying substrates.

    Science.gov (United States)

    Skibicka, Karolina P; Dickson, Suzanne L

    2011-11-01

    The incidence of obesity is increasing at an alarming rate and this worldwide epidemic represents a significant decrease in life span and quality of life of a large part of the affected population. Therefore an understanding of mechanisms underlying food overconsumption and obesity development is urgent and essential to find potential treatments. Research investigating mechanisms underlying obesity and the control of food intake has recently experienced a major shift in focus, from the brain's hypothalamus to additional important neural circuits controlling emotion, cognition and motivated behavior. Among them, the mesolimbic system, and the changes in reward and motivated behavior for food, emerge as new promising treatment targets. Furthermore, there is also growing appreciation of the impact of peripheral hormones that signal nutrition status to the mesolimbic areas, and especially the only known circulating orexigenic hormone, ghrelin. This review article provides a synthesis of recent evidence concerning the impact of manipulation of ghrelin and its receptor on models of food reward/food motivation behavior and the mesolimbic circuitry. Particular attention is given to the potential neurocircuitry and neurotransmitter systems downstream of ghrelin's effects on food reward. Copyright © 2011. Published by Elsevier Inc.

  6. Anti-ghrelin immunoglobulins modulate ghrelin stability and its orexigenic effect in obese mice and humans

    Science.gov (United States)

    Takagi, Kuniko; Legrand, Romain; Asakawa, Akihiro; Amitani, Haruka; François, Marie; Tennoune, Naouel; Coëffier, Moïse; Claeyssens, Sophie; do Rego, Jean-Claude; Déchelotte, Pierre; Inui, Akio; Fetissov, Sergueï O.

    2013-01-01

    Obese individuals often have increased appetite despite normal plasma levels of the main orexigenic hormone ghrelin. Here we show that ghrelin degradation in the plasma is inhibited by ghrelin-reactive IgG immunoglobulins, which display increased binding affinity to ghrelin in obese patients and mice. Co-administration of ghrelin together with IgG from obese individuals, but not with IgG from anorectic or control patients, increases food intake in rats. Similarly, chronic injections of ghrelin together with IgG from ob/ob mice increase food intake, meal frequency and total lean body mass of mice. These data reveal that in both obese humans and mice, IgG with increased affinity for ghrelin enhances ghrelin’s orexigenic effect, which may contribute to increased appetite and overeating. PMID:24158035

  7. Origins of the many NPY-family receptors in mammals

    DEFF Research Database (Denmark)

    Larhammar, D; Wraith, A; Berglund, M M

    2001-01-01

    The NPY system has a multitude of effects and is particularly well known for its role in appetite regulation. We have found that the five presently known receptors in mammals arose very early in vertebrate evolution before the appearance of jawed vertebrates 400 million years ago. The genes Y(1), Y....... These observations pertain to the discussion whether ligands or receptors tend to appear first in evolution. The roles of Y(1) and Y(5) in feeding may differ between species demonstrating the importance of performing functional studies in additional mammals to mouse and rat....

  8. Ghrelin is involved in the paracrine communication between neurons and glial cells.

    Science.gov (United States)

    Avau, B; De Smet, B; Thijs, T; Geuzens, A; Tack, J; Vanden Berghe, P; Depoortere, I

    2013-09-01

    Ghrelin is the only known peripherally active orexigenic hormone produced by the stomach that activates vagal afferents to stimulate food intake and to accelerate gastric emptying. Vagal sensory neurons within the nodose ganglia are surrounded by glial cells, which are able to receive and transmit chemical signals. We aimed to investigate whether ghrelin activates or influences the interaction between both types of cells. The effect of ghrelin was compared with that of leptin and cholecystokinin (CCK). Cultures of rat nodose ganglia were characterized by immunohistochemistry and the functional effects of peptides, neurotransmitters, and pharmacological blockers were measured by Ca(2+) imaging using Fluo-4-AM as an indicator. Neurons responded to KCl and were immunoreactive for PGP-9.5 whereas glial cells responded to lysophosphatidic acid and had the typical SOX-10-positive nuclear staining. Neurons were only responsive to CCK (31 ± 5%) whereas glial cells responded equally to the applied stimuli: ghrelin (27 ± 2%), leptin (21 ± 2%), and CCK (30 ± 2%). In contrast, neurons stained more intensively for the ghrelin receptor than glial cells. ATP induced [Ca(2+) ]i rises in 90% of the neurons whereas ACh and the NO donor, SIN-1, mainly induced [Ca(2+) ]i changes in glial cells (41 and 51%, respectively). The percentage of ghrelin-responsive glial cells was not affected by pretreatment with suramin, atropine, hexamethonium or 1400 W, but was reduced by l-NAME and by tetrodotoxin. Neurons were shown to be immunoreactive for neuronal NO-synthase (nNOS). Our data show that ghrelin induces Ca(2+) signaling in glial cells of the nodose ganglion via the release of NO originating from the neurons. © 2013 John Wiley & Sons Ltd.

  9. Effects of ghrelin on the apoptosis of human neutrophils in vitro

    Science.gov (United States)

    Li, Bin; Zeng, Mian; Zheng, Haichong; Huang, Chunrong; He, Wanmei; Lu, Guifang; Li, Xia; Chen, Yanzhu; Xie, Ruijie

    2016-01-01

    Acute respiratory distress syndrome (ARDS) is characterized by lung inflammation and the diffuse infiltration of neutrophils into the alveolar space. Neutrophils are abundant, short-lived leukocytes that play a key role in immune defense against microbial infections. These cells die via apoptosis following the activation and uptake of microbes, and will also enter apoptosis spontaneously at the end of their lifespan if they do not encounter pathogens. Apoptosis is essential for the removal of neutrophils from inflamed tissues and for the timely resolution of neutrophilic inflammation. Ghrelin is an endogenous ligand for the growth hormone (GH) secretagogue receptor, produced and secreted mainly from the stomach. Previous studies have reported that ghrelin exerts anti-inflammatory effects in lung injury through the regulation of the apoptosis of different cell types; however, the ability of ghrelin to regulate alveolar neutrophil apoptosis remains largely undefined. We hypothesized that ghrelin may have the ability to modulate neutrophil apoptosis. In this study, to examine this hypothesis, we investigated the effects of ghrelin on freshly isolated neutrophils in vitro. Our findings demonstrated a decrease in the apoptotic ratio (as shown by flow cytometry), as well as in the percentage of cells with decreased mitochondrial membrane potential (ΔΨm) and in the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling-positive rate, accompanied by an increased B-cell lymphoma 2/Bax ratio and the downregulation of cleaved caspase-3 in neutrophils following exposure to lipopolysaccharide (100 ng/ml). However, pre-treatment with ghrelin at a physiological level (100 nM) did not have a notable influence on the neutrophils in all the aforementioned tests. Our findings suggest that ghrelin may not possess the ability to modulate the neutrophil lifespan in vitro. PMID:27431014

  10. Genetic diversity of bitter taste receptor gene family in Sichuan ...

    Indian Academy of Sciences (India)

    Previous research had revealed that chicken has only three bitter taste receptor genes (Tas2r1, ... Journal of Genetics, DOI 10.1007/s12041-016-0684-4, Vol. ..... between red-winged blackbirds and European starlings. ... Academic Press,.

  11. Multiple kisspeptin receptors in early Osteichthyans provide new insights into the evolution of this receptor family

    DEFF Research Database (Denmark)

    Pasquier, J.; Lafont, A._G.; Jeng, S.-R.

    2012-01-01

    Deorphanization of GPR54 receptor a decade ago led to the characterization of the kisspeptin receptor (Kissr) in mammals and the discovery of its major role in the brain control of reproduction. While a single gene encodes for Kissr in eutherian mammals including human, other vertebrates present ...

  12. Ghrelin increases intracellular Ca²⁺ concentration in the various hormone-producing cell types of the rat pituitary gland.

    Science.gov (United States)

    Yamazaki, Mami; Aizawa, Sayaka; Tanaka, Toru; Sakai, Takafumi; Sakata, Ichiro

    2012-09-20

    Ghrelin, isolated from the stomach as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), has potent growth hormone release ability in vivo and in vitro. Although GHS-R is abundantly expressed in the pituitary gland, there is no direct evidence of a relationship between hormone-producing cells and functional GHS-R in the pituitary gland. The aim of this study was to determine which anterior pituitary cells respond to ghrelin stimulation in male rats. We performed Fura-2 Ca(2+) imaging analysis using isolated pituitary cells, and performed immunocytochemistry to identify the type of pituitary hormone-producing cells. In Fura-2 Ca(2+) imaging analysis, ghrelin administration increased the intracellular Ca(2+) concentration in approximately 50% of total isolated anterior pituitary cells, and 20% of these cells strongly responded to ghrelin. Immunocytochemical analysis revealed that 82.9 ± 1.3% of cells that responded to ghrelin stimulation were GH-immunopositive. On the other hand, PRL-, LH-, and ACTH-immunopositive cells constituted 2.0 ± 0.3%, 12.6 ± 0.3%, and 2.5 ± 0.8% of ghrelin-responding pituitary cells, respectively. TSH-immunopositive cells did not respond to ghrelin treatment. These results suggest that ghrelin directly acts not only on somatotrophs, but also on mammotrophs, gonadotrophs, and corticotrophs in the rat pituitary gland. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  13. Unraveling the role of the ghrelin gene peptides in the endocrine pancreas.

    Science.gov (United States)

    Granata, Riccarda; Baragli, Alessandra; Settanni, Fabio; Scarlatti, Francesca; Ghigo, Ezio

    2010-09-01

    The ghrelin gene peptides include acylated ghrelin (AG), unacylated ghrelin (UAG), and obestatin (Ob). AG, mainly produced by the stomach, exerts its central and peripheral effects through the GH secretagogue receptor type 1a (GHS-R1a). UAG, although devoid of GHS-R1a-binding affinity, is an active peptide, sharing with AG many effects through an unknown receptor. Ob was discovered as the G-protein-coupled receptor 39 (GPR39) ligand; however, its physiological actions remain unclear. The endocrine pancreas is necessary for glucose homeostasis maintenance. AG, UAG, and Ob are expressed in both human and rodent pancreatic islets from fetal to adult life, and the pancreas is the major source of ghrelin in the perinatal period. GHS-R1a and GPR39 expression has been shown in beta-cells and islets, as well as specific binding sites for AG, UAG, and Ob. Ghrelin colocalizes with glucagon in alpha-islet cells, but is also uniquely expressed in epsilon-islet cells, suggesting a role in islet function and development. Indeed, AG, UAG, and Ob regulate insulin secretion in beta-cells and isolated islets, promote beta-cell proliferation and survival, inhibit beta-cell and human islet cell apoptosis, and modulate the expression of genes that are essential in pancreatic islet cell biology. They even induce beta-cell regeneration and prevent diabetes in streptozotocin-treated neonatal rats. The receptor(s) mediating their effects are not fully characterized, and a signaling crosstalk has been suggested. The present review summarizes the newest findings on AG, UAG, and Ob expression in pancreatic islets and the role of these peptides on beta-cell development, survival, and function.

  14. Modulation of neuronal network activity with ghrelin

    NARCIS (Netherlands)

    Stoyanova, Irina; Rutten, Wim; le Feber, Jakob

    2012-01-01

    Ghrelin is a neuropeptide regulating multiple physiological processes, including high brain functions such as learning and memory formation. However, the effect of ghrelin on network activity patterns and developments has not been studied yet. Therefore, we used dissociated cortical neurons plated

  15. ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5.

    Science.gov (United States)

    Hsu, H; Solovyev, I; Colombero, A; Elliott, R; Kelley, M; Boyle, W J

    1997-05-23

    Members of tumor necrosis factor receptor (TNFR) family signal largely through interactions with death domain proteins and TRAF proteins. Here we report the identification of a novel TNFR family member ATAR. Human and mouse ATAR contain 283 and 276 amino acids, respectively, making them the shortest known members of the TNFR superfamily. The receptor is expressed mainly in spleen, thymus, bone marrow, lung, and small intestine. The intracellular domains of human and mouse ATAR share only 25% identity, yet both interact with TRAF5 and TRAF2. This TRAF interaction domain resides at the C-terminal 20 amino acids. Like most other TRAF-interacting receptors, overexpression of ATAR activates the transcription factor NF-kappaB. Co-expression of ATAR with TRAF5, but not TRAF2, results in synergistic activation of NF-kappaB, suggesting potentially different roles for TRAF2 and TRAF5 in post-receptor signaling.

  16. Ghrelin signalling on food reward: a salient link between the gut and the mesolimbic system.

    Science.gov (United States)

    Perello, M; Dickson, S L

    2015-06-01

    'Hunger is the best spice' is an old and wise saying that acknowledges the fact that almost any food tastes better when we are hungry. The neurobiological underpinnings of this lore include activation of the brain's reward system and the stimulation of this system by the hunger-promoting hormone ghrelin. Ghrelin is produced largely from the stomach and levels are higher preprandially. The ghrelin receptor is expressed in many brain areas important for feeding control, including not only the hypothalamic nuclei involved in energy balance regulation, but also reward-linked areas such as the ventral tegmental area. By targeting the mesoaccumbal dopamine neurones of the ventral tegmental area, ghrelin recruits pathways important for food reward-related behaviours that show overlap with but are also distinct from those important for food intake. We review a variety of studies that support the notion that ghrelin signalling at the level of the mesolimbic system is one of the key molecular substrates that provides a physiological signal connecting gut and reward pathways. © 2014 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.

  17. Genetic variants of ghrelin in metabolic disorders.

    Science.gov (United States)

    Ukkola, Olavi

    2011-11-01

    An increasing understanding of the role of genes in the development of obesity may reveal genetic variants that, in combination with conventional risk factors, may help to predict an individual's risk for developing metabolic disorders. Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis and it is a reasonable candidate gene for obesity-related co-morbidities. In cross-sectional studies low total ghrelin concentrations and some genetic polymorphisms of ghrelin have been associated with obesity-associated diseases. The present review highlights many of the important problems in association studies of genetic variants and complex diseases. It is known that population-specific differences in reported associations exist. We therefore conclude that more studies on variants of ghrelin gene are needed to perform in different populations to get deeper understanding on the relationship of ghrelin gene and its variants to obesity. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. The under-appreciated promiscuity of the epidermal growth factor receptor family.

    Directory of Open Access Journals (Sweden)

    Sean P Kennedy

    2016-08-01

    Full Text Available Each member of the epidermal growth factor receptor (EGFR family plays a key role in normal development, homeostasis and a variety of pathophysiological conditions, most notably in cancer. According to the prevailing dogma, these four receptor tyrosine kinases (RTKs; EGFR, ERBB2, ERBB3 and ERBB4 function exclusively through the formation of homodimers and heterodimers within the EGFR family. These combinatorial receptor interactions are known to generate increased interactome diversity and therefore influence signalling output, subcellular localization and function of the heterodimer. This molecular plasticity is also thought to play a role in the development of resistance towards targeted cancer therapies aimed at these known oncogenes. Interestingly, many studies now challenge this dogma and suggest that the potential for EGFR family receptors to interact with more distantly related RTKs is much greater than currently appreciated. Here we discuss how the promiscuity of these oncogenic receptors may lead to the formation of many unexpected receptor pairings and the significant implications for the efficiency of many targeted cancer therapies.

  19. Plasma ghrelin levels and polymorphisms of ghrelin gene in Chinese obese children and adolescents.

    Science.gov (United States)

    Zhu, J F; Liang, L; Zou, C C; Fu, J F

    2010-09-01

    To evaluate the role of fasting plasma ghrelin levels [ln(ghrelin)] and polymorphisms of ghrelin gene in Chinese obese children. Genotyping for ghrelin polymorphism was performed in 230 obese and 100 normal weight children. Among them, plasma ghrelin levels were measured in 91 obese and 23 health subjects. (1) Bivariate correlation analysis showed the ln(ghrelin) was inversely correlated with abnormality of glucose metabolism (r = -0.240, P = 0.023). Stepwise multiple regression analysis showed that abnormality of glucose metabolism was an independent determinant of plasma ghrelin levels (P = 0.023). (2) There was no difference in frequency of Leu72Met polymorphisms between obese and control groups (36.09 vs. 41.00%). Ghrelin is associated with obesity in childhood, especially associated with the glucose homeostasis. Lower ghrelin levels might be a result of obesity, but not a cause of obesity. The Leu72Met polymorphism of ghrelin gene is not associated with obesity and metabolic syndrome in Chinese children.

  20. Familial Risk for Major Depression is Associated with Lower Striatal 5-HT4 Receptor Binding

    DEFF Research Database (Denmark)

    Madsen, Karine; Torstensen, Eva; Holst, Klaus K

    2014-01-01

    was to determine whether familial risk for MDD is associated with cerebral 5-HT4 receptor binding as measured with [(11)C]SB207145 brain PET imaging. Familial risk is the most potent risk factor of MDD. METHODS: We studied 57 healthy individuals (mean age 36 yrs, range 20-86; 21 women), 26 of which had first......-degree relatives treated for MDD. RESULTS: We found that having a family history of MDD was associated with lower striatal 5-HT4 receptor binding (p = 0.038; in individuals below 40 years, p = 0.013). Further, we found evidence for a "risk-dose effect" on 5-HT4 receptor binding, since the number of first......-degree relatives with a history of MDD binding correlated negatively with 5-HT4 receptor binding in both the striatum (p = 0.001) and limbic regions (p = 0.012). CONCLUSIONS: Our data suggest that the 5-HT4 receptor is involved in the neurobiological mechanism underlying familial risk for depression...

  1. Ligand Activation of TAM Family Receptors-Implications for Tumor Biology and Therapeutic Response.

    Science.gov (United States)

    Davra, Viralkumar; Kimani, Stanley G; Calianese, David; Birge, Raymond B

    2016-11-29

    The TAM family of receptors (i.e., Tyro3, Axl, and Mertk), and their ligands Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) contribute to several oncogenic processes, such as cell survival, invasion, migration, chemo-resistance, and metastasis, whereby expression often correlates with poor clinical outcomes. In recent years, there has been great interest in the study of TAM receptors in cancer, stemming both from their roles as oncogenic signaling receptors, as well as their roles in tumor immunology. As a result, several classes of TAM inhibitors that include small molecule tyrosine kinase inhibitors, monoclonal antibodies, decoy receptors, as well as novel strategies to target TAM ligands are being developed. This paper will review the biology of TAM receptors and their ligands with a focus on cancer, as well as evidence-based data for the continued pursuit of TAM/Gas6 inhibitors in clinical practice.

  2. MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family

    OpenAIRE

    Chan, Li F.; Webb, Tom R.; Chung, Teng-Teng; Meimaridou, Eirini; Cooray, Sadani N.; Guasti, Leonardo; Chapple, J. Paul; Egertová, Michaela; Elphick, Maurice R.; Cheetham, Michael E.; Metherell, Louise A.; Clark, Adrian J. L.

    2009-01-01

    The melanocortin receptor (MCR) family consists of 5 G protein-coupled receptors (MC1R–MC5R) with diverse physiologic roles. MC2R is a critical component of the hypothalamic–pituitary–adrenal axis, whereas MC3R and MC4R have an essential role in energy homeostasis. Mutations in MC4R are the single most common cause of monogenic obesity. Investigating the way in which these receptors signal and traffic to the cell membrane is vital in understanding disease processes related to MCR dysfunction....

  3. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding

    International Nuclear Information System (INIS)

    Innerarity, T.L.; Weisgraber, K.H.; Arnold, K.S.; Mahley, R.W.; Krauss, R.M.; Vega, G.L.; Grundy, S.M.

    1987-01-01

    Previous in vivo turnover studies suggested that retarded clearance of low density lipoproteins (LDL) from the plasma of some hypercholesterolemic patients is due to LDL with defective receptor binding. The present study examined this postulate directly by receptor binding experiments. The LDL from a hypercholesterolemic patient (G.R.) displayed a reduced ability to bind to the LDL receptors on normal human fibroblasts. The G.R. LDL possessed 32% of normal receptor binding activity. Likewise, the G.R. LDL were much less effective than normal LDL in competing with 125 I-labeled normal LDL for cellular uptake and degradation and in stimulating intracellular cholesteryl ester synthesis. The defect in LDL binding appears to be due to a genetic abnormality of apolipoprotein B-100: two brothers of the proband possess LDL defective in receptor binding, whereas a third brother and the proband's son have normally binding LDL. Further, the defect in receptor binding does not appear to be associated wit an abnormal lipid composition or structure of the LDL. Normal and abnormal LDL subpopulations were partially separated from plasma of two subjects by density-gradient ultracentrifugation, a finding consistent with the presence of a normal and a mutant allele. The affected family members appear to be heterozygous for this disorder, which has been designated familial defective apolipoprotein B-100. These studies indicate that the defective receptor binding results in inefficient clearance of LDL and the hypercholesterolemia observed in these patients

  4. The effect of intravenous injection of Ghrelin on the mean plasma concentrations of insulin in immature camels fed different levels of their energy requirements

    Directory of Open Access Journals (Sweden)

    2009-11-01

    Ghrelin is a peptide hormone secreted into the circulation from the stomach, but this peptide is also synthetized in a number of different body tissues including the brain and pancreas, suggesting both endocrine and paracrine effects. These include: stimulation of GH and ACTH secretion, an increase in appetite and diabetogenic effect on carbohydrate metabolism. Furthermore, ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R. Ghrelin and its mRNAas well as GH secretagogue receptor mRNAs are expressed in the pancreas and islet cells and regulates insulin release and glucose metabolism, but because the effect of ghrelin on insulin secretion before puberty in semiruminant animals has never been examined,   therefore the purpose of the present research was to determine the effect of ghrelin on insulin secretion before puberty in camels. In this investigation 12 camels were randomly divided into two groups. Animals in each group were fed either 50% and 100% energy content in diet for 2 weeks. After 2 weeks camels received 8 μg ghrelin/kg body weight via their jugular vein for 4 days. Blood samples were collected from the jugular vein of all animals before, during (30 minutes after injection of ghrelin and after the intervention for 4 continuous days and plasma insulin concentrations determined by RIA. Data obtained were analyzed by repeated measures –ANOVA and paired t-Test. p

  5. Neuro-psychopharmacological perspective of Orphan receptors of Rhodopsin (class A) family of G protein-coupled receptors.

    Science.gov (United States)

    Khan, Muhammad Zahid; He, Ling

    2017-04-01

    In the central nervous system (CNS), G protein-coupled receptors (GPCRs) are the most fruitful targets for neuropsychopharmacological drug development. Rhodopsin (class A) is the most studied class of GPCR and includes orphan receptors for which the endogenous ligand is not known or is unclear. Characterization of orphan GPCRs has proven to be challenging, and the production pace of GPCR-based drugs has been incredibly slow. Determination of the functions of these receptors may provide unexpected insight into physiological and neuropathological processes. Advances in various methods and techniques to investigate orphan receptors including in situ hybridization and knockdown/knockout (KD/KO) showed extensive expression of these receptors in the mammalian brain and unmasked their physiological and neuropathological roles. Due to these rapid progress and development, orphan GPCRs are rising as a new and promising class of drug targets for neurodegenerative diseases and psychiatric disorders. This review presents a neuropsychopharmacological perspective of 26 orphan receptors of rhodopsin (class A) family, namely GPR3, GPR6, GPR12, GPR17, GPR26, GPR35, GPR39, GPR48, GPR49, GPR50, GPR52, GPR55, GPR61, GPR62, GPR63, GPR68, GPR75, GPR78, GPR83, GPR84, GPR85, GPR88, GPR153, GPR162, GPR171, and TAAR6. We discussed the expression of these receptors in mammalian brain and their physiological roles. Furthermore, we have briefly highlighted their roles in neurodegenerative diseases and psychiatric disorders including Alzheimer's disease, Parkinson's disease, neuroinflammation, inflammatory pain, bipolar and schizophrenic disorders, epilepsy, anxiety, and depression.

  6. The nuclear receptor gene family in the Pacific oyster, Crassostrea gigas, contains a novel subfamily group.

    Science.gov (United States)

    Vogeler, Susanne; Galloway, Tamara S; Lyons, Brett P; Bean, Tim P

    2014-05-15

    Nuclear receptors are a superfamily of transcription factors important in key biological, developmental and reproductive processes. Several of these receptors are ligand- activated and through their ability to bind endogenous and exogenous ligands, are potentially vulnerable to xenobiotics. Molluscs are key ecological species in defining aquatic and terrestrial habitats and are sensitive to xenobiotic compounds in the environment. However, the understanding of nuclear receptor presence, function and xenobiotic disruption in the phylum Mollusca is limited. Here, forty-three nuclear receptor sequences were mined from the genome of the Pacific oyster, Crassostrea gigas. They include members of NR0-NR5 subfamilies, notably lacking any NR6 members. Phylogenetic analyses of the oyster nuclear receptors have been conducted showing the presence of a large novel subfamily group not previously reported, which is named NR1P. Homologues to all previous identified nuclear receptors in other mollusc species have also been determined including the putative heterodimer partner retinoid X receptor, estrogen receptor and estrogen related receptor. C. gigas contains a highly diverse set of nuclear receptors including a novel NR1 group, which provides important information on presence and evolution of this transcription factor superfamily in invertebrates. The Pacific oyster possesses two members of NR3, the sex steroid hormone receptor analogues, of which there are 9 in humans. This provides increasing evidence that steroid ligand specific expansion of this family is deuterostome specific. This new knowledge on divergence and emergence of nuclear receptors in C. gigas provides essential information for studying regulation of molluscan gene expression and the potential effects of xenobiotics.

  7. Nutritional State-Dependent Ghrelin Activation of Vasopressin Neurons via Retrograde Trans-Neuronal–Glial Stimulation of Excitatory GABA Circuits

    Science.gov (United States)

    Haam, Juhee; Halmos, Katalin C.; Di, Shi

    2014-01-01

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal–glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal–glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal–glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis. PMID:24790191

  8. Ghrelin and GHS-R1A signaling within the ventral and laterodorsal tegmental area regulate sexual behavior in sexually naïve male mice.

    Science.gov (United States)

    Prieto-Garcia, Luna; Egecioglu, Emil; Studer, Erik; Westberg, Lars; Jerlhag, Elisabet

    2015-12-01

    In addition to food intake and energy balance regulation, ghrelin mediate the rewarding and motivational properties of palatable food as well as addictive drugs. The ability of ghrelin to regulate reinforcement involves the cholinergic-dopaminergic reward link, which encompasses a cholinergic projection from the laterodorsal tegmental area (LDTg) to the ventral tegmental area (VTA) together with mesolimbic dopaminergic projections from the VTA to the nucleus accumbens (NAc). Recently, systemic ghrelin was shown to regulate sexual behavior and motivation in male mice via dopamine neurotransmission. The present study therefore elucidates the role of ghrelin and ghrelin receptor (GHS-R1A) antagonist treatment within NAc, VTA or LDTg for sexual behavior in sexually naïve male mice. Local administration of the GHSR-1A antagonist, JMV2959, into the VTA or LDTg was found to reduce the preference for female mice, the number of mounts and the duration of mounting as well as to prolong the latency to mount. This was further substantiated by the findings that ghrelin administration into the VTA or LDTg increased the number of mounts and the duration of mounting and decreased the latency to mount. Moreover, ghrelin administered into the LDTg increased the preference for female mice. Accumbal administration of ghrelin increased whereas GHS-R1A antagonist decreased the intake of palatable food, but did not alter sexual behavior. In males exposed to sexual interaction, systemic administration of ghrelin increases whereas JMV2959 decreases the turnover of dopamine in the VTA. These data suggest that ghrelin signaling within the tegmental areas is required for sexual behavior in sexually naïve male mice. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Effects of peripherally and centrally applied ghrelin on the oxidative stress induced by renin angiotensin system in a rat model of renovascular hypertension.

    Science.gov (United States)

    Boshra, Vivian; Abbas, Amr M

    2017-07-26

    Renovascular hypertension (RVH) is a result of renal artery stenosis, which is commonly due to astherosclerosis. In this study, we aimed to clarify the central and peripheral effects of ghrelin on the renin-angiotensin system (RAS) in a rat model of RVH. RVH was induced in rats by partial subdiaphragmatic aortic constriction. Experiment A was designed to assess the central effect of ghrelin via the intracerebroventricular (ICV) injection of ghrelin (5 μg/kg) or losartan (0.01 mg/kg) in RVH rats. Experiment B was designed to assess the peripheral effect of ghrelin via the subcutaneous (SC) injection of ghrelin (150 μg/kg) or losartan (10 mg/kg) for 7 consecutive days. Mean arterial blood pressure (MAP), heart rate, plasma renin activity (PRA), and oxidative stress markers were measured in all rats. In addition, angiotensin II receptor type 1 (AT1R) concentration was measured in the hypothalamus of rats in Experiment B. RVH significantly increased brain AT1R, PRA, as well as the brain and plasma oxidative stress. Either SC or ICV ghrelin or losartan caused a significant decrease in MAP with no change in the heart rate. Central ghrelin or losartan caused a significant decrease in brain AT1R with significant alleviation of the brain oxidative stress. Central ghrelin caused a significant decrease in PRA, whereas central losartan caused a significant increase in PRA. SC ghrelin significantly decreased PRA and plasma oxidative stress, whereas SC losartan significantly increased PRA and decreased plasma oxidative stress. The hypotensive effect of ghrelin is mediated through the amelioration of oxidative stress, which is induced by RAS centrally and peripherally.

  10. Long-acting octreotide treatment causes a sustained decrease in ghrelin concentrations but does not affect weight, behaviour and appetite in subjects with Prader-Willi syndrome.

    Science.gov (United States)

    De Waele, Kathleen; Ishkanian, Stacey L; Bogarin, Roberto; Miranda, Charmaine A; Ghatei, Mohammad A; Bloom, Stephen R; Pacaud, Danièle; Chanoine, Jean-Pierre

    2008-10-01

    Ghrelin is secreted primarily by the stomach and circulates as both acylated and desacyl ghrelin. Acylated (but not desacyl) ghrelin stimulates appetite. Both concentrations are elevated in Prader-Willi syndrome (PWS), suggesting that ghrelin may contribute to hyperphagia and overweight in these subjects. We evaluated whether long-acting octreotide (Oct) decreases acylated and desacyl ghrelin concentrations, body mass, appetite and compulsive behaviour towards food in adolescents with PWS. A 56-week prospective, randomized, cross-over trial. Nine subjects with PWS (age 14.6 (10.8-18.9) years, body mass index (BMI) Z-score +1.9 (0.6-3.0)) received either Oct (30 mg) or saline i.m. every 4 weeks for 16 weeks and were switched over to the other treatment after a 24-week washout period. Eight subjects completed the study. Oct caused a decrease in both acylated (-53%) and desacyl (-54%) fasting ghrelin concentrations (P<0.05) but did not significantly affect BMI. Oct had no significant effect on peptide YY concentrations, appetite or compulsive behaviour towards food. Oct caused a decrease in insulin-like growth factor-I concentrations, an increase in HbA1c and transient elevation of blood glucose in two subjects. Three subjects developed gallstones. Oct treatment caused a prolonged decrease in ghrelin concentrations in adolescents with PWS but did not improve body mass or appetite. Future intervention studies aiming at clarifying the role of ghrelin in PWS should focus on the administration of specific inhibitors of ghrelin secretion or ghrelin receptor activity that do not interfere with other appetite-regulating peptides.

  11. Ghrelin-induced hippocampal neurogenesis and enhancement of cognitive function are mediated independently of GH/IGF-1 axis: lessons from the spontaneous dwarf rats.

    Science.gov (United States)

    Li, Endan; Kim, Yumi; Kim, Sehee; Park, Seungjoon

    2013-01-01

    We recently have reported that ghrelin modulates adult hippocampal neurogenesis. However, there is a possibility that the action of ghrelin on hippocampal neurogenesis could be, in part, due to the ability of ghrelin to stimulate the GH/insulin-like growth factor (IGF)-1 axis, where both GH and IGF-1 infusions are known to increase hippocampal neurogenesis. To explore this possibility, we assessed the impact of ghrelin on progenitor cell proliferation and differentiation in the dentate gyrus (DG) of spontaneous dwarf rats (SDRs), a dwarf strain with a mutation of the GH gene resulting in total loss of GH. Double immunohistochemical staining revealed that Ki-67-positive progenitor cells and doublecortin (DCX)-positive neuroblasts in the DG of the SDRs expressed ghrelin receptors. We found that ghrelin treatment in the SDRs significantly increased the number of proliferating cell nuclear antigen- and BrdU-labeled cells in the DG. The number of DCX-labeled cells in the DG of ghrelin-treated SDRs was also significantly increased compared with the vehicle-treated controls. To test whether ghrelin has a direct effect on cognitive performance independently of somatotropic axis, hippocampus-dependent learning and memory were assessed using the Y-maze and novel object recognition (NOR) test in the SDRs. Ghrelin treatment for 4 weeks by subcutaneous osmotic pump significantly increased alternation rates in the Y-maze and exploration time for novel object in the NOR test compared to vehicle-treated controls. Our results indicate that ghrelin-induced adult hippocampal neurogenesis and enhancement of cognitive function are mediated independently of somatotropic axis.

  12. Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor

    DEFF Research Database (Denmark)

    Wellendorph, Petrine; Bräuner-Osborne, Hans

    2004-01-01

    with a significant homology to the human calcium-sensing receptor (CaR, 34% aa sequence identity), the taste receptor 1 (T1R1, 28%), and the metabotropic glutamate receptor 1 (mGluR1, 24%), places GPRC6A in family C of the GPCRs. Interestingly, GPRC6A bears the highest resemblance with an odorant goldfish 5...

  13. Ghrelin in the pilosebaceous unit: alteration of ghrelin in patients with acne vulgaris.

    Science.gov (United States)

    Cicek, Demet; Demir, Betul; Erder, Ilker; Kuloglu, Tuncay; Ucer, Ozlem; Aydin, Suleyman; Ucak, Haydar; Dertlioglu, Selma; Kalayci, Mehmet

    2015-01-01

    Ghrelin in the pilosebaceous tissues of human skin and ghrelin levels in patients with acne vulgaris have not yet been investigated. The purpose of this study was to screen ghrelin immunoreactivity by immunohistochemistry in human pilosebaceous tissues of human skin and also to determine the quantities of ghrelin in the serum of the patients with acne vulgaris. 30 patients presenting with acne vulgaris and 30 control subjects participated in this study. Ghrelin levels were determined by enzyme linked immunosorbent assay (ELISA). Human hair follicles and sebaceous glands were immunohistochemically examined. Immunohistochemistry results showed that there is a strong ghrelin immunoreactivity in the hair follicles and sebaceous glands in sections of human skin. The mean serum ghrelin levels (27.58 ・} 15.44 pg/mL) in patients with acne vulgaris was significantly lower than those of controls (35.62・}20.46 pg/mL). Ghrelin produced in hair follicles and sebaceous glands of the skin might participate in the pathogenesis of acne vulgaris and also acne vulgaris in humans might be associated with decreased serum ghrelin.

  14. Ghrelin plasma levels, gastric ghrelin cell density and bone mineral density in women with rheumatoid arthritis.

    Science.gov (United States)

    Maksud, F A N; Kakehasi, A M; Guimarães, M F B R; Machado, C J; Barbosa, A J A

    2017-05-18

    Generalized bone loss can be considered an extra-articular manifestation of rheumatoid arthritis (RA) that may lead to the occurrence of fractures, resulting in decreased quality of life and increased healthcare costs. The peptide ghrelin has demonstrated to positively affect osteoblasts in vitro and has anti-inflammatory actions, but the studies that correlate ghrelin plasma levels and RA have contradictory results. We aimed to evaluate the correlation between total ghrelin plasma levels, density of ghrelin-immunoreactive cells in the gastric mucosa, and bone mineral density (BMD) in twenty adult women with established RA with 6 months or more of symptoms (mean age of 52.70±11.40 years). Patients with RA presented higher ghrelin-immunoreactive cells density in gastric mucosa (P=0.008) compared with healthy females. There was a positive relationship between femoral neck BMD and gastric ghrelin cell density (P=0.007). However, these same patients presented a negative correlation between plasma ghrelin levels and total femoral BMD (P=0.03). The present results indicate that ghrelin may be involved in bone metabolism of patients with RA. However, the higher density of ghrelin-producing cells in the gastric mucosa of these patients does not seem to induce a corresponding elevation in the plasma levels of this peptide.

  15. Ghrelin plasma levels, gastric ghrelin cell density and bone mineral density in women with rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    F.A.N. Maksud

    Full Text Available Generalized bone loss can be considered an extra-articular manifestation of rheumatoid arthritis (RA that may lead to the occurrence of fractures, resulting in decreased quality of life and increased healthcare costs. The peptide ghrelin has demonstrated to positively affect osteoblasts in vitro and has anti-inflammatory actions, but the studies that correlate ghrelin plasma levels and RA have contradictory results. We aimed to evaluate the correlation between total ghrelin plasma levels, density of ghrelin-immunoreactive cells in the gastric mucosa, and bone mineral density (BMD in twenty adult women with established RA with 6 months or more of symptoms (mean age of 52.70±11.40 years. Patients with RA presented higher ghrelin-immunoreactive cells density in gastric mucosa (P=0.008 compared with healthy females. There was a positive relationship between femoral neck BMD and gastric ghrelin cell density (P=0.007. However, these same patients presented a negative correlation between plasma ghrelin levels and total femoral BMD (P=0.03. The present results indicate that ghrelin may be involved in bone metabolism of patients with RA. However, the higher density of ghrelin-producing cells in the gastric mucosa of these patients does not seem to induce a corresponding elevation in the plasma levels of this peptide.

  16. Mapping and polymorphism of bovine ghreline gene

    OpenAIRE

    Colinet, Frédéric; Eggen, André; Halleux, Caroline; Arnould, Valérie; Portetelle, Daniel; Renaville, Robert

    2006-01-01

    Bovine ghrelin, a 27-amino-acid peptide has been identified in bovine oxyntic glands of the abomasum. It is an endogenous growth hormone secretagogue. Total mRNA was extracted from abomasum and complete ghrelin mRNA was sequenced by rapid amplification of cDNA ends. The gene contains five exons and four introns with a short noncoding first exon of 17 bp similar to mouse and human ghrelin gene. Using a radiation hybrid panel, the gene was mapped to chromosome 22 near microsat...

  17. Ghrelin fibers from lateral hypothalamus project to nucleus tractus solitaries and are involved in gastric motility regulation in cisplatin-treated rats.

    Science.gov (United States)

    Gong, Yanling; Liu, Yang; Liu, Fei; Wang, Shasha; Jin, Hong; Guo, Feifei; Xu, Luo

    2017-03-15

    Ghrelin can alleviate cancer chemotherapy-induced dyspepsia in rodents, though the neural mechanisms involved are not known. Therefore, ghrelin projections from the lateral hypothalamus (LH) and its involvement in the regulation of gastric motility in cisplatin-treated rats were investigated with a multi-disciplined approach. Retrograde tracing combined with fluoro-immunohistochemical staining were used to investigate ghrelin fiber projections arising from LH and projecting to nucleus tractus solitaries (NTS). Results revealed that ghrelin fibers originating in LH project to NTS. Expression of ghrelin and its receptor growth hormone secretagogue receptor (GHS-R1a) in LH and NTS were detected by Western Blot. 2days after cisplatin dosing, expression of ghrelin in LH decreased while GHS-R1a in both LH and NTS increased. In electrophysiological experiments, the effects of N-methyl-d-aspartate (NMDA) microinjection in LH on neuronal discharge of gastric distension-responsive neurons in NTS and gastric motility were assessed. NMDA in LH excited most of ghrelin-responsive gastric distension (GD)-sensitive neurons in NTS and promoted gastric motility. This effect was partially blocked by ghrelin antibody in NTS. Furthermore, the excitatory effects of NMDA in cisplatin-treated rats were weaker than those in saline-treated rats. Behaviorally, cisplatin induced a significant increase of kaolin consumption and decrease of food intake. These studies reveal a decreased expression of ghrelin in LH and up-regulation of GHS-R1a in LH and NTS, which are involved in the regulation of GD neuronal discharge in NTS and gastric motility. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH neurons in an estrous cycle and endocannabinoid signaling dependent manner.

    Directory of Open Access Journals (Sweden)

    Imre Farkas

    Full Text Available The orexigenic peptide, ghrelin is known to influence function of GnRH neurons, however, the direct effects of the hormone upon these neurons have not been explored, yet. The present study was undertaken to reveal expression of growth hormone secretagogue receptor (GHS-R in GnRH neurons and elucidate the mechanisms of ghrelin actions upon them. Ca(2+-imaging revealed a ghrelin-triggered increase of the Ca(2+-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHS-R-antagonist JMV2959 (10 µM suggesting direct action of ghrelin. Estradiol (1nM eliminated the ghrelin-evoked rise of Ca(2+-content, indicating the estradiol dependency of the process. Expression of GHS-R mRNA was then confirmed in GnRH-GFP neurons of transgenic mice by single cell RT-PCR. Firing rate and burst frequency of GnRH-GFP neurons were lower in metestrous than proestrous mice. Ghrelin (40 nM-4 μM administration resulted in a decreased firing rate and burst frequency of GnRH neurons in metestrous, but not in proestrous mice. Ghrelin also decreased the firing rate of GnRH neurons in males. The ghrelin-evoked alterations of the firing parameters were prevented by JMV2959, supporting the receptor-specific actions of ghrelin on GnRH neurons. In metestrous mice, ghrelin decreased the frequency of GABAergic mPSCs in GnRH neurons. Effects of ghrelin were abolished by the cannabinoid receptor type-1 (CB1 antagonist AM251 (1µM and the intracellularly applied DAG-lipase inhibitor THL (10 µM, indicating the involvement of retrograde endocannabinoid signaling. These findings demonstrate that ghrelin exerts direct regulatory effects on GnRH neurons via GHS-R, and modulates the firing of GnRH neurons in an ovarian-cycle and endocannabinoid dependent manner.

  19. CRDB: database of chemosensory receptor gene families in vertebrate.

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    Dong Dong

    Full Text Available Chemosensory receptors (CR are crucial for animals to sense the environmental changes and survive on earth. The emergence of whole-genome sequences provides us an opportunity to identify the entire CR gene repertoires. To completely gain more insight into the evolution of CR genes in vertebrates, we identified the nearly all CR genes in 25 vertebrates using homology-based approaches. Among these CR gene repertoires, nearly half of them were identified for the first time in those previously uncharacterized species, such as the guinea pig, giant panda and elephant, etc. Consistent with previous findings, we found that the numbers of CR genes vary extensively among different species, suggesting an extreme form of 'birth-and-death' evolution. For the purpose of facilitating CR gene analysis, we constructed a database with the goals to provide a resource for CR genes annotation and a web tool for exploring their evolutionary patterns. Besides a search engine for the gene extraction from a specific chromosome region, an easy-to-use phylogenetic analysis tool was also provided to facilitate online phylogeny study of CR genes. Our work can provide a rigorous platform for further study on the evolution of CR genes in vertebrates.

  20. Proghrelin peptides: Desacyl ghrelin is a powerful inhibitor of acylated ghrelin, likely to impair physiological effects of acyl ghrelin but not of obestatin A study of pancreatic polypeptide secretion from mouse islets

    DEFF Research Database (Denmark)

    Kumar, Rajesh; Salehi, Albert; Rehfeld, Jens F

    2010-01-01

    Proghrelin, produced by the ghrelin (A-like) cells of the gastric mucosa, gives rise to cleavage products, including desacyl ghrelin, acyl ghrelin and obestatin. The products are thought to be secreted concomitantly. In an earlier study we found acyl ghrelin and obestatin, but not desacyl ghrelin......, to suppress the release of hormones from isolated islets of mouse and rat pancreas....

  1. Proghrelin peptides: Desacyl ghrelin is a powerful inhibitor of acylated ghrelin, likely to impair physiological effects of acyl ghrelin but not of obestatin A study of pancreatic polypeptide secretion from mouse islets

    DEFF Research Database (Denmark)

    Kumar, Rajesh; Salehi, Albert; Rehfeld, Jens F

    2010-01-01

    Proghrelin, produced by the ghrelin (A-like) cells of the gastric mucosa, gives rise to cleavage products, including desacyl ghrelin, acyl ghrelin and obestatin. The products are thought to be secreted concomitantly. In an earlier study we found acyl ghrelin and obestatin, but not desacyl ghrelin...

  2. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis

    Science.gov (United States)

    Gomez-Ospina, Natalia; Potter, Carol J.; Xiao, Rui; Manickam, Kandamurugu; Kim, Mi-Sun; Kim, Kang Ho; Shneider, Benjamin L.; Picarsic, Jennifer L.; Jacobson, Theodora A.; Zhang, Jing; He, Weimin; Liu, Pengfei; Knisely, A. S.; Finegold, Milton J.; Muzny, Donna M.; Boerwinkle, Eric; Lupski, James R.; Plon, Sharon E.; Gibbs, Richard A.; Eng, Christine M.; Yang, Yaping; Washington, Gabriel C.; Porteus, Matthew H.; Berquist, William E.; Kambham, Neeraja; Singh, Ravinder J.; Xia, Fan; Enns, Gregory M.; Moore, David D.

    2016-01-01

    Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection. PMID:26888176

  3. Trace Amine-Associated Receptor 1 – Family Archetype or Iconoclast?

    Science.gov (United States)

    Grandy, David K.

    2009-01-01

    Interest has recently been rekindled in receptors that are activated by low molecular weight, non-catecholic, biogenic amines that are typically found as trace constituents of various vertebrate and invertebrate tissues and fluids. The timing of this resurgent focus on receptors activated by the ‘trace amines’ (TAs) β-phenylethylamine (PEA), tyramine (TYR), octopamine (OCT), synephrine (SYN), and tryptamine (TRYP) is the direct result of two publications that appeared in 2001 describing the cloning of a novel G protein-coupled receptor (GPCR) referred to by their discoverers as TA1 (Borowsky et al., 2001) and TAR1 (Bunzow et al., 2001). When heterologously expressed in Xenopus laevis oocytes and various eukaryotic cell lines recombinant rodent and human TA receptors dose-dependently couple to the stimulation of cAMP production. Structure-activity profiling based on this functional response has revealed that in addition to the TAs, other biologically active compounds containing a 2 carbon aliphatic side chain linking an amino group to at least one benzene ring are potent and efficacious TA receptor agonists with amphetamine, methamphetamine, 3-iodothyronamine, thyronamine, and dopamine among the most notable. Almost 100 years after the search for TA receptors began numerous TA1/TAR1-related sequences, now called Trace Amine-Associated Receptors (TAARs), have been identified in the genome of every species of vertebrate examined to date. Consequently, even though heterologously expressed TAAR1 fits the pharmacological criteria established for a bona fide TA receptor a major challenge for those working in the field is to discern the in vivo pharmacology and physiology of each purported member of this extended family of GPCRs. Only then will it be possible to establish whether TAAR1 is the family archetype or an iconoclast. PMID:17888514

  4. Tissue distribution and effects of fasting and obesity on the ghrelin axis in mice.

    Science.gov (United States)

    Morash, Michael G; Gagnon, Jeffrey; Nelson, Stephanie; Anini, Younes

    2010-08-09

    Ghrelin is a 28 amino acid peptide hormone derived from the 117 amino acid proghrelin, following cleavage by proprotein convertase 1 (PC1). In this study, we comprehensively assessed the tissue distribution and the effect of fasting and obesity on preproghrelin, Exon-4D, PC1 and GOAT expression and proghrelin-derived peptide (PGDP) secretion. The stomach was the major source of preproghrelin expression and PDGPs, followed by the small intestine. The remaining peripheral tissues (including the brain and pancreas) contained negligible expression levels. We detected obestatin in all stomach proghrelin cells, however, 22% of proghrelin cells in the small intestine did not express obestatin. There were strain differences in ghrelin secretion in response to fasting between CD1 and C57BL/6 mice. After a 24 hour-fast, CD1 mice had increased plasma levels of total ghrelin and obestatin with no change in preproghrelin mRNA or PGDP tissues levels. C57BL/6 mice showed a different response to a 24 hour-fast having increased proghrelin mRNA expression, stomach acylated ghrelin peptide and no change in plasma obestatin in C57BL/6 mice. In obese mice (ob/ob and diet-induced obesity (DIO)) there was a significant increase in preproghrelin mRNA levels while tissue and plasma PGDP levels were significantly reduced. Fasting did not affect PGDP in obese mice. Obese models displayed differences in GOAT expression, which was elevated in DIO mice, but reduced in ob/ob mice. We did not find co-localization of the leptin receptor in ghrelin expressing stomach cells, ruling out a direct effect of leptin on stomach ghrelin synthesis and secretion. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  5. Ghrelin in the fetal pancreas - a digital quantitation study

    DEFF Research Database (Denmark)

    Hasselby, Jane Preuss; Maroun, Lisa Leth; Federspiel, Birgitte Hartnack

    2012-01-01

    Hasselby JP, Maroun LL, Federspiel BH, Vainer B. Ghrelin in the fetal pancreas - a digital quantitation study. APMIS 2011. Ghrelin is a hormone produced by specialized neuroendocrine cells located in the fetal pancreas. In the adult, ghrelin has multiple effects, but in the fetus the role...... of ghrelin and the distribution of ghrelin-producing cells is not well documented. The aim of this study was to describe and quantitate the number of ghrelin positive cells in the pancreas during gestation. The material consisted of pancreatic tissue from 19 fetuses at different gestational ages...

  6. Mapping of Wnt-Frizzled interactions by multiplex CRISPR targeting of receptor gene families.

    Science.gov (United States)

    Voloshanenko, Oksana; Gmach, Philipp; Winter, Jan; Kranz, Dominique; Boutros, Michael

    2017-11-01

    Signaling pathway modules are often encoded by several closely related paralogous genes that can have redundant roles and are therefore difficult to analyze by loss-of-function analysis. A typical example is the Wnt signaling pathway, which in mammals is mediated by 19 Wnt ligands that can bind to 10 Frizzled (FZD) receptors. Although significant progress in understanding Wnt-FZD receptor interactions has been made in recent years, tools to generate systematic interaction maps have been largely lacking. Here we generated cell lines with multiplex mutant alleles of FZD1 , FZD2 , and FZD7 and demonstrate that these cells are unresponsive to canonical Wnt ligands. Subsequently, we performed genetic rescue experiments with combinations of FZDs and canonical Wnts to create a functional ligand-receptor interaction map. These experiments showed that whereas several Wnt ligands, such as Wnt3a, induce signaling through a broad spectrum of FZD receptors, others, such as Wnt8a, act through a restricted set of FZD genes. Together, our results map functional interactions of FZDs and 10 Wnt ligands and demonstrate how multiplex targeting by clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 can be used to systematically elucidate the functions of multigene families.-Voloshanenko, O., Gmach, P., Winter, J., Kranz, D., Boutros, M. Mapping of Wnt-Frizzled interactions by multiplex CRISPR targeting of receptor gene families. © The Author(s).

  7. Transmembrane signal transduction by peptide hormones via family B G protein-coupled receptors

    Directory of Open Access Journals (Sweden)

    Kelly J Culhane

    2015-11-01

    Full Text Available Although family B G protein-coupled receptors (GPCRs contain only 15 members, they play key roles in transmembrane signal transduction of hormones. Family B GPCRs are drug targets for developing therapeutics for diseases ranging from metabolic to neurological disorders. Despite their importance, the molecular mechanism of activation of family B GPCRs remains largely unexplored due to the challenges in expression and purification of functional receptors to the quantity for biophysical characterization. Currently, there is no crystal structure available of a full-length family B GPCR. However, structures of key domains, including the extracellular ligand binding regions and seven-helical transmembrane regions, have been solved by X-ray crystallography and NMR, providing insights into the mechanisms of ligand recognition and selectivity, and helical arrangements within the cell membrane. Moreover, biophysical and biochemical methods have been used to explore functions, key residues for signaling, and the kinetics and dynamics of signaling processes. This review summarizes the current knowledge of the signal transduction mechanism of family B GPCRs at the molecular level and comments on the challenges and outlook for mechanistic studies of family B GPCRs.

  8. Dynamic evolution of toll-like receptor multigene families in echinoderms

    Directory of Open Access Journals (Sweden)

    Katherine M Buckley

    2012-06-01

    Full Text Available The genome of the purple sea urchin, Strongylocentrotus purpuratus, was the first to be sequenced from a long-lived large invertebrate. Analysis of this genome uncovered a surprisingly complex immune system in which the moderately sized sets of pattern recognition receptors that form the core of vertebrate innate immunity are encoded in large multigene families. The sea urchin genome contains 253 Toll-like receptor (TLR genes, more than 200 Nod-like receptors and 1095 scavenger receptor cysteine-rich domains, a ten-fold expansion relative to vertebrates. Given their stereotypic structure and simple intron-exon architecture, the TLRs are the most tractable of these families for more detailed analysis. An immune defense role for these receptors is suggested by their sequence diversity and expression in immunologically active tissues, including phagocytes. This complexity of the sea urchin TLR multigene families largely derives from expansions that are independent of those in vertebrates and protostomes, although a small family of TLRs with structure similar to that of Drosophila Toll likely originated in an ancient eumetazoan ancestor. Several other invertebrate deuterostome genomes have been sequenced, including the cephalochordate, Branchiostoma floridae and the sea urchin Lytechinus variegatus, as well as partial sequences from two other sea urchin species. Here, we present an analysis of the invertebrate deuterostome TLRs with emphasis on the echinoderms. Representatives of most of the S. purpuratus TLR subfamilies and homologs of the protostome-like sequences are found in L. variegatus. The phylogeny of these genes within sea urchins highlights lineage-specific expansions at higher resolution than is evident at the phylum level. These analyses identify quickly evolving TLR subfamilies that are likely to have novel functions and other, more stable, subfamilies that may function similarly to those of vertebrates.

  9. Polymorphisms and haplotypes in the bovine neuropeptide Y, growth hormone receptor, ghrelin, insulin-like growth factor 2, and uncoupling proteins 2 and 3 genes and their associations with measures of growth, performance, feed efficiency, and carcass merit in beef cattle.

    Science.gov (United States)

    Sherman, E L; Nkrumah, J D; Murdoch, B M; Li, C; Wang, Z; Fu, A; Moore, S S

    2008-01-01

    Genes that regulate metabolism and energy partitioning have the potential to influence economically important traits in farm animals, as do polymorphisms within these genes. In the current study, SNP in the bovine neuropeptide Y (NPY), growth hormone receptor (GHR), ghrelin (GHRL), uncoupling proteins 2 and 3 (UCP2 and UCP3), IGF2, corticotrophin-releasing hormone (CRH), cocaine and amphetamine regulated transcript (CART), melanocortin-4 receptor (MC4R), proopiomelanocortin (POMC), and GH genes were evaluated for associations with growth, feed efficiency, and carcass merit in beef steers. In total, 24 SNP were evaluated for associations with these traits and haplotypes were constructed within each gene when 2 or more SNP showed significant associations. An A/G SNP located in intron 4 of the GHR gene had the largest effects on BW of the animals (dominance effect P GHRL gene tended to show effects on residual feed intake, FCR, and partial efficiency of growth (P < 0.10). The IGF2 SNP most strongly affected LM area (P < 0.01), back fat, ADG, and FCR (P < 0.05). The SNP in the CART, MC4R, POMC, GH, and CRH genes did not show associations at P < 0.05 with any of the traits. Although most of the SNP that showed associations do not cause amino acid changes, these SNP could be linked to other yet to be detected causative mutations or nearby QTL. It will be very important to verify these results in other cattle populations.

  10. Natural killer cell receptor genes in the family Equidae: not only Ly49.

    Directory of Open Access Journals (Sweden)

    Jan Futas

    Full Text Available Natural killer (NK cells have important functions in immunity. NK recognition in mammals can be mediated through killer cell immunoglobulin-like receptors (KIR and/or killer cell lectin-like Ly49 receptors. Genes encoding highly variable NK cell receptors (NKR represent rapidly evolving genomic regions. No single conservative model of NKR genes was observed in mammals. Single-copy low polymorphic NKR genes present in one mammalian species may expand into highly polymorphic multigene families in other species. In contrast to other non-rodent mammals, multiple Ly49-like genes appear to exist in the horse, while no functional KIR genes were observed in this species. In this study, Ly49 and KIR were sought and their evolution was characterized in the entire family Equidae. Genomic sequences retrieved showed the presence of at least five highly conserved polymorphic Ly49 genes in horses, asses and zebras. These findings confirmed that the expansion of Ly49 occurred in the entire family. Several KIR-like sequences were also identified in the genome of Equids. Besides a previously identified non-functional KIR-Immunoglobulin-like transcript fusion gene (KIR-ILTA and two putative pseudogenes, a KIR3DL-like sequence was analyzed. In contrast to previous observations made in the horse, the KIR3DL sequence, genomic organization and mRNA expression suggest that all Equids might produce a functional KIR receptor protein molecule with a single non-mutated immune tyrosine-based inhibition motif (ITIM domain. No evidence for positive selection in the KIR3DL gene was found. Phylogenetic analysis including rhinoceros and tapir genomic DNA and deduced amino acid KIR-related sequences showed differences between families and even between species within the order Perissodactyla. The results suggest that the order Perissodactyla and its family Equidae with expanded Ly49 genes and with a potentially functional KIR gene may represent an interesting model for

  11. Natural Killer Cell Receptor Genes in the Family Equidae: Not only Ly49

    Science.gov (United States)

    Futas, Jan; Horin, Petr

    2013-01-01

    Natural killer (NK) cells have important functions in immunity. NK recognition in mammals can be mediated through killer cell immunoglobulin-like receptors (KIR) and/or killer cell lectin-like Ly49 receptors. Genes encoding highly variable NK cell receptors (NKR) represent rapidly evolving genomic regions. No single conservative model of NKR genes was observed in mammals. Single-copy low polymorphic NKR genes present in one mammalian species may expand into highly polymorphic multigene families in other species. In contrast to other non-rodent mammals, multiple Ly49-like genes appear to exist in the horse, while no functional KIR genes were observed in this species. In this study, Ly49 and KIR were sought and their evolution was characterized in the entire family Equidae. Genomic sequences retrieved showed the presence of at least five highly conserved polymorphic Ly49 genes in horses, asses and zebras. These findings confirmed that the expansion of Ly49 occurred in the entire family. Several KIR-like sequences were also identified in the genome of Equids. Besides a previously identified non-functional KIR-Immunoglobulin-like transcript fusion gene (KIR-ILTA) and two putative pseudogenes, a KIR3DL-like sequence was analyzed. In contrast to previous observations made in the horse, the KIR3DL sequence, genomic organization and mRNA expression suggest that all Equids might produce a functional KIR receptor protein molecule with a single non-mutated immune tyrosine-based inhibition motif (ITIM) domain. No evidence for positive selection in the KIR3DL gene was found. Phylogenetic analysis including rhinoceros and tapir genomic DNA and deduced amino acid KIR-related sequences showed differences between families and even between species within the order Perissodactyla. The results suggest that the order Perissodactyla and its family Equidae with expanded Ly49 genes and with a potentially functional KIR gene may represent an interesting model for evolutionary biology of

  12. Metabolic aspects of the ghrelin system: Role of acylated and unacylated ghrelin in glucose homeostasis

    NARCIS (Netherlands)

    C. Gauna (Carlotta)

    2007-01-01

    textabstractIn the last decade the discovery of ghrelin, a gut peptide discovered in 1999 by Kojima and colleagues (1), has led to the identification of a complex system that introduced new perspectives in neuroendocrine and metabolic research. Ghrelin is a peptide-hormone of 28 amino acids,

  13. Association between ghrelin gene (Leu72Met) polymorphism and ghrelin serum level with coronary artery diseases.

    Science.gov (United States)

    Hedayatizadeh-Omran, Akbar; Rafiei, Alireza; Khajavi, Rezvan; Alizadeh-Navaei, Reza; Mokhberi, Vahid; Moradzadeh, Kambiz

    2014-02-01

    Research shows that ghrelin gene polymorphism has some association with coronary artery diseases (CAD). Due to genetic differences among nations and the high prevalence of CAD, we conducted this study to examine the possible association between the polymorphism of ghrelin gene Leu72Met and CAD among an Iranian population. This case-control study was undertaken with patients who were referred to referral heart center, in 2011, with chest pain or a positive exercise test. Patients with risk factors for heart disease or who were surgery candidates, who underwent angiography and echocardiography, were also included. DNA extractions were performed using a modified salting out method, and the ghrelin region was amplified using polymerase chain reaction. The presence of the Leu72Met polymorphism and the serum levels of ghrelin were determined using the restriction fragment length polymorphism method and the enzyme-linked immunosorbent assay, respectively. The results indicated that in CAD patients, the incidence of heart failure was significantly different between the groups with genotypes CC or AA+CA (p=0.041). Mean serum level of ghrelin in the CAD group was significantly higher than that in the control group (pghrelin genotypes and serum levels of ghrelin in both the CAD and control groups (ppolymorphism, as well as an increase in serum levels of ghrelin associated with genotype distribution such that ghrelin levels have an inverse relationship with the frequency of the CC genotype.

  14. Transcription control and neuronal differentiation by agents that activate the LXR nuclear receptor family.

    Science.gov (United States)

    Schmidt, A; Vogel, R; Holloway, M K; Rutledge, S J; Friedman, O; Yang, Z; Rodan, G A; Friedman, E

    1999-09-10

    LXR and PPAR receptors belong to the nuclear receptor superfamily of transcriptional activating factors. Using ligand-dependent transcription assays, we found that 5-tetradecyloxy-2-furancarboxylic acid (TOFA) transactivates chimeric receptors composed of the glucocorticoid receptor DNA binding domain and the ligand binding regions of PPARalpha, PPARbeta (NUC-1) and LXRbeta (NER) receptors. In the same assays, ligands for PPARs (oleic acid, WY-14643 and L-631,033) and LXRs (hydroxycholesterols) maintain their respective receptor selectivity. TOFA and hydroxycholesterols also stimulate transcription from a minimal fibrinogen promoter that is under the control of AP-1 or NF-kappaB transcription factor binding sites. In addition to their effects on transcription, these LXRbeta activators induce neuronal differentiation in rat pheochromocytoma cells. TOFA and the natural LXR agonist, 22 (R)-hydroxycholesterol, stimulate neurite outgrowth in 55 and 28% of cells, respectively. No neurite outgrowth was induced by the related 22(S)-hydroxycholesterol, which does not activate the LXR family. These results suggest that the hydroxycholesterol signaling pathway has a complex effect on transcription that mediates the activity of TOFA and hydroxycholesterol on neuronal differentiation in pheochromocytoma cells.

  15. Ghrelin protects against depleted uranium-induced apoptosis of MC3T3-E1 cells through oxidative stress-mediated p38-mitogen-activated protein kinase pathway

    Energy Technology Data Exchange (ETDEWEB)

    Hao, Yuhui; Liu, Cong; Huang, Jiawei; Gu, Ying; Li, Hong; Yang, Zhangyou; Liu, Jing [State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038 (China); Wang, Weidong, E-mail: wwdwyl@sina.com [Department of Radiation Oncology, Shanghai Jiao Tong University Affiliated Sixth People Hospital, Shanghai 200233 (China); Li, Rong, E-mail: yuhui_hao@126.com [State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038 (China)

    2016-01-01

    Depleted uranium (DU) mainly accumulates in the bone over the long term. Osteoblast cells are responsible for the formation of bone, and they are sensitive to DU damage. However, studies investigating methods of reducing DU damage in osteoblasts are rarely reported. Ghrelin is a stomach hormone that stimulates growth hormones released from the hypothalamic–pituitary axis, and it is believed to play an important physiological role in bone metabolism. This study evaluates the impact of ghrelin on DU-induced apoptosis of the osteoblast MC3T3-E1 and investigates its underlying mechanisms. The results show that ghrelin relieved the intracellular oxidative stress induced by DU, eliminated reactive oxygen species (ROS) and reduced lipid peroxidation by increasing intracellular GSH levels; in addition, ghrelin effectively suppressed apoptosis, enhanced mitochondrial membrane potential, and inhibited cytochrome c release and caspase-3 activation after DU exposure. Moreover, ghrelin significantly reduced the expression of DU-induced phosphorylated p38-mitogen-activated protein kinase (MAPK). A specific inhibitor (SB203580) or specific siRNA of p38-MAPK could significantly suppress DU-induced apoptosis and related signals, whereas ROS production was not affected. In addition, ghrelin receptor inhibition could reduce the anti-apoptosis effect of ghrelin on DU and reverse the effect of ghrelin on intracellular ROS and p38-MAPK after DU exposure. These results suggest that ghrelin can suppress DU-induced apoptosis of MC3T3-E1 cells, reduce DU-induced oxidative stress by interacting with its receptor, and inhibit downstream p38-MAPK activation, thereby suppressing the mitochondrial-dependent apoptosis pathway. - Highlights: • Ghrelin suppressed DU-induced apoptosis of MC3T3-E1 cells. • Ghrelin inhibited DU-induced oxidative stress and further p38-MAPK activation. • Ghrelin further suppressed mitochondrial-dependent apoptosis pathway. • The anti-oxidation effect of

  16. Novel skeletal muscle ryanodine receptor mutation in a large Brazilian family with malignant hyperthermia.

    Science.gov (United States)

    McWilliams, S; Nelson, T; Sudo, R T; Zapata-Sudo, G; Batti, M; Sambuughin, N

    2002-07-01

    Malignant hyperthermia (MH) is an autosomal dominant disorder that predisposes susceptible individuals to a potentially life-threatening crisis when exposed to commonly used anesthetics. Mutations in the skeletal muscle calcium release channel, ryanodine receptor (RYR1) are associated with MH in over 50% of affected families. Linkage analysis of the RYR1 gene region at 19q13 was performed in a large Brazilian family and a distinct disease co-segregating haplotype was revealed in the majority of members with diagnosis of MH. Subsequent sequencing of RYR1 mutational hot spots revealed a nucleotide substitution of C to T at position 7062, causing a novel amino acid change from Arg2355 to Cys associated with MH in the family. Haplotype analysis of the RYR1 gene area at 19q13 in the family with multiple MH members is an important tool in identification of genetic cause underlying this disease.

  17. The Role of Nuclear Receptor-Binding SET Domain Family Histone Lysine Methyltransferases in Cancer.

    Science.gov (United States)

    Bennett, Richard L; Swaroop, Alok; Troche, Catalina; Licht, Jonathan D

    2017-06-01

    The nuclear receptor-binding SET Domain (NSD) family of histone H3 lysine 36 methyltransferases is comprised of NSD1, NSD2 (MMSET/WHSC1), and NSD3 (WHSC1L1). These enzymes recognize and catalyze methylation of histone lysine marks to regulate chromatin integrity and gene expression. The growing number of reports demonstrating that alterations or translocations of these genes fundamentally affect cell growth and differentiation leading to developmental defects illustrates the importance of this family. In addition, overexpression, gain of function somatic mutations, and translocations of NSDs are associated with human cancer and can trigger cellular transformation in model systems. Here we review the functions of NSD family members and the accumulating evidence that these proteins play key roles in tumorigenesis. Because epigenetic therapy is an important emerging anticancer strategy, understanding the function of NSD family members may lead to the development of novel therapies. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  18. Effects of gastric emptying on the postprandial ghrelin response

    NARCIS (Netherlands)

    Blom, W.A.M.; Lluch, A.; Vinoy, S.; Stafleu, A.; Berg, van den R.; Holst, J.J.; Kok, F.J.; Hendriks, H.F.J.

    2006-01-01

    Distension and chemosensitization of the stomach are insufficient to induce a ghrelin response, suggesting that postgastric feedback is required. This postgastric feedback may be regulated through insulin. We investigated the relation between gastric emptying rate and the postprandial ghrelin

  19. A survey of the pyrabactin resistance-like abscisic acid receptor gene family in poplar.

    Science.gov (United States)

    Yu, Jingling; Li, Hejuan; Peng, Yajing; Yang, Lei; Zhao, Fugeng; Luan, Sheng; Lan, Wenzhi

    2017-08-03

    The conserved PYR/PYL/RCAR family acts as abscisic acid (ABA) receptors for land plants to adapt to terrestrial environments. Our recent study reported that the exogenous overexpression of poplar PtPYRL1 and PtPYRL5, the PYR/PYL/RCAR orthologs, promoted the sensitivity of transgenic Arabidopsis to ABA responses. Here, we surveyed the PtPYRL family in poplar, and revealed that although the sequence and structure are relatively conserved among these receptors, PtPYRL members have differential expression patterns and the sensitivity to ABA or drought treatment, suggesting that PtPYRLs might be good candidates to a future biotechnological use to enhance poplar resistance to water-stress environments.

  20. Sickness behaviour after lipopolysaccharide treatment in ghrelin deficient mice

    OpenAIRE

    Szentirmai, Éva; Krueger, James M.

    2013-01-01

    Ghrelin is an orexigenic hormone produced mainly by the gastrointestinal system and the brain. Much evidence also indicates a role for ghrelin in sleep and thermoregulation. Further, ghrelin was recently implicated in immune system modulation. Administration of bacterial lipopolysaccharide (LPS) induces fever, anorexia, and increased non-rapid-eye movement sleep (NREMS) and these actions are mediated primarily by proinflammatory cytokines. Ghrelin reduces LPS-induced fever, ...

  1. The D1 family dopamine receptor, DopR, potentiates hind leg grooming behavior in Drosophila.

    Science.gov (United States)

    Pitmon, E; Stephens, G; Parkhurst, S J; Wolf, F W; Kehne, G; Taylor, M; Lebestky, T

    2016-03-01

    Drosophila groom away debris and pathogens from the body using their legs in a stereotyped sequence of innate motor behaviors. Here, we investigated one aspect of the grooming repertoire by characterizing the D1 family dopamine receptor, DopR. Removal of DopR results in decreased hind leg grooming, as substantiated by quantitation of dye remaining on mutant and RNAi animals vs. controls and direct scoring of behavioral events. These data are also supported by pharmacological results that D1 receptor agonists fail to potentiate grooming behaviors in headless DopR flies. DopR protein is broadly expressed in the neuropil of the thoracic ganglion and overlaps with TH-positive dopaminergic neurons. Broad neuronal expression of dopamine receptor in mutant animals restored normal grooming behaviors. These data provide evidence for the role of DopR in potentiating hind leg grooming behaviors in the thoracic ganglion of adult Drosophila. This is a remarkable juxtaposition to the considerable role of D1 family dopamine receptors in rodent grooming, and future investigations of evolutionary relationships of circuitry may be warranted. © 2016 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

  2. Changes in subcellular distribution of n-octanoyl or n-decanoyl ghrelin in ghrelin-producing cells

    Directory of Open Access Journals (Sweden)

    Yoshihiro eNishi

    2013-07-01

    Full Text Available Background: The enzyme ghrelin O-acyltransferase (GOAT catalyzes the acylation of ghrelin. The molecular form of GOAT, together with its reaction in vitro, has been reported previously. However, the sub-cellular processes governing the acylation of ghrelin remain to be elucidated.Methods: Double immunoelectron microscopy was used to examine changes in the relative proportions of secretory granules containing n-octanoyl ghrelin (C8-ghrelin or n-decanoyl ghrelin (C10-ghrelin in ghrelin-producing cells of mouse stomachs. The dynamics of C8-type (possessing C8-ghrelin exclusively, C10-type (possessing C10-ghrelin only and mixed-type secretory granules (possessing both C8- and C10-ghrelin were investigated after fasting for 48h or after two weeks’ feeding with chow containing glyceryl-tri-octanoate (C8-MCT or glyceryl-tri-decanoate (C10-MCT. The dynamics of C8- or C10-ghrelin immunoreactivity (ir-C8- or ir-C10-ghrelin within the mixed-type granules were also investigated.Results: Immunoelectron microscopic analysis revealed the co-existence of C8- and C10-ghrelin within the same secretory granules (mixed-type in ghrelin-producing cells. Compared to control mice fed standard chow, the ratio of C10-type secretory granules increased significantly after ingestion of C10-MCT, whereas that of C8-type granules declined significantly under the same treatment. After ingestion of C8-MCT, the proportion of C8-type secretory granules increased significantly. Within the mixed-type granules the ratio of ir-C10-ghrelin increased significantly and that of ir-C8-ghrelin decreased significantly upon fasting. Conclusions: These findings confirmed that C10-ghrelin, another acyl-form of active ghrelin, is stored within the same secretory granules as C8-ghrelin, and suggested that the types of medium-chain acyl-molecules surrounding and available to the ghrelin-GOAT system may affect the physiological processes of ghrelin acylation.

  3. Changes in Subcellular Distribution of n-Octanoyl or n-Decanoyl Ghrelin in Ghrelin-Producing Cells

    Science.gov (United States)

    Nishi, Yoshihiro; Mifune, Hiroharu; Yabuki, Akira; Tajiri, Yuji; Hirata, Rumiko; Tanaka, Eiichiro; Hosoda, Hiroshi; Kangawa, Kenji; Kojima, Masayasu

    2013-01-01

    Background: The enzyme ghrelin O-acyltransferase (GOAT) catalyzes the acylation of ghrelin. The molecular form of GOAT, together with its reaction in vitro, has been reported previously. However, the subcellular processes governing the acylation of ghrelin remain to be elucidated. Methods: Double immunoelectron microscopy was used to examine changes in the relative proportions of secretory granules containing n-octanoyl ghrelin (C8-ghrelin) or n-decanoyl ghrelin (C10-ghrelin) in ghrelin-producing cells of mouse stomachs. The dynamics of C8-type (possessing C8-ghrelin exclusively), C10-type (possessing C10-ghrelin only), and mixed-type secretory granules (possessing both C8- and C10-ghrelin) were investigated after fasting for 48 h or after 2 weeks feeding with chow containing glyceryl-tri-octanoate (C8-MCT) or glyceryl-tri-decanoate (C10-MCT). The dynamics of C8- or C10-ghrelin-immunoreactivity (ir-C8- or ir-C10-ghrelin) within the mixed-type granules were also investigated. Results: Immunoelectron microscopic analysis revealed the co-existence of C8- and C10-ghrelin within the same secretory granules (mixed-type) in ghrelin-producing cells. Compared to control mice fed standard chow, the ratio of C10-type secretory granules increased significantly after ingestion of C10-MCT, whereas that of C8-type granules declined significantly under the same treatment. After ingestion of C8-MCT, the proportion of C8-type secretory granules increased significantly. Within the mixed-type granules the ratio of ir-C10-ghrelin increased significantly and that of ir-C8-ghrelin decreased significantly upon fasting. Conclusion: These findings confirmed that C10-ghrelin, another acyl-form of active ghrelin, is stored within the same secretory granules as C8-ghrelin, and suggested that the types of medium-chain acyl-molecules surrounding and available to the ghrelin-GOAT system may affect the physiological processes of ghrelin acylation. PMID:23847595

  4. Nicotine enhances modulation of food-cue reactivity by leptin and ghrelin in the ventromedial prefrontal cortex.

    Science.gov (United States)

    Kroemer, Nils B; Wuttig, Franziska; Bidlingmaier, Martin; Zimmermann, Ulrich S; Smolka, Michael N

    2015-07-01

    Endocrine signals such as ghrelin and leptin are known to modulate the mesocorticolimbic dopaminergic system and, consequently, show associations with food and drug reward. In animal models, nicotine was demonstrated to reduce body weight by attenuating food intake and effects of leptin and ghrelin are partly modulated by nicotinic acetylcholine receptors which hint at potential interactions. However, the neuropharmacological modulation of endocrine signals by nicotine in healthy humans remains to be tested experimentally. We used functional magnetic resonance imaging to investigate food-cue reactivity after an overnight fast and following a caloric load (oral glucose tolerance test, OGTT) in 26 healthy normal-weight never-smokers. Moreover, we administered either nicotine (2 mg) or placebo gums using a randomized cross-over design and assessed blood plasma levels of ghrelin and leptin. During fasting, nicotine administration decreased correlations with ghrelin levels in the mesocorticolimbic system whereas correlations with leptin were increased. After the OGTT, nicotine increased the modulatory effects of ghrelin and leptin on food-cue reactivity, particularly in the ventromedial prefrontal cortex (vmPFC) and the amygdala. Critically, this led to an indirect modulation of the behavioral 'appetizer effect' (i.e. cue-induced increases in subjective appetite) by homeostatic feedback signals via food-cue reactivity in vmPFC. We conclude that nicotine enhances the effect of ghrelin and leptin in the valuation and relevance network which might, in turn, reduce appetite. This highlights that amplifying the impact of homeostatic signals such as ghrelin and leptin in normal-weight individuals might hint at a mechanism contributing to nicotine's anorexic potential. © 2014 Society for the Study of Addiction.

  5. Increase in hypothalamic AMPK phosphorylation induced by prolonged exposure to LPS involves ghrelin and CB1R signaling.

    Science.gov (United States)

    Rivas, Priscila M S; Vechiato, Fernanda M V; Borges, Beatriz C; Rorato, Rodrigo; Antunes-Rodrigues, Jose; Elias, Lucila L K

    2017-07-01

    Acute administration of lipopolysaccharide (LPS) from Gram-negative bacteria induces hypophagia. However, the repeated administration of LPS leads to desensitization of hypophagia, which is associated with increased hypothalamic p-AMPK expression. Because ghrelin and endocannabinoids modulate AMPK activity in the hypothalamus, we hypothesized that these neuromodulators play a role in the reversal of tolerance to hypophagia in rats under long-term exposure to LPS. Male Wistar rats were treated with single (1 LPS, 100μg/kg body weight, ip) or repeated injections of LPS over 6days (6 LPS). Food intake was reduced in the 1 LPS, but not in the 6 LPS group. 6 LPS rats showed an increased serum concentration of acylated ghrelin and reduced ghrelin receptor mRNA expression in the hypothalamus. Ghrelin injection (40μg/kg body weight, ip) increased food intake, body weight gain, p-AMPK hypothalamic expression, neuropeptide Y (NPY) and Agouti related peptide (AgRP) mRNA expression in control animals (Saline). However, in 6 LPS rats, ghrelin did not alter these parameters. Central administration of a CB1R antagonist (AM251, 200ng/μl in 5μl/rat) induced hypophagia in 6 LPS animals, suggesting that the endocannabinoid system contributes to preserved food intake during LPS tolerance. In the presence of AM251, the ability of ghrelin to phosphorylate AMPK in the hypothalamus of 6 LPS group was restored, but not its orexigenic effect. Our data highlight that the orexigenic effects of ghrelin require CB1R signaling downstream of AMPK activation. Moreover, CB1R-mediated pathways contribute to the absence of hypophagia during repeated exposure to endotoxin. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Driving the need to feed: Insight into the collaborative interaction between ghrelin and endocannabinoid systems in modulating brain reward systems.

    Science.gov (United States)

    Edwards, Alexander; Abizaid, Alfonso

    2016-07-01

    Independent stimulation of either the ghrelin or endocannabinoid system promotes food intake and increases adiposity. Given the similar distribution of their receptors in feeding associated brain regions and organs involved in metabolism, it is not surprising that evidence of their interaction and its importance in modulating energy balance has emerged. This review documents the relationship between ghrelin and endocannabinoid systems within the periphery and hypothalamus (HYP) before presenting evidence suggesting that these two systems likewise work collaboratively within the ventral tegmental area (VTA) to modulate non-homeostatic feeding. Mechanisms, consistent with current evidence and local infrastructure within the VTA, will be proposed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Ghrelin suppresses cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) in the intestine, and attenuates the anorectic effects of CCK, PYY and GLP-1 in goldfish (Carassius auratus).

    Science.gov (United States)

    Blanco, Ayelén Melisa; Bertucci, Juan Ignacio; Valenciano, Ana Isabel; Delgado, María Jesús; Unniappan, Suraj

    2017-07-01

    Ghrelin is an important gut-derived hormone with an appetite stimulatory role, while most of the intestinal hormones, including cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), are appetite-inhibitors. Whether these important peptides with opposing roles on food intake interact to regulate energy balance in fish is currently unknown. The aim of this study was to characterize the putative crosstalk between ghrelin and CCK, PYY and GLP-1 in goldfish (Carassius auratus). We first determined the localization of CCK, PYY and GLP-1 in relation to ghrelin and its main receptor GHS-R1a (growth hormone secretagogue 1a) in the goldfish intestine by immunohistochemistry. Colocalization of ghrelin/GHS-R1a and CCK/PYY/GLP-1 was found primarily in the luminal border of the intestinal mucosa. In an intestinal explant culture, a significant decrease in prepro-cck, prepro-pyy and proglucagon transcript levels was observed after 60min of incubation with ghrelin, which was abolished by preincubation with the GHS-R1a ghrelin receptor antagonist [D-Lys3]-GHRP-6 (except for proglucagon). The protein expression of PYY and GLP-1 was also downregulated by ghrelin. Finally, intraperitoneal co-administration of CCK, PYY or GLP-1 with ghrelin results in no modification of food intake in goldfish. Overall, results of the present study show for the first time in fish that ghrelin exerts repressive effects on enteric anorexigens. It is likely that these interactions mediate the stimulatory effects of ghrelin on feeding and metabolism in fish. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Demonstration of functional low-density lipoprotein receptors by protein blotting in fibroblasts from a subject with homozygous receptor-negative familial hypercholesterolemia

    International Nuclear Information System (INIS)

    Semenkovich, C.F.; Ostlund, R.E. Jr.; Yang, J.; Reaban, M.E.

    1985-01-01

    We report the detection of low-density lipoprotein (LDL) receptors by the technique of receptor blotting in fibroblasts from a patient with homozygous familial hypercholesterolemia (FHC) previously classified as ''receptor negative.'' Solubilized receptors were electrophoresed, transferred to nitrocellulose paper, treated with LDL followed by radiolabeled antibody to LDL, and visualized by autoradiography. GM 2000 FHC fibroblasts revealed LDL receptors with an apparent molecular weight of approximately 140,000, the same as in normal cells. LDL receptor activity by blotting in GM 2000 cells was greatly diminished in comparison with normal cells, but was calcium dependent. Receptor activity was also detectable by conventional monolayer binding and degradation assays. Thus, GM 2000 cells have profoundly diminished LDL receptor activity, but retain the genetic capacity to make LDL receptor material of normal molecular weight that is capable of binding LDL. Previous studies have demonstrated the presence of trace amounts of immunoreactive LDL receptor protein in fibroblasts from some receptor-negative FHC homozygotes. These studies are extended by demonstrating the ability of this material to bind LDL

  9. Ghrelin promotes human non-small cell lung cancer A549 cell proliferation through PI3K/Akt/mTOR/P70S6K and ERK signaling pathways.

    Science.gov (United States)

    Zhu, Jianhua; Yao, Jianfeng; Huang, Rongfu; Wang, Yueqin; Jia, Min; Huang, Yan

    2018-04-06

    Ghrelin is a gastric acyl-peptide that plays an important role in cell proliferation. In the present study, we explored the role of ghrelin in A549 cell proliferation and the possible molecular mechanisms. We found that ghrelin promotes A549 cell proliferation, knockdown of the growth hormone secretagogue receptor (GHSR) attenuated A549 cell proliferation caused by ghrelin. Ghrelin induced the rapid phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, ERK, mammalian target of rapamycin (mTOR) and P70S6K. PI3K inhibitor (LY 294002), ERK inhibitor (PD98059) and mTOR inhibitor (Rapamycin) inhibited ghrelin-induced A549 cell proliferation. Moreover, GHSR siRNA inhibited phosphorylation of PI3K, Akt, ERK, mTOR and P70S6K induced by ghrelin. Akt and mTOR/P70S6K phosphorylation was inhibited by LY 294002 but not by PD98059. These results indicate that ghrelin promotes A549 cell proliferation via GHSR-dependent PI3K/Akt/mTOR/P70S6K and ERK signaling pathways. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Complex Determinants in Specific Members of the Mannose Receptor Family Govern Collagen Endocytosis

    DEFF Research Database (Denmark)

    Jürgensen, Henrik J; Johansson, Kristina; Madsen, Daniel H

    2014-01-01

    Members of the well-conserved mannose receptor (MR) protein family have been functionally implicated in diverse biological and pathological processes. Importantly, a proposed common function is the internalization of collagen for intracellular degradation occurring during bone development, cancer...... invasion, and fibrosis protection. This functional relationship is suggested by a common endocytic capability and a candidate collagen-binding domain. Here we conducted a comparative investigation of each member's ability to facilitate intracellular collagen degradation. As expected, the family members u......PARAP/Endo180 and MR bound collagens in a purified system and internalized collagens for degradation in cellular settings. In contrast, the remaining family members, PLA2R and DEC-205, showed no collagen binding activity and were unable to mediate collagen internalization. To pinpoint the structural elements...

  11. The relationship between metabolic status and levels of adiponectin and ghrelin in lean women with polycystic ovary syndrome.

    Science.gov (United States)

    Bik, Wojciech; Baranowska-Bik, Agnieszka; Wolinska-Witort, Ewa; Chmielowska, Magdalena; Martynska, Lidia; Baranowska, Boguslawa

    2007-06-01

    Polycystic ovary syndrome (PCOS) is commonly associated with insulin resistance, obesity, dyslipidemia and hypertension. Adiponectin, an adipocyte-specific protein with important roles in glucose and lipid homeostasis, possesses antidiabetic and insulin-sensitizing properties. Ghrelin, a protein ligand for the growth hormone secretagog receptor, has been shown to stimulate food intake and to influence energy balance, insulin signaling and glucose metabolism. We aimed to evaluate the relationships between metabolic alterations and adiponectin and ghrelin levels in lean PCOS women, compared with lean and obese women. The study was carried out on 20 non-obese PCOS women aged 20 - 48 years and age-matched groups of 45 healthy lean and 37 obese women. Hormonal and biochemical parameters, adiponectin and ghrelin concentrations and anthropometric data were determined. In PCOS subjects, we found increased homeostasis model assessment - insulin resistance index (HOMA-IR) with non-significant differences in adiponectin and ghrelin concentrations compared with healthy women, although the PCOS group showed a tendency to lower adiponectin levels. However, ghrelin levels in PCOS women were significantly higher than in obese women. Moreover, we observed a negative correlation between adiponectin and testosterone, cholesterol, triglycerides, glucose and diastolic blood pressure in PCOS. In conclusion, it can be suggested that higher values of HOMA-IR with lower adiponectin levels may indicate future development of metabolic syndrome or other metabolic disturbances in lean PCOS women.

  12. Chitosan-coated liposome dry-powder formulations loaded with ghrelin for nose-to-brain delivery.

    Science.gov (United States)

    Salade, Laurent; Wauthoz, Nathalie; Vermeersch, Marjorie; Amighi, Karim; Goole, Jonathan

    2018-06-11

    The nose-to-brain delivery of ghrelin loaded in liposomes is a promising approach for the management of cachexia. It could limit the plasmatic degradation of ghrelin and provide direct access to the brain, where ghrelin's specific receptors are located. Anionic liposomes coated with chitosan in either a liquid or a dry-powder formulation were compared. The powder formulation showed stronger adhesion to mucins (89 ± 4% vs 61 ± 4%), higher ghrelin entrapment efficiency (64 ± 2% vs 55 ± 4%), higher enzymatic protection against trypsin (26 ± 2% vs 20 ± 3%) and lower ghrelin storage degradation at 25°C (2.67 ± 1.1% vs 95.64 ± 0.85% after 4 weeks). The powder formulation was also placed in unit-dose system devices that were able to generate an appropriate aerosol characterized by a Dv50 of 38 ± 6 µm, a limited percentage of particles smaller than 10 µm of 4 ± 1% and a reproducible mass delivery (CV: 1.49%). In addition, the device was able to deposit a large amount of powder (52.04% w/w) in the olfactory zone of a 3D-printed nasal cast. The evaluated combination of the powder formulation and the device could provide a promising treatment for cachexia. Copyright © 2018. Published by Elsevier B.V.

  13. The relaxin family peptide receptors and their ligands : new developments and paradigms in the evolution from jawless fish to mammals

    NARCIS (Netherlands)

    Yegorov, Sergey; Bogerd, Jan; Good, Sara V

    2014-01-01

    Relaxin family peptide receptors (Rxfps) and their ligands, relaxin (Rln) and insulin-like (Insl) peptides, are broadly implicated in the regulation of reproductive and neuroendocrine processes in mammals. Most placental mammals harbour genes for four receptors, namely rxfp1, rxfp2, rxfp3 and rxfp4.

  14. Ghrelin signaling in the ventral tegmental area mediates both reward-based feeding and fasting-induced hyperphagia on high-fat diet.

    Science.gov (United States)

    Wei, X J; Sun, B; Chen, K; Lv, B; Luo, X; Yan, J Q

    2015-08-06

    Ghrelin is a potent orexigenic hormone that acts in the central nervous system to stimulate food intake via the growth hormone secretagogue receptor (GHSR) that is abundantly expressed in the ventral tegmental area (VTA). Not only does ghrelin modulate feeding behavior via a homeostatic mechanism, but numerous studies have identified ghrelin as a key regulator of reward-based hedonic feeding behaviors. Nutritional states influence ghrelin and GHSR expression as well as the behavioral sensitivity to reward-inducing stimuli. In the current study, we examined the role of ghrelin at the VTA level in food intake in two different nutritional states, satiety and hunger, by using a restricted feeding model. In this model, rats were conditioned to a daily 3-h (h) feeding session on standard chow for 10days and a high-fat diet (HFD) was supplied either in the third hour after 2h of chow diet intake, or at the beginning of a daily meal on the test day. We found that intra-VTA microinjection of 1, 2, and 4μg of ghrelin, induced a dose-related increase of 1h of reward-based feeding on HFD in sated rats, as well as a 24-h body weight gain. The overconsumption stimulated by ghrelin could be attenuated by 10μg of direct infusion of the ghrelin receptor antagonist D-Lys3-GHRP-6 into the VTA. Moreover, our data showed that the injection of 1, 2, and 4μg of ghrelin in the VTA, enhanced fasting-induced hyperphagia on HFD in a dose-related manner following a 21-h food restriction as well as a 24-h body weight gain. Conversely, hyperphagia on HFD that is potentiated by ghrelin could be blocked by pretreatment with a 10-μg D-Lys3-GHRP-6 intra-VTA microinjection. Collectively, these data demonstrate that ghrelin signaling at the VTA level mediates both reward-based eating and fasting-induced hyperphagia and provides a primary target for the control of the intake of rewarding food. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Using paleogenomics to study the evolution of gene families: origin and duplication history of the relaxin family hormones and their receptors.

    Directory of Open Access Journals (Sweden)

    Sergey Yegorov

    Full Text Available Recent progress in the analysis of whole genome sequencing data has resulted in the emergence of paleogenomics, a field devoted to the reconstruction of ancestral genomes. Ancestral karyotype reconstructions have been used primarily to illustrate the dynamic nature of genome evolution. In this paper, we demonstrate how they can also be used to study individual gene families by examining the evolutionary history of relaxin hormones (RLN/INSL and relaxin family peptide receptors (RXFP. Relaxin family hormones are members of the insulin superfamily, and are implicated in the regulation of a variety of primarily reproductive and neuroendocrine processes. Their receptors are G-protein coupled receptors (GPCR's and include members of two distinct evolutionary groups, an unusual characteristic. Although several studies have tried to elucidate the origins of the relaxin peptide family, the evolutionary origin of their receptors and the mechanisms driving the diversification of the RLN/INSL-RXFP signaling systems in non-placental vertebrates has remained elusive. Here we show that the numerous vertebrate RLN/INSL and RXFP genes are products of an ancestral receptor-ligand system that originally consisted of three genes, two of which apparently trace their origins to invertebrates. Subsequently, diversification of the system was driven primarily by whole genome duplications (WGD, 2R and 3R followed by almost complete retention of the ligand duplicates in most vertebrates but massive loss of receptor genes in tetrapods. Interestingly, the majority of 3R duplicates retained in teleosts are potentially involved in neuroendocrine regulation. Furthermore, we infer that the ancestral AncRxfp3/4 receptor may have been syntenically linked to the AncRln-like ligand in the pre-2R genome, and show that syntenic linkages among ligands and receptors have changed dynamically in different lineages. This study ultimately shows the broad utility, with some caveats, of

  16. Ghrelin and its promoter variant associated with cardiac hypertrophy.

    Science.gov (United States)

    Ukkola, O; Pääkkö, T; Kesäniemi, Y A

    2012-07-01

    The roles of ghrelin, a peptide hormone that has a role in regulating food intake and energy homeostasis, in the cardiovascular system have not yet been unambiguously established. We evaluated the association between plasma ghrelin concentrations and -501A>C single-nucleotide polymorphism (SNP) in the ghrelin gene 5' flanking area and echocardiographic measurements in 1037 middle-aged subjects. Left ventricular mass index (LVMI) was calculated according to Devereux's method. The ambulatory blood pressure (BP) was recorded using the fully automatic SpaceLabs 90207 oscillometric unit. Results suggested that plasma ghrelin was not related to mean ambulatory BP values. However, the highest plasma ghrelin tertile was associated with increased intraventricular septum (P=0.043) and posterior ventricular wall (P=0.002) thicknesses as well as left ventricular mass (P=0.05). After adjustment for age, sex, body mass index and systolic BP, the association persisted between ghrelin tertiles and intraventricular septum (P=0.05) and posterior ventricular wall (P=0.001) thicknesses. The SNP -501A>C polymorphism was associated with LVMI after adjustments for age, sex and systolic BP. In conclusion, ghrelin and its promoter variant are associated with cardiac hypertrophy indexes independent of BP. Positive correlation between ghrelin levels and increased wall thickness parameters may reflect compensatory up-regulation of ghrelin concentrations or direct effects of ghrelin on myocardium. The effects of the SNP seem not to be mediated through its effects on ghrelin plasma levels.

  17. Obesity Impairs the Action of the Neuroendocrine Ghrelin System

    Science.gov (United States)

    Zigman, Jeffrey M.; Bouret, Sebastien G.; Andrews, Zane B.

    2016-01-01

    Ghrelin is a metabolic hormone that promotes energy conservation by regulating appetite and energy expenditure. Although some studies suggest that antagonizing ghrelin function attenuates body weight gain and glucose intolerance on a high calorie diet, there is little information about the metabolic actions of ghrelin in the obese state. In this review, we discuss the novel concept of obesity-induced central ghrelin resistance in neural circuits regulating behavior, and impaired ghrelin secretion from the stomach. Interestingly, weight loss restores ghrelin secretion and function, and we hypothesize that ghrelin resistance is a mechanism designed to protect a higher body weight set-point established during times of food availability, to maximize energy reserves during a time of food scarcity. PMID:26542050

  18. The role of TAM family receptors and ligands in the nervous system: From development to pathobiology.

    Science.gov (United States)

    Shafit-Zagardo, Bridget; Gruber, Ross C; DuBois, Juwen C

    2018-03-04

    Tyro3, Axl, and Mertk, referred to as the TAM family of receptor tyrosine kinases, are instrumental in maintaining cell survival and homeostasis in mammals. TAM receptors interact with multiple signaling molecules to regulate cell migration, survival, phagocytosis and clearance of metabolic products and cell debris called efferocytosis. The TAMs also function as rheostats to reduce the expression of proinflammatory molecules and prevent autoimmunity. All three TAM receptors are activated in a concentration-dependent manner by the vitamin K-dependent growth arrest-specific protein 6 (Gas6). Gas6 and the TAMs are abundantly expressed in the nervous system. Gas6, secreted by neurons and endothelial cells, is the sole ligand for Axl. ProteinS1 (ProS1), another vitamin K-dependent protein functions mainly as an anti-coagulant, and independent of this function can activate Tyro3 and Mertk, but not Axl. This review will focus on the role of the TAM receptors and their ligands in the nervous system. We highlight studies that explore the function of TAM signaling in myelination, the visual cortex, neural cancers, and multiple sclerosis (MS) using Gas6 -/- and TAM mutant mice models. Copyright © 2018. Published by Elsevier Inc.

  19. The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry.

    Science.gov (United States)

    Meertens, Laurent; Carnec, Xavier; Lecoin, Manuel Perera; Ramdasi, Rasika; Guivel-Benhassine, Florence; Lew, Erin; Lemke, Greg; Schwartz, Olivier; Amara, Ali

    2012-10-18

    Dengue viruses (DVs) are responsible for the most medically relevant arboviral diseases. However, the molecular interactions mediating DV entry are poorly understood. We determined that TIM and TAM proteins, two receptor families that mediate the phosphatidylserine (PtdSer)-dependent phagocytic removal of apoptotic cells, serve as DV entry factors. Cells poorly susceptible to DV are robustly infected after ectopic expression of TIM or TAM receptors. Conversely, DV infection of susceptible cells is inhibited by anti-TIM or anti-TAM antibodies or knockdown of TIM and TAM expression. TIM receptors facilitate DV entry by directly interacting with virion-associated PtdSer. TAM-mediated infection relies on indirect DV recognition, in which the TAM ligand Gas6 acts as a bridging molecule by binding to PtdSer within the virion. This dual mode of virus recognition by TIM and TAM receptors reveals how DVs usurp the apoptotic cell clearance pathway for infectious entry. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Familial Risk for Major Depression is Associated with Lower Striatal 5-HT4 Receptor Binding

    DEFF Research Database (Denmark)

    Madsen, Karine; Torstensen, Eva; Holst, Klaus Kähler

    2015-01-01

    was to determine whether familial risk for MDD is associated with cerebral 5-HT4 receptor binding as measured with [(11)C]SB207145 brain PET imaging. Familial risk is the most potent risk factor of MDD. METHODS: We studied 57 healthy individuals (mean age 36 yrs, range 20-86; 21 women), 26 of which had first...

  1. Working memory span capacity improved by a D2 but not D1 receptor family agonist.

    Science.gov (United States)

    Tarantino, Isadore S; Sharp, Richard F; Geyer, Mark A; Meves, Jessica M; Young, Jared W

    2011-06-01

    Patients with schizophrenia exhibit poor working memory (WM). Although several subcomponents of WM can be measured, evidence suggests the primary subcomponent affected in schizophrenia is span capacity (WMC). Indeed, the NIMH-funded MATRICS initiative recommended assaying the WMC when assessing the efficacy of a putative therapeutic for FDA approval. Although dopamine D1 receptor agonists improve delay-dependent memory in animals, evidence for improvements in WMC due to dopamine D1 receptor activation is limited. In contrast, the dopamine D2-family agonist bromocriptine improves WMC in humans. The radial arm maze (RAM) can be used to assess WMC, although complications due to ceiling effects or strategy confounds have limited its use. We describe a 12-arm RAM protocol designed to assess whether the dopamine D1-family agonist SKF 38393 (0, 1, 3, and 10 mg/kg) or bromocriptine (0, 1, 3, and 10 mg/kg) could improve WMC in C57BL/6N mice (n=12) in cross-over designs. WMC increased and strategy usage decreased with training. The dopamine D1 agonist SKF 38393 had no effect on WMC or long-term memory. Bromocriptine decreased WMC errors, without affecting long-term memory, consistent with human studies. These data confirm that WMC can be measured in mice and reveal drug effects that are consistent with reported effects in humans. Future research is warranted to identify the subtype of the D2-family of receptors responsible for the observed improvement in WMC. Finally, this RAM procedure may prove useful in developing animal models of deficient WMC to further assess putative treatments for the cognitive deficits in schizophrenia. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Polymorphisms of the ghrelin/obestatin gene and ghrelin levels in Chinese children with short stature.

    Science.gov (United States)

    Zou, Chao Chun; Huang, Ke; Liang, Li; Zhao, Zheng Yan

    2008-07-01

    To investigate the role of ghrelin and polymorphisms of ghrelin/obestatin gene in children with short stature. A total of 117 GH deficient (GHD) and 81 idiopathic short stature (ISS) children were studied. The controls consisted of 125 age and gender-matched healthy children. The Arg51Gln, Leu72Met and Gln90Leu polymorphisms were genotyped using MassArray and total plasma ghrelin was measured by radioimmunoassay. In this study, the frequency of the Arg51Gln polymorphism was very low (0% in controls and 1.0% in patients). The frequency of the Gln90Leu polymorphism was 1.6% in controls and 0.5% in patients, respectively. Higher frequencies of Leu72Met (34.4% in controls and 39.9% in patients) and Met72Met genotypes (4.0% in controls and 2.0% in patients) were found. The differences in the Arg51Gln, Leu72Met or Gln90Leu genotypes and allele frequencies between patients and controls were not significant. Also, there were no significant differences in the Leu72Met genotypes and allele frequencies between GHD and ISS subgroups. There were no significant differences in clinical characteristics and biochemistry markers (including ghrelin levels) among the different genotypes of Leu72Met. However, plasma ghrelin levels in the GHD group were significantly lower than those of controls (P = 0.001). These results suggest that ghrelin may have a role in GH secretion and controlling growth. Lower ghrelin levels, but not ghrelin/obestatin polymorphism, might contribute to GHD.

  3. Three family members with elevated plasma cobalamin, transcobalamin and soluble transcobalamin receptor (sCD320)

    DEFF Research Database (Denmark)

    Hoffmann-Lücke, Elke; Arendt, Johan F B; Nissen, Peter H

    2013-01-01

    deficiency were found. DNA sequencing of the TCN2 gene revealed several known polymorphisms not associated with highly elevated transcobalamin levels. Upon gel filtration, sCD320 eluted as a larger molecule than previously reported. By incubation with anti-transcobalamin antibodies, we precipitated both...... transcobalamin and part of sCD320. CONCLUSIONS: The high cobalamin levels were mainly explained by high levels of holoTC, possibly caused by complex formation with its soluble receptor, sCD320. The family occurrence points to a genetic explanation....

  4. [Coactivators in energy metabolism: peroxisome proliferator-activated receptor-gamma coactivator 1 family].

    Science.gov (United States)

    Wang, Rui; Chang, Yong-sheng; Fang, Fu-de

    2009-12-01

    Peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1) family is highly expressed in tissues with high energy metabolism. They coactivate transcription factors in regulating genes engaged in processes such as gluconeogenesis, adipose beta-oxydation, lipoprotein synthesis and secretion, mitochondrial biogenesis, and oxidative metabolism. Protein conformation studies demonstrated that they lack DNA binding domains and act as coactivators through physical interaction with transcription factors. PGC1 activity is regulated at transcription level or by multiple covalent chemical modifications such as phosphorylation, methylation and acetylation/deacetylation. Abnormal expression of PGC1 coactivators usually is closely correlated with diseases such as diabetes, obesity, hyperglycemia, hyperlipemia, and arterial and brain neuron necrosis diseases.

  5. Association of pro-ghrelin and GHS-R1A gene polymorphisms and haplotypes with heavy alcohol use and body mass.

    Science.gov (United States)

    Landgren, Sara; Jerlhag, Elisabet; Zetterberg, Henrik; Gonzalez-Quintela, Arturo; Campos, Joaquin; Olofsson, Ulrica; Nilsson, Staffan; Blennow, Kaj; Engel, Jörgen A

    2008-12-01

    Ghrelin, an orexigenic peptide, acts on growth hormone secretagogue receptors (GHS-R1A), expressed in the hypothalamus as well as in important reward nodes such as the ventral tegmental area. Interestingly, ghrelin has been found to activate an important part of the reward systems, i.e., the cholinergic-dopaminergic reward link. Additionally, the rewarding and neurochemical properties of alcohol are, at least in part, mediated via this reward link. There is comorbidity between alcohol dependence and eating disorders. Thus, plasma levels of ghrelin are altered in patients with addictive behaviors such as alcohol and nicotine dependence and in binge eating disorder. This overlap prompted as to investigate the pro-ghrelin and GHS-R1A genes in a haplotype analysis of heavy alcohol-using individuals. A total of 417 Spanish individuals (abstainers, moderate, and heavy alcohol drinkers) were investigated in a haplotype analysis of the pro-ghrelin and GHS-R1A genes. Tag SNPs were chosen using HapMap data and the Tagger and Haploview softwares. These SNPs were then genotyped using TaqMan Allelic Discrimination. SNP rs2232165 of the GHS-R1A gene was associated with heavy alcohol consumption and SNP rs2948694 of the same gene as well as haplotypes of both the pro-ghrelin and the GHS-R1A genes were associated with body mass in heavy alcohol consuming individuals. The present findings are the first to disclose an association between the pro-ghrelin and GHS-R1A genes and heavy alcohol use, further strengthening the role of the ghrelin system in addictive behaviors and brain reward.

  6. Ghrelin, leptin and adiponectin as possible predictors of the hedonic value of odors.

    Science.gov (United States)

    Trellakis, Sokratis; Tagay, Sefik; Fischer, Cornelia; Rydleuskaya, Alena; Scherag, André; Bruderek, Kirsten; Schlegl, Sandra; Greve, Jens; Canbay, Ali E; Lang, Stephan; Brandau, Sven

    2011-02-25

    Several lines of evidence point to a close relationship between the hormones of energy homeostasis and the olfactory system. Examples are the localization of leptin and adiponectin receptors in the olfactory system or increased activation of brain regions related to the palatability and the hedonic value of food in response to food pictures after application of ghrelin. In this preliminary study, we tested in 31 subjects (17 male and 14 female) if and to what extent the peripheral blood concentrations of "satiety" hormones, such as leptin, adiponectin, and ghrelin (acyl and total), are correlated with the self-ratings of odor pleasantness and with the objective olfactory and gustatory ability. The hedonic values of some odors were found to be differently rated between donors depending on gender and body weight. The concentrations of leptin, adiponectin and total ghrelin were significantly associated with the hedonic value of pepper black oil, but failed to show significant correlations for 5 other odors tested. Except for a significant association between leptin and odor identification, hormone concentrations were not linked to the abilities of smell and taste. Peripheral adipokines and gut hormones may alter the perception and pleasantness of specific odors, presumably either directly through their receptors in the olfactory system or indirectly through central interfaces between the regulation systems of olfaction, appetite control, memory and motivation. Copyright © 2010 Elsevier B.V. All rights reserved.

  7. An 8bp indel in exon 1 of Ghrelin gene associated with chicken growth.

    Science.gov (United States)

    Fang, Meixia; Nie, Qinghua; Luo, Chenglong; Zhang, Dexiang; Zhang, Xiquan

    2007-04-01

    Ghrelin, acts as the endogenous ligand for growth hormone secretagogues receptor (GHS-R), is a novel growth hormone (GH) releasing peptide with reported effects on food intake in chickens. In this study, an 8 bp indel polymorphism in exon 1 of the chicken Ghrelin (cGHRL) gene was genotyped in a F(2) designed full-sib population to analyze its associations with chicken growth and carcass traits. Later, mRNA level in the proventriculus was determined by real-time PCR to reveal the expression feature of cGHRL gene. Result showed that this 8 bp indel was significantly associated with body weight at the age of 28 days (BW28) and 56 days (BW56), eviscerated weight (EW) and leg muscle weight (LMW) (PGhrelin on chicken growth were indicated by this study.

  8. Ghrelin treatment prevents development of activity based anorexia in mice.

    Science.gov (United States)

    Legrand, Romain; Lucas, Nicolas; Breton, Jonathan; Azhar, Saïda; do Rego, Jean-Claude; Déchelotte, Pierre; Coëffier, Moïse; Fetissov, Sergueï O

    2016-06-01

    Stimulation of feeding is necessary for treatment of pathological conditions of chronic malnutrition due to anorexia. Ghrelin, a hunger hormone, is one of the candidate for pharmacological treatments of anorexia, but because of its instability in plasma has limited efficacy. We previously showed that plasmatic IgG protect ghrelin from degradation and that IgG from obese subjects and mice may increase ghrelin׳s orexigenic effect. In this study we tested if ghrelin alone or combined with IgG may improve feeding in chronically food-restricted mice with or without physical activity-based anorexia (ABA) induced by free access to a running wheel. Mice received a single daily intraperitoneal injection of ghrelin (1nM) together or not with total IgG (1nM) from obese ob/ob or lean mice before access to food during 8 days of 3h/day feeding time. We found that both ghrelin and ghrelin combined with IgG from obese, but not lean mice, prevented ABA, however, they were not able to diminish body weight loss. Physical activity was lower during the feeding period and was increased shortly after feeding in mice receiving ghrelin together with IgG from obese mice. In food-restricted mice without ABA, ghrelin treatments did not have significant effects on food intake. Thus, this study supports pharmacological use of ghrelin or ghrelin combined with IgG from obese animals for treatment of anorexia accompanied by elevated physical activity. The utility of combining ghrelin with protective IgG should be further determined in animal models of anorexia with unrestricted access to food. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  9. Localization of acyl ghrelin- and des-acyl ghrelin-immunoreactive cells in the rat stomach and their responses to intragastric pH.

    Science.gov (United States)

    Mizutani, Makoto; Atsuchi, Kaori; Asakawa, Akihiro; Matsuda, Norifumi; Fujimura, Masaki; Inui, Akio; Kato, Ikuo; Fujimiya, Mineko

    2009-11-01

    Acyl ghrelin has a 28-amino acid sequence with O-n-octanoyl acid modification at the serine 3 position, whereas des-acyl ghrelin has no octanoyl acid modification. Although these peptides exert different physiological functions, no previous studies have shown the different localization of acyl ghrelin and des-acyl ghrelin in the stomach. Here we have developed an antibody specific for des-acyl ghrelin that does not crossreact with acyl ghrelin. Both acyl ghrelin- and des-acyl ghrelin-immunoreactive cells were distributed in the oxyntic and antral mucosa of the rat stomach, with higher density in the antral mucosa than oxyntic mucosa. Immunofluorescence double staining showed that acyl ghrelin- and des-acyl ghrelin-positive reactions overlapped in closed-type round cells, whereas des-acyl ghrelin-positive reaction was found in open-type cells in which acyl ghrelin was negative. Acyl ghrelin-/des-acyl ghrelin-positive closed-type cells contain obestatin; on the other hand, des-acyl ghrelin-positive open-type cells contain somatostatin. We measured the release of acyl ghrelin and des-acyl ghrelin in vascularly perfused rat stomach by ELISA, and the effects of different intragastric pH levels on the release of each peptide were examined. The release of des-acyl ghrelin from the perfused stomach was greater at pH 2 than at pH 4; however, the release of acyl ghrelin was not affected by intragastric pH. The present study demonstrated the differential localization of acyl ghrelin and des-acyl ghrelin in the rat stomach and their different responses to the intragastric pH.

  10. Des-Acyl Ghrelin and Ghrelin O-Acyltransferase Regulate Hypothalamic-Pituitary-Adrenal Axis Activation and Anxiety in Response to Acute Stress

    NARCIS (Netherlands)

    Stark, R.; Santos, V.V.; Geenen, B.; Cabral, A.; Dinan, T.; Bayliss, J.A.; Lockie, S.H.; Reichenbach, A.; Lemus, M.B.; Perello, M.; Spencer, S.J.; Kozicz, L.T.; Andrews, Z.B.

    2016-01-01

    Ghrelin exists in two forms in circulation, acyl ghrelin and des-acyl ghrelin, both of which have distinct and fundamental roles in a variety of physiological functions. Despite this fact, a large proportion of papers simply measure and refer to plasma ghrelin without specifying the acylation

  11. Increased ghrelin but low ghrelin-reactive immunoglobulins in a rat model of methotrexate chemotherapy-induced anorexia

    Directory of Open Access Journals (Sweden)

    Marie François

    2016-07-01

    Full Text Available Background and aims: Cancer chemotherapy is commonly accompanied by mucositis, anorexia, weight loss and anxiety independently from cancer-induced anorexia-cachexia, further aggravating clinical outcome. Ghrelin is a peptide hormone produced in gastric mucosa that reaches the brain to stimulate appetite. In plasma, ghrelin is protected from degradation by ghrelin-reactive immunoglobulins (Ig. To analyze possible involvement of ghrelin in the chemotherapy-induced anorexia and anxiety, gastric ghrelin expression, plasma levels of ghrelin and ghrelin-reactive IgG were studied in rats treated with methotrexate (MTX.Methods: Rats received MTX (2.5 mg/kg, S.C. for three consecutive days and were killed 3 days later, at the peak of anorexia and weight loss. Control rats received phosphate-buffered saline. Preproghrelin mRNA expression in the stomach was analyzed by in situ hybridization. Plasma levels of ghrelin and ghrelin-reactive IgG were measured by immunoenzymatic assays and IgG affinity kinetics by surface plasmon resonance. Anxiety- and depression-like behaviors in MTX-treated anorectic and in control rats were evaluated in the elevated plus-maze and the forced-swim test, respectively.Results: In MTX-treated anorectic rats the number of preproghrelin mRNA-producing cells was found increased (by 51.3%, p<0.001 as well were plasma concentrations of both ghrelin and des-acyl-ghrelin (by 70.4%, p<0.05 and 98.3%, p<0.01, respectively. In contrast, plasma levels of total IgG reactive with ghrelin and des-acyl-ghrelin were drastically decreased (by 87.2% and 88.4%, respectively, both p<0.001, and affinity kinetics of these IgG were characterized by increased small and big Kd, respectively. MTX-treated rats displayed increased anxiety- but not depression-like behavior.Conclusion: MTX-induced anorexia, weight loss and anxiety are accompanied by increased ghrelin production and by a decrease of ghrelin-reactive IgG levels and affinity binding properties

  12. Cross-talk between the NR3B and NR4A families of orphan nuclear receptors

    International Nuclear Information System (INIS)

    Lammi, Johanna; Rajalin, Ann-Marie; Huppunen, Johanna; Aarnisalo, Piia

    2007-01-01

    Estrogen-related receptors (NR3B family) and Nurr1, NGFI-B, and Nor1 (NR4A family) are orphan nuclear receptors lacking identified natural ligands. The mechanisms regulating their transcriptional activities have remained elusive. We have previously observed that the members of NR3B and NR4A families are coexpressed in certain cell types such as osteoblasts and that the ability of Nurr1 to transactivate the osteopontin promoter is repressed by ERRs. We have now studied the cross-talk between NR3B and NR4A receptors. We show that NR3B and NR4A receptors mutually repress each others' transcriptional activity. The repression involves intact DNA-binding domains and dimerization interfaces but does not result from competition for DNA binding or from heterodimerization. The activation functions of NR3B and NR4A receptors are dispensable for the cross-talk. In conclusion, we report that cross-talk between NR3B and NR4A receptors is a mechanism modulating the transcriptional activities of these orphan nuclear receptors

  13. International Union of Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors

    Science.gov (United States)

    Bachelerie, Francoise; Ben-Baruch, Adit; Burkhardt, Amanda M.; Combadiere, Christophe; Farber, Joshua M.; Graham, Gerard J.; Horuk, Richard; Sparre-Ulrich, Alexander Hovard; Locati, Massimo; Luster, Andrew D.; Mantovani, Alberto; Matsushima, Kouji; Nibbs, Robert; Nomiyama, Hisayuki; Power, Christine A.; Proudfoot, Amanda E. I.; Rosenkilde, Mette M.; Rot, Antal; Sozzani, Silvano; Thelen, Marcus; Yoshie, Osamu; Zlotnik, Albert

    2014-01-01

    Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145–176]. Since then, several new receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other areas. The first two drugs acting at chemokine receptors have been approved by the U.S. Food and Drug Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical chemokine receptors has emerged that may signal through arrestins instead of G proteins to act as chemokine scavengers, and many microbial and invertebrate G protein-coupled chemokine receptors and soluble chemokine-binding proteins have been described. Here, we review this extended family of chemokine receptors and chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development. We also introduce a new nomenclature for atypical chemokine receptors with the stem ACKR (atypical chemokine receptor) approved by the Nomenclature Committee of the International Union of Pharmacology and the Human

  14. Nuclear functions and subcellular trafficking mechanisms of the epidermal growth factor receptor family

    Science.gov (United States)

    2012-01-01

    Accumulating evidence suggests that various diseases, including many types of cancer, result from alteration of subcellular protein localization and compartmentalization. Therefore, it is worthwhile to expand our knowledge in subcellular trafficking of proteins, such as epidermal growth factor receptor (EGFR) and ErbB-2 of the receptor tyrosine kinases, which are highly expressed and activated in human malignancies and frequently correlated with poor prognosis. The well-characterized trafficking of cell surface EGFR is routed, via endocytosis and endosomal sorting, to either the lysosomes for degradation or back to the plasma membrane for recycling. A novel nuclear mode of EGFR signaling pathway has been gradually deciphered in which EGFR is shuttled from the cell surface to the nucleus after endocytosis, and there, it acts as a transcriptional regulator, transmits signals, and is involved in multiple biological functions, including cell proliferation, tumor progression, DNA repair and replication, and chemo- and radio-resistance. Internalized EGFR can also be transported from the cell surface to several intracellular compartments, such as the Golgi apparatus, the endoplasmic reticulum, and the mitochondria, in addition to the nucleus. In this review, we will summarize the functions of nuclear EGFR family and the potential pathways by which EGFR is trafficked from the cell surface to a variety of cellular organelles. A better understanding of the molecular mechanism of EGFR trafficking will shed light on both the receptor biology and potential therapeutic targets of anti-EGFR therapies for clinical application. PMID:22520625

  15. Multi-species sequence comparison reveals conservation of ghrelin gene-derived splice variants encoding a truncated ghrelin peptide.

    Science.gov (United States)

    Seim, Inge; Jeffery, Penny L; Thomas, Patrick B; Walpole, Carina M; Maugham, Michelle; Fung, Jenny N T; Yap, Pei-Yi; O'Keeffe, Angela J; Lai, John; Whiteside, Eliza J; Herington, Adrian C; Chopin, Lisa K

    2016-06-01

    The peptide hormone ghrelin is a potent orexigen produced predominantly in the stomach. It has a number of other biological actions, including roles in appetite stimulation, energy balance, the stimulation of growth hormone release and the regulation of cell proliferation. Recently, several ghrelin gene splice variants have been described. Here, we attempted to identify conserved alternative splicing of the ghrelin gene by cross-species sequence comparisons. We identified a novel human exon 2-deleted variant and provide preliminary evidence that this splice variant and in1-ghrelin encode a C-terminally truncated form of the ghrelin peptide, termed minighrelin. These variants are expressed in humans and mice, demonstrating conservation of alternative splicing spanning 90 million years. Minighrelin appears to have similar actions to full-length ghrelin, as treatment with exogenous minighrelin peptide stimulates appetite and feeding in mice. Forced expression of the exon 2-deleted preproghrelin variant mirrors the effect of the canonical preproghrelin, stimulating cell proliferation and migration in the PC3 prostate cancer cell line. This is the first study to characterise an exon 2-deleted preproghrelin variant and to demonstrate sequence conservation of ghrelin gene-derived splice variants that encode a truncated ghrelin peptide. This adds further impetus for studies into the alternative splicing of the ghrelin gene and the function of novel ghrelin peptides in vertebrates.

  16. Polymorphisms of the low-density lipoprotein receptor gene in Brazilian individuals with heterozygous familial hypercholesterolemia

    Directory of Open Access Journals (Sweden)

    L.A. Salazar

    2000-11-01

    Full Text Available Familial hypercholesterolemia (FH is a metabolic disorder inherited as an autosomal dominant trait characterized by an increased plasma low-density lipoprotein (LDL level. The disease is caused by several different mutations in the LDL receptor gene. Although early identification of individuals carrying the defective gene could be useful in reducing the risk of atherosclerosis and myocardial infarction, the techniques available for determining the number of the functional LDL receptor molecules are difficult to carry out and expensive. Polymorphisms associated with this gene may be used for unequivocal diagnosis of FH in several populations. The aim of our study was to evaluate the genotype distribution and relative allele frequencies of three polymorphisms of the LDL receptor gene, HincII1773 (exon 12, AvaII (exon 13 and PvuII (intron 15, in 50 unrelated Brazilian individuals with a diagnosis of heterozygous FH and in 130 normolipidemic controls. Genomic DNA was extracted from blood leukocytes by a modified salting-out method. The polymorphisms were detected by PCR-RFLP. The FH subjects showed a higher frequency of A+A+ (AvaII, H+H+ (HincII1773 and P1P1 (PvuII homozygous genotypes when compared to the control group (P<0.05. In addition, FH probands presented a high frequency of A+ (0.58, H+ (0.61 and P1 (0.78 alleles when compared to normolipidemic individuals (0.45, 0.45 and 0.64, respectively. The strong association observed between these alleles and FH suggests that AvaII, HincII1773 and PvuII polymorphisms could be useful to monitor the inheritance of FH in Brazilian families.

  17. Receptor Activity-modifying Protein-directed G Protein Signaling Specificity for the Calcitonin Gene-related Peptide Family of Receptors.

    Science.gov (United States)

    Weston, Cathryn; Winfield, Ian; Harris, Matthew; Hodgson, Rose; Shah, Archna; Dowell, Simon J; Mobarec, Juan Carlos; Woodlock, David A; Reynolds, Christopher A; Poyner, David R; Watkins, Harriet A; Ladds, Graham

    2016-10-14

    The calcitonin gene-related peptide (CGRP) family of G protein-coupled receptors (GPCRs) is formed through the association of the calcitonin receptor-like receptor (CLR) and one of three receptor activity-modifying proteins (RAMPs). Binding of one of the three peptide ligands, CGRP, adrenomedullin (AM), and intermedin/adrenomedullin 2 (AM2), is well known to result in a Gα s -mediated increase in cAMP. Here we used modified yeast strains that couple receptor activation to cell growth, via chimeric yeast/Gα subunits, and HEK-293 cells to characterize the effect of different RAMP and ligand combinations on this pathway. We not only demonstrate functional couplings to both Gα s and Gα q but also identify a Gα i component to CLR signaling in both yeast and HEK-293 cells, which is absent in HEK-293S cells. We show that the CGRP family of receptors displays both ligand- and RAMP-dependent signaling bias among the Gα s , Gα i , and Gα q/11 pathways. The results are discussed in the context of RAMP interactions probed through molecular modeling and molecular dynamics simulations of the RAMP-GPCR-G protein complexes. This study further highlights the importance of RAMPs to CLR pharmacology and to bias in general, as well as identifying the importance of choosing an appropriate model system for the study of GPCR pharmacology. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Genome-wide scan for serum ghrelin detects linkage on chromosome 1p36 in Hispanic children: results from the Viva La Familia study.

    Science.gov (United States)

    Voruganti, V Saroja; Göring, Harald H H; Diego, Vincent P; Cai, Guowen; Mehta, Nitesh R; Haack, Karin; Cole, Shelley A; Butte, Nancy F; Comuzzie, Anthony G

    2007-10-01

    This study was conducted to investigate genetic influence on serum ghrelin and its relationship with adiposity-related phenotypes in Hispanic children (n=1030) from the Viva La Familia study (VFS). Anthropometric measurements and levels of serum ghrelin were estimated and genetic analyses conducted according to standard procedures. Mean age, body mass index (BMI), and serum ghrelin were 11+/-0.13 y, 25+/-0.24 kg/m2 and 38+/-0.5 ng/mL, respectively. Significant heritabilities (p<0.001) were obtained for BMI, weight, fat mass, percent fat, waist circumference, waist-to-height ratio, and ghrelin. Bivariate analyses of ghrelin with adiposity traits showed significant negative genetic correlations (p<0.0001) with weight, BMI, fat mass, percent fat, waist circumference, and waist-to-height ratio. A genome-wide scan for ghrelin detected significant linkage on chromosome 1p36.2 between STR markers D1S2697 and D1S199 (LOD=3.2). The same region on chromosome 1 was the site of linkage for insulin (LOD=3.3), insulinlike growth factor binding protein 1 (IGFBP1) (LOD=3.4), homeostatic model assessment method (HOMA) (LOD=2.9), and C-peptide (LOD=2.0). Several family-based studies have reported linkages for obesity-related phenotypes in the region of 1p36. These results indicate the importance of this region in relation to adiposity in children from the VFS.

  19. Synthetic triterpenoid inhibition of human ghrelin O-acyltransferase: Involvement of a functionally required cysteine provides mechanistic insight into ghrelin acylation

    OpenAIRE

    McGovern-Gooch, Kayleigh R.; Mahajani, Nivedita S.; Garagozzo, Ariana; Schramm, Anthony J.; Hannah, Lauren G.; Sieburg, Michelle A.; Chisholm, John D.; Hougland, James L.

    2017-01-01

    The peptide hormone ghrelin plays a key role in regulating hunger and energy balance within the body. Ghrelin signaling presents a promising and unexploited target for development of small-molecule therapeutics to treat obesity, diabetes, and other health conditions. Inhibition of ghrelin O-acyltransferase (GOAT), which catalyzes an essential octanoylation step in ghrelin maturation, offers a potential avenue for controlling ghrelin signaling. Through screening a small molecule library, we ha...

  20. Ghrelin and its Association with Nutritional and Inflammatory Status ...

    African Journals Online (AJOL)

    ... 4Department of Pharmacy Practice, Saastra College of Pharmaceutical Education and Research, ... Keywords: Appetite, Ghrelin, Hemodialysis, Inflammation, Nutritional status .... the control groups included hemoglobin, packed cell volume,.

  1. Neonatal ghrelin programs development of hypothalamic feeding circuits

    Science.gov (United States)

    Steculorum, Sophie M.; Collden, Gustav; Coupe, Berengere; Croizier, Sophie; Lockie, Sarah; Andrews, Zane B.; Jarosch, Florian; Klussmann, Sven; Bouret, Sebastien G.

    2015-01-01

    A complex neural network regulates body weight and energy balance, and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases, such as obesity. The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice. Ghrelin blockade in neonatal mice resulted in enhanced ARH neural projections and long-term metabolic effects, including increased body weight, visceral fat, and blood glucose levels and decreased leptin sensitivity. In addition, chronic administration of ghrelin during postnatal life impaired the normal development of ARH projections and caused metabolic dysfunction. Consistent with these observations, direct exposure of postnatal ARH neuronal explants to ghrelin blunted axonal growth and blocked the neurotrophic effect of the adipocyte-derived hormone leptin. Moreover, chronic ghrelin exposure in neonatal mice also attenuated leptin-induced STAT3 signaling in ARH neurons. Collectively, these data reveal that ghrelin plays an inhibitory role in the development of hypothalamic neural circuits and suggest that proper expression of ghrelin during neonatal life is pivotal for lifelong metabolic regulation. PMID:25607843

  2. Metabolic Changes and Serum Ghrelin Level in Patients with Psoriasis

    Directory of Open Access Journals (Sweden)

    Haydar Ucak

    2014-01-01

    Full Text Available Background. Serum ghrelin levels may be related to metabolic and clinical changes in patients with psoriasis. Objective. This study was performed to determine the possible effects of serum ghrelin in patients with psoriasis. Methods. The study population consisted of 25 patients with plaque psoriasis. The patients were questioned with regard to age, gender, age of onset, duration of disease, height, weight, and body mass index (BMI. In addition, fasting blood sugar, triglyceride, cholesterol levels, insulin, and ghrelin levels were measured. Results. The mean serum ghrelin level was 45.41 ± 22.41 in the psoriasis group and 29.92 ± 14.65 in the healthy control group. Serum ghrelin level was significantly higher in the psoriasis group compared with the controls (P=0.01. The mean ghrelin level in patients with a lower PASI score was significantly higher than in those with a higher PASI score (P=0.02. Conclusion. The present study was performed to determine the effects of ghrelin in psoriasis patients. We found a negative correlation between severity of psoriasis and ghrelin level. Larger and especially experimental studies focusing on correlation of immune system-ghrelin levels and severity of psoriasis may be valuable to clarify the etiopathogenesis of the disease.

  3. Familial risks and estrogen receptor-positive breast cancer in Hong Kong Chinese women.

    Directory of Open Access Journals (Sweden)

    Lap Ah Tse

    Full Text Available The role of family history to the risk of breast cancer was analyzed by incorporating menopausal status in Hong Kong Chinese women, with a particular respect to the estrogen receptor-positive (ER+ type.Seven hundred and forty seven breast cancer incident cases and 781 hospital controls who had completed information on family cancer history in first-degree relatives (nature father, mother, and siblings were recruited. Odds ratio for breast cancer were calculated by unconditional multiple logistic regression, stratified by menopausal status (a surrogate of endogenous female sex hormone level and age and type of relative affected with the disease. Further subgroup analysis by tumor type according to ER status was investigated.Altogether 52 (6.96% breast cancer cases and 23 (2.95% controls was found that the patients' one or more first-degree relatives had a history of breast cancer, showing an adjusted odds ratio (OR of 2.41 (95%CI: 1.45-4.02. An excess risk of breast cancer was restricted to the ER+ tumor (OR = 2.43, 95% CI: 1.38-4.28, with a relatively higher risk associated with an affected mother (OR = 3.97, 95%CI: 1.46-10.79 than an affected sister (OR = 2.06, 95%CI: 1.07-3.97, while the relative risk was more prominent in the subgroup of pre-menopausal women. Compared with the breast cancer overall, the familial risks to the ER+ tumor increased progressively with the number of affected first-degree relatives.This study provides new insights on a relationship between family breast cancer history, menopausal status, and the ER+ breast cancer. A separate risk prediction model for ER+ tumor in Asian population is desired.

  4. Familial risks and estrogen receptor-positive breast cancer in Hong Kong Chinese women.

    Science.gov (United States)

    Tse, Lap Ah; Li, Mengjie; Chan, Wing-cheong; Kwok, Chi-hei; Leung, Siu-lan; Wu, Cherry; Yu, Ignatius Tak-sun; Yu, Wai-cho; Lao, Xiangqian; Wang, Xiaorong; Wong, Carmen Ka-man; Lee, Priscilla Ming-yi; Wang, Feng; Yang, Xiaohong Rose

    2015-01-01

    The role of family history to the risk of breast cancer was analyzed by incorporating menopausal status in Hong Kong Chinese women, with a particular respect to the estrogen receptor-positive (ER+) type. Seven hundred and forty seven breast cancer incident cases and 781 hospital controls who had completed information on family cancer history in first-degree relatives (nature father, mother, and siblings) were recruited. Odds ratio for breast cancer were calculated by unconditional multiple logistic regression, stratified by menopausal status (a surrogate of endogenous female sex hormone level and age) and type of relative affected with the disease. Further subgroup analysis by tumor type according to ER status was investigated. Altogether 52 (6.96%) breast cancer cases and 23 (2.95%) controls was found that the patients' one or more first-degree relatives had a history of breast cancer, showing an adjusted odds ratio (OR) of 2.41 (95%CI: 1.45-4.02). An excess risk of breast cancer was restricted to the ER+ tumor (OR = 2.43, 95% CI: 1.38-4.28), with a relatively higher risk associated with an affected mother (OR = 3.97, 95%CI: 1.46-10.79) than an affected sister (OR = 2.06, 95%CI: 1.07-3.97), while the relative risk was more prominent in the subgroup of pre-menopausal women. Compared with the breast cancer overall, the familial risks to the ER+ tumor increased progressively with the number of affected first-degree relatives. This study provides new insights on a relationship between family breast cancer history, menopausal status, and the ER+ breast cancer. A separate risk prediction model for ER+ tumor in Asian population is desired.

  5. The effects of DL-AP5 and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived broiler cockerels

    NARCIS (Netherlands)

    Taati, Majid; Nayebzadeh, Hassan; Zendehdel, Morteza

    This study was designed to examine the effects of intracerebroventricular injection of DL-AP5 (N-methyl-D-aspartate (NMDA) receptor antagonist) and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived (FD3) broiler cockerels. At first, guide cannula was surgically implanted in the

  6. Association of plasma ghrelin levels and ghrelin rs4684677 polymorphism with mild cognitive impairment in type 2 diabetic patients.

    Science.gov (United States)

    Huang, Rong; Han, Jing; Tian, Sai; Cai, Rongrong; Sun, Jie; Shen, Yanjue; Wang, Shaohua

    2017-02-28

    People with insulin resistance and type 2 diabetes mellitus (T2DM) are at increased risks of cognitive impairment. We aimed to investigate the association of plasma ghrelin levels and ghrelin rs4684677 polymorphism with mild cognitive impairment (MCI) in T2DM patients. In addition to elevated glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG) and homeostasis model assessment of insulin resistance (HOMA-IR), T2DM patients with MCI had decreased plasma ghrelin levels compared with their healthy-cognition subjects (all p ghrelin level was one of independent factors for MCI in T2DM patients (p ghrelin levels were positively associated with the scores of Montreal Cognitive Assessment (r = 0.196, p = 0.041) and Auditory Verbal Learning Test-delayed recall (r = 0.197, p = 0.040) after adjustment for HbA1c, FBG and HOMA-IR, wherein the latter represented episodic memory functions. No significant differences were found for the distributions of genotype and allele of ghrelin rs4684677 polymorphism between MCI and control group. A total of 218 T2DM patients, with 112 patients who satisfied the MCI diagnostic criteria and 106 who exhibited healthy cognition, were enrolled in this study. Demographic characteristics, clinical variables and cognitive performances were extensively assessed. Plasma ghrelin levels and ghrelin rs4684677 polymorphism were also determined. Our results suggest that decreased ghrelin levels are associated with MCI, especially with episodic memory dysfunction in T2DM populations.

  7. Minireview: nuclear receptor coregulators of the p160 family: insights into inflammation and metabolism.

    Science.gov (United States)

    Rollins, David A; Coppo, Maddalena; Rogatsky, Inez

    2015-04-01

    Nuclear receptor coactivators (NCOAs) are multifunctional transcriptional coregulators for a growing number of signal-activated transcription factors. The members of the p160 family (NCOA1/2/3) are increasingly recognized as essential and nonredundant players in a number of physiological processes. In particular, accumulating evidence points to the pivotal roles that these coregulators play in inflammatory and metabolic pathways, both under homeostasis and in disease. Given that chronic inflammation of metabolic tissues ("metainflammation") is a driving force for the widespread epidemic of obesity, insulin resistance, cardiovascular disease, and associated comorbidities, deciphering the role of NCOAs in "normal" vs "pathological" inflammation and in metabolic processes is indeed a subject of extreme biomedical importance. Here, we review the evolving and, at times, contradictory, literature on the pleiotropic functions of NCOA1/2/3 in inflammation and metabolism as related to nuclear receptor actions and beyond. We then briefly discuss the potential utility of NCOAs as predictive markers for disease and/or possible therapeutic targets once a better understanding of their molecular and physiological actions is achieved.

  8. Ghrelin gene polymorphisms in rheumatoid arthritis.

    Science.gov (United States)

    Ozgen, Metin; Koca, Suleyman Serdar; Etem, Ebru Onalan; Yuce, Huseyin; Aydin, Suleyman; Isik, Ahmet

    2011-07-01

    Ghrelin, an endogenous orexigenic peptide, has anti-inflammatory effects, down-regulates pro-inflammatory cytokines, and its altered levels are reported in various inflammatory diseases. The human preproghrelin (ghrelin/obestatin) gene shows several single nucleotide polymorphisms (SNPs) including Arg51Gln, Leu72Met, Gln90Leu, and A-501C. The aim of this study was to investigate the frequency, and clinical significance, of these four SNPs in a small cohort of Turkish patients with rheumatoid arthritis (RA). The study included 103 patients with RA and 103 healthy controls. In the RA group, disease activity and disease-related damage were assessed using the Disease Activity Score-28 (DAS-28), and the modified Larsen scoring (MLS) methods. In all the participants, genomic DNA was isolated and genotyped by polymerase chain reaction and restriction fragment length polymorphism analysis. The frequencies of ghrelin gene SNPs were 82.5 and 79.6% in the RA and control groups, respectively, and there were no significant differences in terms of genotype distributions and allele frequencies for these four SNPs between the groups. However, the A-501C SNP was found to be associated with early disease onset, and Gln90Leu SNP with less frequent rheumatoid factor positivity, in the RA group. A-501C SNP is associated with earlier onset of RA suggesting that genetic variations in the ghrelin gene may have an impact on RA. Copyright © 2010 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

  9. Sequence comparisons of odorant receptors among tortricid moths reveal different rates of molecular evolution among family members.

    Directory of Open Access Journals (Sweden)

    Colm Carraher

    Full Text Available In insects, odorant receptors detect volatile cues involved in behaviours such as mate recognition, food location and oviposition. We have investigated the evolution of three odorant receptors from five species within the moth genera Ctenopseustis and Planotrotrix, family Tortricidae, which fall into distinct clades within the odorant receptor multigene family. One receptor is the orthologue of the co-receptor Or83b, now known as Orco (OR2, and encodes the obligate ion channel subunit of the receptor complex. In comparison, the other two receptors, OR1 and OR3, are ligand-binding receptor subunits, activated by volatile compounds produced by plants--methyl salicylate and citral, respectively. Rates of sequence evolution at non-synonymous sites were significantly higher in OR1 compared with OR2 and OR3. Within the dataset OR1 contains 109 variable amino acid positions that are distributed evenly across the entire protein including transmembrane helices, loop regions and termini, while OR2 and OR3 contain 18 and 16 variable sites, respectively. OR2 shows a high level of amino acid conservation as expected due to its essential role in odour detection; however we found unexpected differences in the rate of evolution between two ligand-binding odorant receptors, OR1 and OR3. OR3 shows high sequence conservation suggestive of a conserved role in odour reception, whereas the higher rate of evolution observed in OR1, particularly at non-synonymous sites, may be suggestive of relaxed constraint, perhaps associated with the loss of an ancestral role in sex pheromone reception.

  10. Ghrelin response to carbohydrate-enriched breakfast is related to insulin

    NARCIS (Netherlands)

    Blom, W.A.M.; Stafleu, A.; Graaf, de C.; Kok, F.J.; Schaafsma, G.; Hendriks, H.F.J.

    2005-01-01

    Ghrelin plays an important role in the regulation of food intake. Little is known about how ghrelin concentrations are modified by dietary factors. Objective: We examined the effects of both amount and type of carbohydrate on ghrelin concentrations and all correlations among the variables ghrelin,

  11. Plasma levels of acylated ghrelin in patients with functional dyspepsia

    Science.gov (United States)

    Kim, Yeon Soo; Lee, Joon Seong; Lee, Tae Hee; Cho, Joo Young; Kim, Jin Oh; Kim, Wan Jung; Kim, Hyun Gun; Jeon, Seong Ran; Jeong, Hoe Su

    2012-01-01

    AIM: To investigate the relationship between plasma acylated ghrelin levels and the pathophysiology of functional dyspepsia. METHODS: Twenty-two female patients with functional dyspepsia and twelve healthy volunteers were recruited for the study. The functional dyspepsia patients were each diagnosed based on the Rome III criteria. Eligible patients completed a questionnaire concerning the severity of 10 symptoms. Plasma acylated ghrelin levels before and after a meal were determined in the study participants using a commercial human acylated enzyme immunoassay kit; electrogastrograms were performed for 50 min before and after a standardized 10-min meal containing 265 kcal. RESULTS: There were no significant differences in plasma acylated ghrelin levels between healthy volunteers and patients with functional dyspepsia. However, in patients with functional dyspepsia, there was a negative correlation between fasting plasma acylated ghrelin levels and the sum score of epigastric pain (r = -0.427, P = 0.047) and a positive correlation between the postprandial/fasting plasma acylated ghrelin ratio and the sum score of early satiety (r = 0.428, P =0.047). Additionally, there was a negative correlation between fasting acylated ghrelin plasma levels and fasting normogastria (%) (r = -0.522, P = 0.013). Interestingly, two functional dyspepsia patients showed paradoxically elevated plasma acylated ghrelin levels after the meal. CONCLUSION: Abnormal plasma acylated ghrelin levels before or after a meal may be related to several of the dyspeptic symptoms seen in patients with functional dyspepsia. PMID:22611317

  12. Ghrelin expression in dissociated cultures, of the rat neocortex

    NARCIS (Netherlands)

    Stoyanova, Irina; Wiertz, Remy; Rutten, Wim

    2009-01-01

    Ghrelin is a hormone, initially described as a gastric peptide stimulating appetite and growth hormone secretrion, which also has an important role in the regulation of many other processes including higher brain functions. Ghrelin has been described in situ in different part of the brain, but so

  13. Effect of ghrelin on inflammatory response in lung contusion

    Directory of Open Access Journals (Sweden)

    Berrak Guven

    2013-02-01

    Full Text Available The purpose of this study was to investigate the effects of ghrelin on inflammatory response and tissue damage following trauma-induced acute lung injury. Thirty male wistar albino rats (300–400 g were randomly assigned into three groups: control group (n = 6, lung contusion plus saline (saline-treated, n = 12, and lung contusion plus ghrelin (ghrelin-treated, n = 12. Saline- or ghrelin-treated traumatic rats were sacrificed at two time points (24 and 72 hours after lung contusion. Blood was collected for the analysis of serum adenosine deaminase (ADA. Tissue transforming growth factor-beta 1 (TGF-β1 and matrix metalloproteinase-2 (MMP-2 levels were measured by enzyme-linked immunosorbent assay and histopathological examination was performed on the lung tissue samples. Our results indicated that ghrelin significantly reduced morphologic damages. Serum ADA activities were significantly decreased after lung contusion and this decline started early with ghrelin treatment. TGF-β1 and MMP-2 levels in lung tissue were elevated at 72 hours after lung contusion and treatment with ghrelin significantly increased TGF-β1 level and reduced MMP-2 level. In conclusion, our study demonstrates that acute lung injury initiated proinflammatory responses and ghrelin administration showed an anti-inflammatory effect in lung contusion.

  14. The effects of ghrelin on colonic anastomosis healing in rats

    Directory of Open Access Journals (Sweden)

    Canan Ceran

    2013-01-01

    Full Text Available OBJECTIVES: In addition to its roles in the stimulation of growth hormone secretion and the regulation of appetite and metabolism, ghrelin exerts immunomodulatory, anti-inflammatory and antioxidant actions in several organ systems. In this study, we investigated the effects of ghrelin on the healing of experimental colonic anastomoses. METHODS: Wistar rats were randomly divided into two groups (n = 10 in each. A segment of colon was excised, and an end-to-end anastomosis was performed in the distal colon. The Ghrelin Group received 10 ng/kg/day IP ghrelin for seven days postoperatively, whereas the Control Group received an identical volume of saline. On the seventh postoperative day, the anastomotic bursting pressures and hydroxyproline levels were measured, and adhesion formation around the anastomoses was examined. Histopathological analyses were performed to evaluate inflammatory cell infiltration, fibroblast infiltration, collagen density and neovascularization. RESULTS: In the Ghrelin Group, the bursting pressure and hydroxyproline levels were significantly higher than in the Control Group. The adhesion formation scores were lower in the Ghrelin Group than in the Control Group. Although the inflammatory cell infiltration was diminished in the Ghrelin Group, the degrees of fibroblast infiltration, collagen density and neovascularization were not significantly different between the groups. CONCLUSION: Our results indicate that ghrelin improves the healing of colonic anastomoses in rats.

  15. Serum Adiponectin and Ghrelin, Metabolic Syndrome and Diabetes ...

    African Journals Online (AJOL)

    Purpose: Metabolic syndrome (MetS) is associated with the development of cardiovascular disease (CVD) and type 2 diabetes. Decreases in circulating adiponectin and ghrelin have been associated with MetS. Our primary aim was to evaluate the relationship of MetS with adiponectin and ghrelin for Cuban Americans with ...

  16. Plasma ghrelin levels during exercise - effects of intensity and duration.

    Science.gov (United States)

    Erdmann, Johannes; Tahbaz, Rana; Lippl, Florian; Wagenpfeil, Stefan; Schusdziarra, Volker

    2007-10-04

    Ghrelin, a recently discovered hormone of gastric origin has been shown to stimulate appetite and food intake. In man it is considered to play a role in energy homeostasis and regulation of somatropic function. As exercise affects hunger/satiety sensations and food intake, at least under some experimental conditions, we investigated the effect of exercise intensity and duration on ghrelin release and subsequent ad libitum food intake in normal weight subjects. Bicycle exercise on an ergometer for 30 min at 50 W which was below the aerob-anaerobic threshold led to an increase of ghrelin which remained unchanged during the higher intensity at 100 W. Respective hunger/satiety ratings and subsequent food intake and postprandial ghrelin suppression were identical and not different from controls. In a second group 7 subjects cycled at 50 W for 30, 60 and 120 min, respectively. Ghrelin concentrations rose significantly by 50-70 pg/ml above baseline for the respective period of exercise. While postexercise premeal ghrelin levels were not significantly different subsequent food intake after 120 min of cycling was significantly greater compared to control, 30 min and 60 min exercise, respectively. The present data suggest that low rather than high-intensity exercise stimulates ghrelin levels independent of exercise duration. Stimulation of food intake during prolonged exercise is most likely not due to changes of ghrelin.

  17. Cardiovascular effects of intravenous ghrelin infusion in healthy young men

    DEFF Research Database (Denmark)

    Vestergaard, Esben Thyssen; Andersen, Niels Holmark; Hansen, Troels Krarup

    2007-01-01

    Ghrelin infusion improves cardiac function in patients suffering from cardiac failure, and bolus administration of ghrelin increases cardiac output in healthy subjects. The cardiovascular effects of more continuous intravenous ghrelin exposure remain to be studied. We therefore studied the cardio......Ghrelin infusion improves cardiac function in patients suffering from cardiac failure, and bolus administration of ghrelin increases cardiac output in healthy subjects. The cardiovascular effects of more continuous intravenous ghrelin exposure remain to be studied. We therefore studied...... the cardiovascular effects of a constant infusion of human ghrelin at a rate of 5 pmol/kg per minute for 180 min. Fifteen healthy, young (aged 23.2 ± 0.5 yr), normal-weight (23.0 ± 0.4 kg/m2) men volunteered in a randomized double-blind, placebo-controlled crossover study. With the subjects remaining fasting, peak...... myocardial systolic velocity S′, tissue tracking TT, left ventricular ejection fraction EF, and endothelium-dependent flow-mediated vasodilatation were measured. Ghrelin infusion increased S′ 9% (P = 0.002) and TT 10% (P

  18. Metformin increases plasma ghrelin in Type 2 diabetes.

    Science.gov (United States)

    Doogue, Matthew P; Begg, Evan J; Moore, M Peter; Lunt, Helen; Pemberton, Chris J; Zhang, Mei

    2009-12-01

    * Metformin, unlike the other major antihyperglycaemic drugs, is not associated with weight gain. * Ghrelin is an appetite-stimulating hormone whose concentrations vary in relation to food, obesity and diabetes control. * Reports are conflicting about how metformin affects ghrelin concentrations, and this study was aimed at resolving this issue in patients with Type 2 diabetes. * In this study an increase in ghrelin concentrations was seen in response to metformin treatment in patients with Type 2 diabetes. * This effect was opposite to what might be expected if the effect of metformin on weight control was mediated via suppression of ghrelin. * It is likely that the ghrelin response was secondary to improved glycaemic control. * Meal time changes in appetite and satiety did not correlate with changes in ghrelin, which suggests ghrelin may not be important in meal initiation. Metformin treatment of Type 2 diabetes is not usually associated with weight gain, and may assist with weight reduction. Plasma ghrelin concentrations are inversely associated with obesity and food intake. Metformin might therefore affect ghrelin concentrations, although previous studies have shown variable results in this regard. The primary aim of this study was to determine the effect of metformin on plasma ghrelin, appetite and satiety in patients with Type 2 diabetes. Eighteen patients with Type 2 diabetes were studied before and after 6 weeks of metformin treatment, which was titrated to 1 g b.d. On the study days patients were fed standard meals of 390 kcal at 08.00 and 12.30 h, plasma samples were collected at 15- and 30-min intervals, and appetite and satiety were measured on visual analogue scales. Changes in the area under the concentration-time curves (AUCs) of plasma ghrelin, insulin, glucose, appetite and satiety were assessed and examined for correlations with metformin AUCs. Changes in fasting adiponectin and leptin were also measured. Treatment with metformin increased the

  19. Ghrelin secretion in humans - a role for the vagus nerve?

    DEFF Research Database (Denmark)

    Veedfald, S; Plamboeck, A; Hartmann, B

    2018-01-01

    BACKGROUND: Ghrelin, an orexigenic peptide, is secreted from endocrine cells in the gastric mucosa. Circulating levels rise in the preprandial phase, suggesting an anticipatory or cephalic phase of release, and decline in the postprandial phase, suggesting either the loss of a stimulatory factor...... or inhibition by factors released when nutrients enter the intestine. We hypothesized that vagal signals are not required for the (i) preprandial increase or (ii) postprandial suppression of ghrelin levels. Further, we wanted to investigate the hypothesis that (iii) glucagon-like peptide-1 might be implicated...... in the postprandial decline in ghrelin levels. METHODS: We measured ghrelin levels in plasma from sham-feeding and meal studies carried out in vagotomized individuals and controls, and from a GLP-1 infusion study carried out in fasting healthy young individuals. KEY RESULTS: We find that (i) ghrelin secretion...

  20. Central ghrelin production does not substantially contribute to systemic ghrelin concentrations: a study in two subjects with active acromegaly

    NARCIS (Netherlands)

    F.M. van der Toorn (Fanny); W.W. de Herder (Wouter); F. Broglio (Fabio); E. Ghigo (Ezio); A-J. van der Lely (Aart-Jan); J.A.M.J.L. Janssen (Joseph)

    2002-01-01

    textabstractINTRODUCTION: In an animal model of acromegaly (PEPCK-hGH transgenic mice), low systemic levels of ghrelin have been observed compared with normal mice. We hypothesized that systemic circulating ghrelin levels are also decreased in humans with active acromegaly and

  1. Radiation-induced pulmonary fibrosis: examination of chemokine and chemokine receptor families.

    Science.gov (United States)

    Johnston, Carl J; Williams, Jacqueline P; Okunieff, Paul; Finkelstein, Jacob N

    2002-03-01

    Fibrosis is a common outcome of chronic inflammation or injury. Pulmonary fibrosis may be the result of abnormal repair after an acute inflammatory response. The process of repair initiated by a tissue insult is largely a function of the activation of cells to produce important biological mediators such as cytokines, growth factors and chemokines, which orchestrate most aspects of the inflammatory response. Consequently, altered regulation of the production of inflammatory cell cytokines and chemokines after injury and repair likely contributes to the fibrosis. Our hypothesis is that chronic expression of specific chemokine and chemokine receptors during the fibrotic phase induced by thoracic irradiation may perpetuate the recruitment and activation of lymphocytes and macrophages, which may contribute to the development of fibrosis. Fibrosis-sensitive (C57BL/6) and fibrosis-resistant (C3H/HeJ) mice were irradiated with a single dose of 12.5 Gy to the thorax. Total lung RNA was prepared and hybridized using microarray analysis and RNase protection assays. At 26 weeks postirradiation, messages encoding the chemokines BLC (now known as Scyb13), C10 (now known as Scya6), IP-10 (now known as Scyb10), MCP-1 (now known as Scya2), MCP-3 (now known as Scya7), MIP-1gamma (now known as Scya9), and RANTES (now known as Scya5) and the chemokine receptors Ccr1, Ccr2, Ccr5 and Ccr6 were elevated in fibrosis-sensitive (C57BL/6) mice. In contrast, only the messages encoding SDF-1alpha (now known as Sdf1) and Ccr1 were elevated 26 weeks postirradiation in fibrosis-resistant (C3H/HeJ) mice. Our results point to the CC and CCR family members as the predominant chemokine responders during the development of fibrosis. These studies suggest that monocyte/macrophage and lymphocyte recruitment and activation are key components of radiation-induced fibrosis.

  2. Chronic central administration of Ghrelin increases bone mass through a mechanism independent of appetite regulation.

    Directory of Open Access Journals (Sweden)

    Hyung Jin Choi

    Full Text Available Leptin plays a critical role in the central regulation of bone mass. Ghrelin counteracts leptin. In this study, we investigated the effect of chronic intracerebroventricular administration of ghrelin on bone mass in Sprague-Dawley rats (1.5 μg/day for 21 days. Rats were divided into control, ghrelin ad libitum-fed (ghrelin ad lib-fed, and ghrelin pair-fed groups. Ghrelin intracerebroventricular infusion significantly increased body weight in ghrelin ad lib-fed rats but not in ghrelin pair-fed rats, as compared with control rats. Chronic intracerebroventricular ghrelin infusion significantly increased bone mass in the ghrelin pair-fed group compared with control as indicated by increased bone volume percentage, trabecular thickness, trabecular number and volumetric bone mineral density in tibia trabecular bone. There was no significant difference in trabecular bone mass between the control group and the ghrelin ad-lib fed group. Chronic intracerebroventricular ghrelin infusion significantly increased the mineral apposition rate in the ghrelin pair-fed group as compared with control. In conclusion, chronic central administration of ghrelin increases bone mass through a mechanism that is independent of body weight, suggesting that ghrelin may have a bone anabolic effect through the central nervous system.

  3. Ghrelin for the management of cachexia associated with cancer.

    Science.gov (United States)

    Khatib, Mahalaqua Nazli; Shankar, Anuraj H; Kirubakaran, Richard; Gaidhane, Abhay; Gaidhane, Shilpa; Simkhada, Padam; Quazi Syed, Zahiruddin

    2018-02-28

    Cancer sufferers are amongst the most malnourished of all the patient groups. Studies have shown that ghrelin, a gut hormone can be a potential therapeutic agent for cachexia (wasting syndrome) associated with cancer. A variety of mechanisms of action of ghrelin in people with cancer cachexia have been proposed. However, safety and efficacy of ghrelin for cancer-associated cachexia have not been systematically reviewed. The aim of this review was to assess whether ghrelin is associated with better food intake, body composition and survival than other options for adults with cancer cachexia. To assess the efficacy and safety of ghrelin in improving food intake, body composition and survival in people with cachexia associated with cancer. We searched CENTRAL, MEDLINE and Embase without language restrictions up to July 2017. We also searched for ongoing studies in trials registers, performed handsearching, checked bibliographic references of relevant articles and contacted authors and experts in the field to seek potentially relevant research. We applied no restrictions on language, date, or publication status. We included randomised controlled (parallel-group or cross-over) trials comparing ghrelin (any formulation or route of administration) with placebo or an active comparator in adults (aged 18 years and over) who met any of the international criteria for cancer cachexia. Two review authors independently assessed studies for eligibility. Two review authors then extracted data and assessed the risk of bias for individual studies using standard Cochrane methodology. For dichotomous variables, we planned to calculate risk ratio with 95% confidence intervals (CI) and for continuous data, we planned to calculate mean differences (MD) with 95% CI. We assessed the evidence using GRADE and created 'Summary of findings' tables. We screened 926 individual references and identified three studies that satisfied the inclusion criteria. Fifty-nine participants (37 men and 22

  4. Ghrelin system in alcohol-dependent subjects: role of plasma ghrelin levels in alcohol drinking and craving.

    Science.gov (United States)

    Leggio, Lorenzo; Ferrulli, Anna; Cardone, Silvia; Nesci, Antonio; Miceli, Antonio; Malandrino, Noemi; Capristo, Esmeralda; Canestrelli, Benedetta; Monteleone, Palmiero; Kenna, George A; Swift, Robert M; Addolorato, Giovanni

    2012-03-01

    Animal studies suggest that the gut-brain peptide ghrelin plays an important role in the neurobiology of alcohol dependence (AD). Human studies show an effect of alcohol on ghrelin levels and a correlation between ghrelin levels and alcohol craving in alcoholics. This investigation consisted of two studies. Study 1 was a 12-week study with alcohol-dependent subjects, where plasma ghrelin determinations were assessed four times (T0-T3) and related to alcohol intake and craving [Penn Alcohol Craving Score (PACS) and Obsessive Compulsive Drinking Scale (OCDS)]. Serum growth hormone levels and assessment of the nutritional/metabolic status were also performed. Study 2 was a pilot case-control study to assess ghrelin gene polymorphisms (Arg51Gln and Leu72Met) in alcohol-dependent individuals. Study 1 showed no significant differences in ghrelin levels in the whole sample, while there was a statistical difference for ghrelin between non-abstinent and abstinent subjects. Baseline ghrelin levels were significantly and positively correlated with the PACS score at T1 and with all craving scores both at T2 and T3 (PACS, OCDS, obsessive and compulsive OCDS subscores). In Study 2, although there was a higher frequency of the Leu72Met ghrelin gene polymorphism in alcohol-dependent individuals, the distribution between healthy controls and alcohol dependent individuals was not statistically significant. This investigation suggests that ghrelin is potentially able to affect alcohol-seeking behaviors, such as alcohol drinking and craving, representing a new potential neuropharmacological target for AD. © 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.

  5. Parathyroid hormone induces the Nrna family of nuclear orphan receptors in vivo

    International Nuclear Information System (INIS)

    Pirih, Flavia Q.; Aghaloo, Tara L.; Bezouglaia, Olga; Nervina, Jeanne M.; Tetradis, Sotirios

    2005-01-01

    Parathyroid hormone (PTH) has both anabolic and catabolic effects on bone metabolism, although the molecular mechanisms mediating these effects are largely unknown. Among the transcription factors induced by Pth in osteoblasts are the nerve growth factor-inducible factor B (NR4A; NGFI-B) family of orphan nuclear receptors: Nurr1, Nur77, and NOR-1. PTH induces NR4A members through the cAMP-protein kinase A (PKA) pathway in vitro. We report here that PTH rapidly and transiently induced expression of all three NR4A genes in PTH-target tissues in vivo. In calvaria, long bones, and kidneys, NR4A induction was maximal 0.5-1 h after a single intraperitoneal (i.p.) injection of 80 μg/kg PTH. Nur77 demonstrated the highest expression, followed, in order, by Nurr1 and NOR-1. In calvaria and long bone, PTH-induced expression of each NR4A gene was detectable at 10 μg/kg i.p. with maximum induction at 40-80 μg/kg. PTH (3-34) did not induce NR4A mRNA levels in calvaria, long bone, and kidney in vivo, confirming our in vitro results that NR4A genes are induced primarily through the cAMP-PKA pathway. The magnitude of PTH-induced NR4A expression was comparable in vivo and in vitro. However, NR4A mRNA levels peaked and returned to baseline faster in vivo. Both in vivo and in vitro, PTH induced NR4A pre-mRNA levels suggesting that induction of these genes is, at least in part, through activation of mRNA synthesis. The in vivo induction of the NR4A family members by PTH suggests their involvement in, at least some, PTH-induced changes in bone metabolism

  6. Tissue-type plasminogen activator-binding RNA aptamers inhibiting low-density lipoprotein receptor family-mediated internalisation.

    Science.gov (United States)

    Bjerregaard, Nils; Bøtkjær, Kenneth A; Helsen, Nicky; Andreasen, Peter A; Dupont, Daniel M

    2015-07-01

    Recombinant tissue-type plasminogen activator (tPA, trade name Alteplase), currently the only drug approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of cerebral ischaemic stroke, has been implicated in a number of adverse effects reportedly mediated by interactions with the low-density lipoprotein (LDL) family receptors, including neuronal cell death and an increased risk of cerebral haemorrhage. The tissue-type plasminogen activator is the principal initiator of thrombolysis in human physiology, an effect that is mediated directly via localised activation of the plasmin zymogen plasminogen at the surface of fibrin clots in the vascular lumen. Here, we sought to identify a ligand to tPA capable of inhibiting the relevant LDL family receptors without interfering with the fibrinolytic activity of tPA. Systematic evolution of ligands by exponential enrichment (SELEX) was employed to isolate tPA-binding RNA aptamers, which were characterised in biochemical assays of tPA association to low density lipoprotein receptor-related protein-1 (LRP-1, an LDL receptor family member); tPA-mediated in vitro and ex vivo clot lysis; and tPA-mediated plasminogen activation in the absence and presence of a stimulating soluble fibrin fragment. Two aptamers, K18 and K32, had minimal effects on clot lysis, but were able to efficiently inhibit tPA-LRP-1 association and LDL receptor family-mediated endocytosis in human vascular endothelial cells and astrocytes. These observations suggest that coadministration alongside tPA may be a viable strategy to improve the safety of thrombolytic treatment of cerebral ischaemic stroke by restricting tPA activity to the vascular lumen.

  7. THESEUS 1, FERONIA and relatives: a family of cell wall-sensing receptor kinases?

    Science.gov (United States)

    Cheung, Alice Y; Wu, Hen-Ming

    2011-12-01

    The plant cell wall provides form and integrity to the cell as well as a dynamic interface between a cell and its environment. Therefore mechanisms capable of policing changes in the cell wall, signaling cellular responses including those that would feedback regulate cell wall properties are expected to play important roles in facilitating growth and ensuring survival. Discoveries in the last few years that the Arabidopsis THESEUS 1 receptor-like kinase (RLK) may function as a sensor for cell wall defects to regulate growth and that its relatives FERONIA and ANXURs regulate pollen tube integrity imply strongly that they play key roles in cell wall-related processes. Furthermore, FERONIA acts as a cell surface regulator for RAC/ROP GTPases and activates production of reactive oxygen species which are, respectively, important molecular switches and mediators for diverse processes. These findings position the THESEUS 1/FERONIA family RLKs as surface regulators and potential cell wall sensors capable of broadly and profoundly impacting cellular pathways in response to diverse signals. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Toward a better understanding of the interaction between TGF-β family members and their ALK receptors

    KAUST Repository

    Romano, Valentina; Raimondo, Domenico; Calvanese, Luisa; D’ Auria, Gabriella; Tramontano, Anna; Falcigno, Lucia

    2012-01-01

    Transforming growth factor-beta (TGF-β) proteins are a family of structurally related extracellular proteins that trigger their signaling functions through interaction with the extracellular domains of their cognate serine/threonine kinase receptors. The specificity of TGF-β/receptor binding is complex and gives rise to multiple functional roles. Additionally, it is not completely understood at the atomic level. Here, we use the most reliable computational methods currently available to study systems involving activin-like kinase (ALK) receptors ALK4 and ALK7 and their multiple TGF-β ligands. We built models for all these proteins and their complexes for which experimental structures are not available. By analyzing the surfaces of interaction in six different TGF-β/ALK complexes we could infer which are the structural distinctive features of the ligand-receptor binding mode. Furthermore, this study allowed us to rationalize why binding of the growth factors GDF3 and Nodal to the ALK4 receptor requires the Cripto co-factor, whilst binding to the ALK7 receptor does not. © Springer-Verlag 2012.

  9. Toward a better understanding of the interaction between TGF-β family members and their ALK receptors

    KAUST Repository

    Romano, Valentina

    2012-02-22

    Transforming growth factor-beta (TGF-β) proteins are a family of structurally related extracellular proteins that trigger their signaling functions through interaction with the extracellular domains of their cognate serine/threonine kinase receptors. The specificity of TGF-β/receptor binding is complex and gives rise to multiple functional roles. Additionally, it is not completely understood at the atomic level. Here, we use the most reliable computational methods currently available to study systems involving activin-like kinase (ALK) receptors ALK4 and ALK7 and their multiple TGF-β ligands. We built models for all these proteins and their complexes for which experimental structures are not available. By analyzing the surfaces of interaction in six different TGF-β/ALK complexes we could infer which are the structural distinctive features of the ligand-receptor binding mode. Furthermore, this study allowed us to rationalize why binding of the growth factors GDF3 and Nodal to the ALK4 receptor requires the Cripto co-factor, whilst binding to the ALK7 receptor does not. © Springer-Verlag 2012.

  10. Ghrelin improves vascular autophagy in rats with vascular calcification.

    Science.gov (United States)

    Xu, Mingming; Liu, Lin; Song, Chenfang; Chen, Wei; Gui, Shuyan

    2017-06-15

    This study aimed to investigate whether ghrelin ameliorated vascular calcification (VC) through improving autophagy. VC model was induced by nicotine plus vitamin D 3 in rats and β-glycerophosphate in vascular smooth muscle cell (VSMC). Calcium deposition was detected by von Kossa staining or alizarin red S staining. ALP activity was also detected. Western blot was used to assess the protein expression. Ghrelin treatment attenuated the elevation of calcium deposition and ALP activity in VC model both in vivo and in vitro. Interesting, the protein levels of autophagy markers, LC3 and beclin1 were significantly upregulated by ghrelin in VC model. An autophagy inhibitor, 3-methyladenine blocks the ameliorative effect of ghrelin on VC. Furthermore, protein expressions of phosphate-AMPK were increased by ghrelin treatment both in calcified aorta and VSMC. The effect of ghrelin on autophagy induction and VC attenuation was prevented by AMPK inhibitor, compound C. Our results suggested that ghrelin improved autophagy through AMPK activation, which was resulted in VC amelioration. These data maybe throw light on prevention and therapy of VC. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. A novel mutation in the calcium-sensing receptor gene in an Irish pedigree showing familial hypocalciuric hypercalcemia: a case report.

    LENUS (Irish Health Repository)

    Elamin, Wael F

    2010-01-01

    Familial hypocalciuric hypercalcemia is a rare autosomal dominant disorder characterized by asymptomatic and non-progressive hypercalcemia due to mutations of the calcium-sensing receptor gene. Disorders of calcium metabolism are very common in the elderly, and they can coexist with familial hypocalciuric hypercalcemia in affected families.

  12. Synergistic effect of melatonin and ghrelin in preventing cisplatin-induced ovarian damage via regulation of FOXO3a phosphorylation and binding to the p27Kip1 promoter in primordial follicles.

    Science.gov (United States)

    Jang, Hoon; Na, Younghwa; Hong, Kwonho; Lee, Sangho; Moon, Sohyeon; Cho, Minha; Park, Miseon; Lee, Ok-Hee; Chang, Eun Mi; Lee, Dong Ryul; Ko, Jung Jae; Lee, Woo Sik; Choi, Youngsok

    2017-10-01

    Premature ovarian failure during chemotherapy is a serious problem for young women with cancer. To preserve the fertility of these patients, approaches to prevent chemotherapy-induced ovarian failure are needed. In a previous study, we reported that melatonin treatment prevents the depletion of the dormant follicle pool via repression of the simultaneous activation of dormant primordial follicles by cisplatin. However, melatonin's protective effect was only partial and thus insufficient. In this study, we found that the hormone ghrelin enhances the protective effect of melatonin against cisplatin-induced ovarian failure in mouse model. Co-administration of melatonin and ghrelin more effectively prevented cisplatin-induced follicle disruption. Simultaneous treatment with melatonin and ghrelin almost restored the number of primordial follicles and the corpus luteum in cisplatin-treated ovaries, compared with single administration. We found melatonin and ghrelin receptors on the cell membrane of premature oocytes of primordial follicles. In addition, melatonin and ghrelin co-administration inhibited the cisplatin-induced phosphorylation of PTEN and FOXO3a that induces cytoplasmic translocation of FOXO3a. Inhibition of FOXO3a phosphorylation by melatonin and ghrelin increased the binding affinity of FOXO3a for the p27 Kip1 promoter in primordial follicles. Co-administration of melatonin and ghrelin in cisplatin-treated ovaries restored the expression of p27 Kip1 , which is critical for retention of the dormant status of primordial follicles. In conclusion, these findings suggest that melatonin and ghrelin co-administration is suitable for use as a fertoprotective adjuvant therapy during cisplatin chemotherapy in young female cancer patients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Chronic inflammation modulates ghrelin levels in humans and rats.

    Science.gov (United States)

    Otero, M; Nogueiras, R; Lago, F; Dieguez, C; Gomez-Reino, J J; Gualillo, O

    2004-03-01

    The aim of this work was to investigate whether changes in plasma ghrelin, the recently discovered 28-amino acid gastric hormone that regulates growth hormone (GH) secretion and energy homeostasis, occur during inflammation in adjuvant-induced arthritis (AA) in rats. For completeness, ghrelin plasma levels were measured in rheumatoid arthritis (RA) patients. AA was induced in male Lewis rats using Freund's complete adjuvant. Animals were monitored for weight and food intake, every 2 or 3 days, along all time-course experiments. Plasma ghrelin concentrations in 31 RA patients and 18 healthy controls, as well as in rats, were determined by a specific double-antibody radioimmunoassay. Gastric ghrelin mRNA expression was evaluated by northern blot analysis. Human GH and insulin-like growth factor (IGF)-1 were determined by quantitative chemiluminescence assay. Compared with controls, arthritic rats gained significantly (P Ghrelin plasma levels were significantly lower at day 7 after arthritis induction than in controls (AA 7 = 91.2 +/- 5.6 pg/ml vs controls = 124.75 +/- 5.9 pg/ml), but they recovered to control levels by day 15. RA patients had ghrelin plasma levels significantly lower than healthy controls (RA = 24.54 +/- 2.57 pg/ml vs 39.01 +/- 4.47 pg/ml of healthy controls; P = 0.0041). In AA, there is a compensatory variation of ghrelin levels that relates to body weight adjustments. Recovery of ghrelin levels in the latter stage suggests an adaptive response and may represent a compensatory mechanism under catabolic conditions. In RA patients, chronic imbalance in ghrelin levels suggests that this gastric hormone may participate, together with other factors, in alterations of metabolic status during inflammatory stress.

  14. Effects of ghrelin on circulating neuropeptide Y levels in humans.

    Science.gov (United States)

    Coiro, Vittorio; Saccani-Jotti, Gloria; Rubino, Pasquale; Manfredi, Guido; Melani, Andrea; Chiodera, Paolo

    2006-12-01

    Ghrelin is a 28 amino-acid peptide with a strong GH-releasing activity and a complex role in regulation of appetite, fuel utilization, body weight and composition. Neuropeptide Y (NPY) is a well-known stimulator of pathways favouring food intake and energy storage. Recently, studies in rodents suggested a possible mediation of ghrelin action by NPY. In contrast, until now no evidence of ghrelin-NPY interaction in humans has been provided. In the present study, we examined whether ghrelin influences NPY secretion in normal men. Twelve healthy normal men (aged 24-35 years; body mass index (BMI) 22.3+/-0.93 kg/m2) were tested twice at 08.00 AM on two different days, in random order at weekly intervals, after an overnight fast and rest in bed. An intravenous bolus of 1 microg/kg body weight ghrelin (esperimental test) or an equal amount of normal saline (control test) was injected at time 0. Blood was taken before and over 90 minutes after injections, and was used for the measurement of plasma NPY levels. Plasma levels of NPY slightly, but significantly rose in response to ghrelin, with a mean peak level at 15 min after injection, whereas no significant change was observed after saline administration. Our results show a significant enhancement of plasma NPY levels under ghrelin stimulation. To our knowledge, this is the first demonstration of a ghrelin-NPY interaction in humans, which may suggest a possible mediation of ghrelin action by NPY in humans.

  15. Changes in acyl and total ghrelin concentrations and their association with dry matter intake, average daily gain, and feed efficiency of finishing beef steers and heifers

    Science.gov (United States)

    Ghrelin is a peptide hormone produced in the gut that is implicated in signaling appetite and regulating DMI. The objective of this experiment was to determine the change in acyl ghrelin, total ghrelin, and the ghrelin ratio (acyl ghrelin/total ghrelin) over an 84-d DMI and ADG measurement period a...

  16. Characterization of low active ghrelin ratio in patients with advanced pancreatic cancer.

    Science.gov (United States)

    Miura, Tomofumi; Mitsunaga, Shuichi; Ikeda, Masafumi; Ohno, Izumi; Takahashi, Hideaki; Suzuki, Hidetaka; Irisawa, Ai; Kuwata, Takeshi; Ochiai, Atsushi

    2018-05-18

    Acyl ghrelin is an orexigenic peptide. Active ghrelin ratio, the ratio of acyl ghrelin to total ghrelin, has an important role in physiological functions and gastrointestinal symptoms. However, low active ghrelin ratio-related characteristics, gastrointestinal symptoms, and chemotherapy-induced gastrointestinal toxicity in patients with advanced pancreatic cancer have not been previously evaluated. The goal of this study was to identify low active ghrelin ratio-related factors in treatment-naïve advanced pancreatic cancer patients. Patients with treatment-naïve advanced pancreatic cancer were eligible for inclusion in this study. Active ghrelin ratio and clinical parameters of patients were prospectively recorded. Factors correlated with low active ghrelin ratio and survival were analyzed. In total, 92 patients were analyzed. Low active ghrelin ratio-related factors were advanced age (P advanced pancreatic cancer.

  17. Ghrelin and melatonin as biomarkers in patients with giardiasis

    Directory of Open Access Journals (Sweden)

    Saleem Khteer Al-Hadraawy

    2016-05-01

    Full Text Available Giardia is the most frequently reported intestinal parasite worldwide. The aim of this study was to investigate the ghrelin, melatonin, glucose and cholesterol concentration in male patients infected with Giardia lamblia. We enrolled 66 patients with Giardiasis and the control groups consisted of healthy subjects (n = 30. The results demonstrated that there was a significant decrease (P < 0.05 in ghrelin levels, while the melatonin, glucose and cholesterol levels were significantly increased (P < 0.05 in giardiasis patients as compared to the healthy group. The obtained results suggest that ghrelin and melatonin could serve as biomarkers in patients infected with G. lamblia.

  18. Insight into pattern of codon biasness and nucleotide base usage in serotonin receptor gene family from different mammalian species.

    Science.gov (United States)

    Dass, J Febin Prabhu; Sudandiradoss, C

    2012-07-15

    5-HT (5-Hydroxy-tryptamine) or serotonin receptors are found both in central and peripheral nervous system as well as in non-neuronal tissues. In the animal and human nervous system, serotonin produces various functional effects through a variety of membrane bound receptors. In this study, we focus on 5-HT receptor family from different mammals and examined the factors that account for codon and nucleotide usage variation. A total of 110 homologous coding sequences from 11 different mammalian species were analyzed using relative synonymous codon usage (RSCU), correspondence analysis (COA) and hierarchical cluster analysis together with nucleotide base usage frequency of chemically similar amino acid codons. The mean effective number of codon (ENc) value of 37.06 for 5-HT(6) shows very high codon bias within the family and may be due to high selective translational efficiency. The COA and Spearman's rank correlation reveals that the nucleotide compositional mutation bias as the major factors influencing the codon usage in serotonin receptor genes. The hierarchical cluster analysis suggests that gene function is another dominant factor that affects the codon usage bias, while species is a minor factor. Nucleotide base usage was reported using Goldman, Engelman, Stietz (GES) scale reveals the presence of high uracil (>45%) content at functionally important hydrophobic regions. Our in silico approach will certainly help for further investigations on critical inference on evolution, structure, function and gene expression aspects of 5-HT receptors family which are potential antipsychotic drug targets. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Unique expression pattern of the three insulin receptor family members in the rat mammary gland

    DEFF Research Database (Denmark)

    Hvid, Henning; Klopfleisch, Robert; Vienberg, Sara Gry

    2011-01-01

    mammary gland. Using laser micro-dissection, quantitative RT-PCR and immunohistochemistry, we examined the expression of IR (insulin receptor), IGF-1R (IGF-1 receptor), IRR (insulin receptor-related receptor), ERα (estrogen receptor alpha), ERβ (estrogen receptor beta) and PR (progesteron receptor......) in young, virgin, female Sprague-Dawley rats and compared to expression in reference organs. The mammary gland displayed the highest expression of IRR and IGF-1R. In contrast, low expression of IR transcripts was observed in the mammary gland tissue with expression of the IR-A isoform being 5-fold higher...... than the expression of the IR-B. By immunohistochemistry, expression of IR and IGF-1R was detected in all mammary gland epithelial cells. Expression of ERα and PR was comparable between mammary gland and ovary, whereas expression of ERβ was lower in mammary gland than in the ovary. Finally, expression...

  20. Molecular cloning of a novel, putative G protein-coupled receptor from sea anemones structurally related to members of the FSH, TSH, LH/CG receptor family from mammals

    DEFF Research Database (Denmark)

    Nothacker, H P; Grimmelikhuijzen, C J

    1993-01-01

    hormone (FSH, TSH, LH/CG) receptor family from mammals, including a very large, extracellular N terminus (18-25% sequence identity) and a 7 transmembrane region (44-48% sequence identity). As with the mammalian glycoprotein hormone receptor genes, the sea anemone receptor gene yields transcripts which can...... be alternatively spliced, thereby yielding a shortened receptor variant only containing the large extracellular (soluble) N terminus. All this is strong evidence that the putative glycoprotein hormone receptor from sea anemones is evolutionarily related to those from mammals. This is the first report showing...

  1. Modes of Action and Functions of ERECTA-family Receptor-like Kinases in Plant Organ Growth and Development

    Energy Technology Data Exchange (ETDEWEB)

    TORII, Keiko U.

    2012-05-01

    Higher plants constitute the central resource for renewable lignocellulose biomass that can supplement for the world's depleting stores of fossil fuels. As such, understanding the molecular and genetic mechanisms of plant organ growth will provide key knowledge and genetic resources that enables manipulation of plant biomass feedstock for better growth and productivity. The goal of this proposal is to understand how cell proliferation and growth are coordinated during aboveground organ morphogenesis, and how cell-cell signaling mediated by a family of receptor kinases coordinates plant organogenesis. The well-established model plant Arabidopsis thaliana is used for our research to facilitate rapid progress. Specifically, we focus on how ERECTA-family leucine-rich repeat receptor kinases (LRR-RLKs) interact in a synergistic manner to promote organogenesis and pattern formation in Arabidopsis. This project was highly successful, resulted in fourteen publications including nine peer-reviewed original research articles. One provisional US patent has been filed through this DOE funding. We have addressed the critical roles for a family of receptor kinases in coordinating proliferation and differentiation of plants, and we successfully elucidated the downstream targets of this signaling pathway in specifying stomatal patterning.

  2. Acute food deprivation enhances fear extinction but inhibits long-term depression in the lateral amygdala via ghrelin signaling.

    Science.gov (United States)

    Huang, Chiung-Chun; Chou, Dylan; Yeh, Che-Ming; Hsu, Kuei-Sen

    2016-02-01

    Fear memory-encoding thalamic input synapses to the lateral amygdala (T-LA) exhibit dynamic efficacy changes that are tightly correlated with fear memory strength. Previous studies have shown that auditory fear conditioning involves strengthening of synaptic strength, and conversely, fear extinction training leads to T-LA synaptic weakening and occlusion of long-term depression (LTD) induction. These findings suggest that the mechanisms governing LTD at T-LA synapses may determine the behavioral outcomes of extinction training. Here, we explored this hypothesis by implementing food deprivation (FD) stress in mice to determine its effects on fear extinction and LTD induction at T-LA synapses. We found that FD increased plasma acylated ghrelin levels and enhanced fear extinction and its retention. Augmentation of fear extinction by FD was blocked by pretreatment with growth hormone secretagogue receptor type-1a antagonist D-Lys(3)-GHRP-6, suggesting an involvement of ghrelin signaling. Confirming previous findings, two distinct forms of LTD coexist at thalamic inputs to LA pyramidal neurons that can be induced by low-frequency stimulation (LFS) or paired-pulse LFS (PP-LFS) paired with postsynaptic depolarization, respectively. Unexpectedly, we found that FD impaired the induction of PP-LFS- and group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD, but not LFS-induced LTD. Ghrelin mimicked the effects of FD to impair the induction of PP-LFS- and DHPG-induced LTD at T-LA synapses, which were blocked by co-application of D-Lys(3)-GHRP-6. The sensitivity of synaptic transmission to 1-naphthyl acetyl spermine was not altered by either FD or ghrelin treatment. These results highlight distinct features of fear extinction and LTD at T-LA synapses. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. The CRF Family of Neuropeptides and their Receptors - Mediators of the Central Stress Response

    Science.gov (United States)

    Dedic, Nina; Chen, Alon; Deussing, Jan M.

    2018-01-01

    Background: Dysregulated stress neurocircuits, caused by genetic and/or environmental changes, underlie the development of many neuropsychiatric disorders. Corticotropin-releasing factor (CRF) is the major physiological activator of the hypothalamic-pituitary-adrenal (HPA) axis and conse-quently a primary regulator of the mammalian stress response. Together with its three family members, urocortins (UCNs) 1, 2, and 3, CRF integrates the neuroendocrine, autonomic, metabolic and behavioral responses to stress by activating its cognate receptors CRFR1 and CRFR2. Objective: Here we review the past and current state of the CRF/CRFR field, ranging from pharmacologi-cal studies to genetic mouse models and virus-mediated manipulations. Results: Although it is well established that CRF/CRFR1 signaling mediates aversive responses, includ-ing anxiety and depression-like behaviors, a number of recent studies have challenged this viewpoint by revealing anxiolytic and appetitive properties of specific CRF/CRFR1 circuits. In contrast, the UCN/CRFR2 system is less well understood and may possibly also exert divergent functions on physiol-ogy and behavior depending on the brain region, underlying circuit, and/or experienced stress conditions. Conclusion: A plethora of available genetic tools, including conventional and conditional mouse mutants targeting CRF system components, has greatly advanced our understanding about the endogenous mecha-nisms underlying HPA system regulation and CRF/UCN-related neuronal circuits involved in stress-related behaviors. Yet, the detailed pathways and molecular mechanisms by which the CRF/UCN-system translates negative or positive stimuli into the final, integrated biological response are not completely un-derstood. The utilization of future complementary methodologies, such as cell-type specific Cre-driver lines, viral and optogenetic tools will help to further dissect the function of genetically defined CRF/UCN neurocircuits in the context of

  4. Ryanodine receptors, a family of intracellular calcium ion channels, are expressed throughout early vertebrate development

    Directory of Open Access Journals (Sweden)

    Wu Houdini HT

    2011-12-01

    Full Text Available Abstract Background Calcium signals ([Ca2+]i direct many aspects of embryo development but their regulation is not well characterised. Ryanodine receptors (RyRs are a family of intracellular Ca2+ release channels that control the flux of Ca2+ from internal stores into the cytosol. RyRs are primarily known for their role in excitation-contraction coupling in adult striated muscle and ryr gene mutations are implicated in several human diseases. Current evidence suggests that RyRs do not have a major role to play prior to organogenesis but regulate tissue differentiation. Findings The sequences of the five zebrafish ryr genes were confirmed, their evolutionary relationship established and the primary sequences compared to other vertebrates, including humans. RyRs are differentially expressed in slow (ryr1a, fast (ryr3 and both types (ryr1b of developing skeletal muscle. There are two ryr2 genes (ryr2a and ryr2b which are expressed exclusively in developing CNS and cardiac tissue, respectively. In addition, ryr3 and ryr2a mRNA is detectable in the initial stages of development, prior to embryonic axis formation. Conclusions Our work reveals that zebrafish ryr genes are differentially expressed throughout the developing embryo from cleavage onwards. The data suggests that RyR-regulated Ca2+ signals are associated with several aspects of embryonic development, from organogenesis through to the differentiation of the musculoskeletal, cardiovascular and nervous system. These studies will facilitate further work to explore the developmental function of RyRs in each of these tissue types.

  5. Sex bias in copy number variation of olfactory receptor gene family depends on ethnicity

    Directory of Open Access Journals (Sweden)

    Farideh eShadravan

    2013-03-01

    Full Text Available Gender plays a pivotal role in the human genetic identity and is also manifested in many genetic disorders particularly mental retardation. In this study its effect on copy number variation (CNV, known to cause genetic disorders was explored. As the olfactory receptor (OR repertoire comprises the largest human gene family, it was selected for this study, which was carried out within and between three populations, derived from 150 individuals from the 1000 Genome Project. Analysis of 3872 CNVs detected among 791 OR loci, in which 307 loci showed CNV, revealed the following novel findings: Sex bias in CNV was significantly more prevalent in uncommon than common CNV variants of OR pseudogenes, in which the male genome showed more CNVs; and in one-copy number loss compared to complete deletion of OR pseudogenes; both findings implying a more recent evolutionary role for gender. Sex bias in copy number gain was also detected. Another novel finding was that the observed six bias was largely dependent on ethnicity and was in general absent in East Asians. Using a CNV public database for sick children (ISCA the application of these findings for improving clinical molecular diagnostics is discussed by showing an example of sex bias in CNV among kids with autism. Additional clinical relevance is discussed, as the most polymorphic CNV-enriched OR cluster in the human genome, located on chr 15q11.2, is found near the PWS/AS bi-directionally imprinted region associated with two well-known mental retardation syndromes. As olfaction represents the primitive cognition in most mammals, arguably in competition with the development of a larger brain, the extensive retention of OR pseudogenes in females of this study, might point to a parent-of-origin indirect regulatory role for OR pseudogenes in the embryonic development of human brain. Thus any perturbation in the temporal regulation of olfactory system could lead to developmental delay disorders including

  6. Leptin inhibits and ghrelin augments hypothalamic noradrenaline release after stress.

    Science.gov (United States)

    Kawakami, Akio; Okada, Nobukazu; Rokkaku, Kumiko; Honda, Kazufumi; Ishibashi, Shun; Onaka, Tatsushi

    2008-09-01

    Metabolic conditions affect hypothalamo-pituitary-adrenal responses to stressful stimuli. Here we examined effects of food deprivation, leptin and ghrelin upon noradrenaline release in the hypothalamic paraventricular nucleus (PVN) and plasma adrenocorticotropic hormone (ACTH) concentrations after stressful stimuli. Food deprivation augmented both noradrenaline release in the PVN and the increase in plasma ACTH concentration following electrical footshocks (FSs). An intracerebroventricular injection of leptin attenuated the increases in hypothalamic noradrenaline release and plasma ACTH concentrations after FSs, while ghrelin augmented these responses. These data suggest that leptin inhibits and ghrelin facilitates neuroendocrine stress responses via noradrenaline release and indicate that a decrease in leptin and an increase in ghrelin release after food deprivation might contribute to augmentation of stress-induced ACTH release in a fasting state.

  7. The role of ghrelin in anorexia-cachexia syndromes.

    Science.gov (United States)

    Guillory, Bobby; Splenser, Andres; Garcia, Jose

    2013-01-01

    Anorexia, sarcopenia, and cachexia are common complications of many chronic conditions including cancer, rheumatoid arthritis, HIV infection, aging, and chronic lung, heart, or kidney disease. Currently, there is no effective treatment for muscle atrophy or wasting conditions although they typically take a significant toll on the quality of life of patients and are associated with poor prognosis and decreased survival. Ghrelin affects multiple key pathways in the regulation of body weight, body composition, and appetite in the setting of cachexia that may lead to an increase in appetite and growth hormone secretion and a reduction in energy expenditure and inflammation. The net effect is increased lean body mass and fat mass preservation. In this chapter, we review the mechanisms of action of ghrelin and present the available data in animal models and human trials using ghrelin or ghrelin mimetics in different settings of cachexia. Copyright © 2013 Published by Elsevier Inc. Published by Elsevier Science & Technology.. All rights reserved.

  8. Scheduled feeding results in adipogenesis and increased acylated ghrelin

    OpenAIRE

    Verbaeys, I.; Tolle, V.; SWENNEN, Quirine; Zizzari, P.; Buyse, J.; Epelbaum, J.; Cokelaere, M.

    2011-01-01

    Ghrelin, known to stimulate adipogenesis, displays an endogenous secretory rhythmicity closely related to meal patterns. Therefore, a chronic imposed feeding schedule might induce modified ghrelin levels and consequently adiposity. Growing Wistar rats were schedule-fed by imposing a particular fixed feeding schedule of 3 meals/day without caloric restriction compared with total daily control intake. After 14 days, their body composition was measured by DEXA and compared with ad libitum-fed co...

  9. Therapeutic action of ghrelin in a mouse model of colitis.

    Science.gov (United States)

    Gonzalez-Rey, Elena; Chorny, Alejo; Delgado, Mario

    2006-05-01

    Ghrelin is a novel growth hormone-releasing peptide with potential endogenous anti-inflammatory activities ameliorating some pathologic inflammatory conditions. Crohn's disease is a chronic debilitating disease characterized by severe T helper cell (Th)1-driven inflammation of the colon. The aim of this study was to investigate the therapeutic effect of ghrelin in a murine model of colitis. We examined the anti-inflammatory action of ghrelin in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid. Diverse clinical signs of the disease were evaluated, including weight loss, diarrhea, colitis, and histopathology. We also investigated the mechanisms involved in the potential therapeutic effect of ghrelin, such as inflammatory cytokines and chemokines, Th1-type response, and regulatory factors. Ghrelin ameliorated significantly the clinical and histopathologic severity of the trinitrobenzene sulfonic acid-induced colitis; abrogating body weight loss, diarrhea, and inflammation; and increasing survival. The therapeutic effect was associated with down-regulation of both inflammatory and Th1-driven autoimmune response through the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of interluekin-10/transforming growth factor-beta1-secreting regulatory T cells in this therapeutic effect was demonstrated. Importantly, the ghrelin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. Our data demonstrate novel anti-inflammatory actions for ghrelin in the gastrointestinal tract, ie, the capacity to deactivate the intestinal inflammatory response and to restore mucosal immune tolerance at multiple levels. Consequently, ghrelin administration represents a novel possible therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis.

  10. Plasma levels of acylated and total ghrelin in pediatric patients with chronic kidney disease.

    Science.gov (United States)

    Naufel, Maria Fernanda Soares; Bordon, Milena; de Aquino, Talita Marques; Ribeiro, Eliane Beraldi; de Abreu Carvalhaes, João Tomás

    2010-12-01

    This cross-sectional study set out to compare total and acyl ghrelin levels in children with mild chronic kidney disease (CKD) undergoing conservative treatment (n = 19) with children with end-stage renal disease (ESRD) undergoing hemodialysis (n = 24), and with healthy controls (n = 20). The relationship between ghrelin levels and parameters of renal function, nutritional status, and selective hormones were investigated. ESRD patients had higher total ghrelin levels than those with mild CKD or control individuals. However, acyl ghrelin did not differ between groups, indicating that the excess circulating ghrelin was desacylated. Since desacyl ghrelin has been shown to inhibit appetite, increased levels might contribute to protein-energy wasting in pediatric renal patients. When all 43 renal patients were combined, multiple regression analysis found age and glomerular filtration rate (GFR) to be significant negative predictors of total ghrelin. Acyl ghrelin was influenced negatively by age and positively by energy intake. Acyl to total ghrelin ratio related positively to GFR and energy intake. The results indicate that total but not acyl ghrelin is influenced by low GFR in children with CKD and suggests that ghrelin activation may be impaired in these patients. Since energy intake is a positive predictor of acyl ghrelin, the physiological control of ghrelin secretion appears to be altered in pediatric renal patients.

  11. Relevance of the NR4A sub-family of nuclear orphan receptors in trophoblastic BeWo cell differentiation.

    Science.gov (United States)

    Malhotra, Sudha Saryu; Gupta, Satish Kumar

    2017-01-01

    Nur-77, a member of the NR4A sub-family of nuclear orphan receptors, is downregulated in the placentae of pre-eclamptic women. Here, we investigate the relevance of Nor-1, Nurr-1 and Nur-77 in trophoblastic cell differentiation. Their transcript levels were found to be significantly upregulated in BeWo cells treated with forskolin. The maximum increase was observed after 2 h, with a second peak in the expression levels after 48 h. The expression of NR4A sub-family members was also found to be upregulated in BeWo cells after treatment with hCG and GnRH. A similar significant increase was observed at the respective protein levels after 2 and 48 h of treatment with forskolin, hCG or GnRH. Silencing Nor-1, Nurr-1 or Nur-77 individually did not show any effect on forskolin-, hCG- and/or GnRH-mediated BeWo cell fusion and/or hCG secretion. After silencing any one member of the NR4A sub-family, an increase in the transcript levels of the other sub-family members was observed, indicating a compensatory effect due to their functional redundancy. Simultaneously silencing all three NR4A sub-family members significantly downregulated forskolin- and hCG-mediated BeWo cell fusion and/or hCG secretion. However, a considerable amount of cell death occurred after forskolin or hCG treatment as compared to the control siRNA-transfected cells. These results suggest that the NR4A sub-family of nuclear orphan receptors has a role in trophoblastic cell differentiation.

  12. Ghrelin Ameliorates Asthma by Inhibiting Endoplasmic Reticulum Stress.

    Science.gov (United States)

    Fu, Tian; Wang, Lei; Zeng, Qingdi; Zhang, Yan; Sheng, Baowei; Han, Liping

    2017-12-01

    This study aimed to confirm the ameliorative effect of ghrelin on asthma and investigate its mechanism. The murine model of asthma was induced by ovalbumin (OVA) treatment and assessed by histological pathology and airway responsiveness to methacholine. The total and differential leukocytes were counted. Tumor necrosis factor α, interferon γ, interleukin-5 and interleukin-13 levels in bronchoalveolar lavage fluid were quantified by commercial kits. The protein levels in pulmonary tissues were measured by Western blot analysis. Ghrelin ameliorated the histological pathology and airway hyperresponsiveness in the OVA-induced asthmatic mouse model. Consistently, OVA-increased total and differential leukocytes and levels of tumor necrosis factor α, interferon γ, interleukin-5 and interleukin-13 in bronchoalveolar lavage fluid were significantly attenuated by ghrelin. Ghrelin prevented the increased protein levels of the endoplasmic reticulum stress markers glucose regulated protein 78 and CCAAT/enhancer binding protein homologous protein and reversed the reduced levels of p-Akt in asthmatic mice. Ghrelin might prevent endoplasmic reticulum stress activation by stimulating the Akt signaling pathway, which attenuated inflammation and ameliorated asthma in mice. Ghrelin might be a new target for asthma therapy. Copyright © 2017. Published by Elsevier Inc.

  13. Interpersonal Stressors Predict Ghrelin and Leptin Levels in Women

    Science.gov (United States)

    Jaremka, Lisa M.; Belury, Martha A.; Andridge, Rebecca R.; Malarkey, William B.; Glaser, Ronald; Christian, Lisa; Emery, Charles F.; Kiecolt-Glaser, Janice K.

    2014-01-01

    Objective Stressful events enhance risk for weight gain and adiposity. Ghrelin and leptin, two hormones that are implicated in appetite regulation, may link stressful events to weight gain; a number of rodent studies suggest that stressors increase ghrelin production. The present study investigated the links among daily stressors, ghrelin and leptin, and dietary intake in humans. Method Women (N = 50) completed three study appointments that were scheduled at least 2 weeks apart. At each visit, women arrived fasting and ate a standardized breakfast and lunch. Blood samples were collected 45 minutes after each meal. Women completed a self-report version of the Daily Inventory of Stressful Events (DISE) at each appointment. Two composites were created from the DISE data, reflecting the number of stressors that did and did not involve interpersonal tension. Results Women who experienced more stressors involving interpersonal tension had higher ghrelin and lower leptin levels than those who experienced fewer interpersonal stressors. Furthermore, women who experienced more interpersonal stressors had a diet that was higher in calories, fat, carbohydrates, protein, sugar, sodium, and fiber, and marginally higher in cholesterol, vegetables (but not fruits), vitamin A, and vitamin C. Stressors that did not involve interpersonal tension were unrelated to ghrelin and leptin levels or any of the dietary components examined. Conclusions These data suggest that ghrelin and leptin may link daily interpersonal stressors to weight gain and obesity. PMID:25032903

  14. Expression analysis of the Toll-like receptor and TIR domain adaptor families of zebrafish.

    NARCIS (Netherlands)

    Meijer, A.H.; Krens, SF Gabby; Rodriguez, IA Medina; He, S; Bitter, W.; Snaar-Jagalska, B Ewa; Spaink, H.P.

    2004-01-01

    The zebrafish genomic sequence database was analysed for the presence of genes encoding members of the Toll-like receptors (TLR) and interleukin receptors (IL-R) and associated adaptor proteins containing a TIR domain. The resulting predictions show the presence of one or more counterparts for the

  15. Genetic variation of the ghrelin signalling system in individuals with amphetamine dependence.

    Science.gov (United States)

    Suchankova, Petra; Jerlhag, Elisabet; Jayaram-Lindström, Nitya; Nilsson, Staffan; Toren, Kjell; Rosengren, Annika; Engel, Jörgen A; Franck, Johan

    2013-01-01

    The development of amphetamine dependence largely depends on the effects of amphetamine in the brain reward systems. Ghrelin, an orexigenic peptide, activates the reward systems and is required for reward induced by alcohol, nicotine, cocaine and amphetamine in mice. Human genetic studies have shown that polymorphisms in the pre-proghrelin (GHRL) as well as GHS-R1A (GHSR) genes are associated with high alcohol consumption, increased weight and smoking in males. Since the heritability factor underlying drug dependence is shared between different drugs of abuse, we here examine the association between single nucleotide polymorphisms (SNPs) and haplotypes in the GHRL and GHSR, and amphetamine dependence. GHRL and GHSR SNPs were genotyped in Swedish amphetamine dependent individuals (n = 104) and controls from the general population (n = 310). A case-control analysis was performed and SNPs and haplotypes were additionally tested for association against Addiction Severity Interview (ASI) composite score of drug use. The minor G-allele of the GHSR SNP rs2948694, was more common among amphetamine dependent individuals when compared to controls (pc  = 0.02). A significant association between the GHRL SNP rs4684677 and ASI composite score of drug use was also reported (pc  = 0.03). The haplotype analysis did not add to the information given by the individual polymorphisms. Although genetic variability of the ghrelin signalling system is not a diagnostic marker for amphetamine dependence and problem severity of drug use, the present results strengthen the notion that ghrelin and its receptor may be involved in the development of addictive behaviours and may thus serve as suitable targets for new treatments of such disorders.

  16. Genetic variation of the ghrelin signalling system in individuals with amphetamine dependence.

    Directory of Open Access Journals (Sweden)

    Petra Suchankova

    Full Text Available The development of amphetamine dependence largely depends on the effects of amphetamine in the brain reward systems. Ghrelin, an orexigenic peptide, activates the reward systems and is required for reward induced by alcohol, nicotine, cocaine and amphetamine in mice. Human genetic studies have shown that polymorphisms in the pre-proghrelin (GHRL as well as GHS-R1A (GHSR genes are associated with high alcohol consumption, increased weight and smoking in males. Since the heritability factor underlying drug dependence is shared between different drugs of abuse, we here examine the association between single nucleotide polymorphisms (SNPs and haplotypes in the GHRL and GHSR, and amphetamine dependence. GHRL and GHSR SNPs were genotyped in Swedish amphetamine dependent individuals (n = 104 and controls from the general population (n = 310. A case-control analysis was performed and SNPs and haplotypes were additionally tested for association against Addiction Severity Interview (ASI composite score of drug use. The minor G-allele of the GHSR SNP rs2948694, was more common among amphetamine dependent individuals when compared to controls (pc  = 0.02. A significant association between the GHRL SNP rs4684677 and ASI composite score of drug use was also reported (pc  = 0.03. The haplotype analysis did not add to the information given by the individual polymorphisms. Although genetic variability of the ghrelin signalling system is not a diagnostic marker for amphetamine dependence and problem severity of drug use, the present results strengthen the notion that ghrelin and its receptor may be involved in the development of addictive behaviours and may thus serve as suitable targets for new treatments of such disorders.

  17. Association of plasma ghrelin levels and ghrelin rs4684677 polymorphism with mild cognitive impairment in type 2 diabetic patients

    OpenAIRE

    Huang, Rong; Han, Jing; Tian, Sai; Cai, Rongrong; Sun, Jie; Shen, Yanjue; Wang, Shaohua

    2017-01-01

    Background and aims People with insulin resistance and type 2 diabetes mellitus (T2DM) are at increased risks of cognitive impairment. We aimed to investigate the association of plasma ghrelin levels and ghrelin rs4684677 polymorphism with mild cognitive impairment (MCI) in T2DM patients. Results In addition to elevated glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG) and homeostasis model assessment of insulin resistance (HOMA-IR), T2DM patients with MCI had decreased plasma ghre...

  18. Ghrelin stimulates synaptic formation in cultured cortical networks in a dose-dependent manner

    NARCIS (Netherlands)

    Herzig, K.H.; Stoyanova, Irina; le Feber, Jakob; Rutten, Wim

    2013-01-01

    Ghrelin was initially related to appetite stimulation and growth hormone secretion. These findings suggest that ghrelin may provide a novel therapeutic strategy for the treatment of disorders related to synaptic impairment.

  19. Interferon-γ inhibits ghrelin expression and secretion via a somatostatin-mediated mechanism

    DEFF Research Database (Denmark)

    Strickertsson, Jesper A B; Døssing, Kristina B V; Aabakke, Anna JM

    2011-01-01

    To investigate if and how the proinflammatory cytokine interferon ¿ (IFN¿) affects ghrelin expression in mice.......To investigate if and how the proinflammatory cytokine interferon ¿ (IFN¿) affects ghrelin expression in mice....

  20. Interferon-γ inhibits ghrelin expression and secretion via a somatostatin-mediated mechanism

    DEFF Research Database (Denmark)

    Strickertsson, Jesper A B; Døssing, Kristina B V; Aabakke, Anna JM

    2011-01-01

    To investigate if and how the proinflammatory cytokine interferon γ (IFNγ) affects ghrelin expression in mice.......To investigate if and how the proinflammatory cytokine interferon γ (IFNγ) affects ghrelin expression in mice....

  1. Cytokine-like factor-1, a novel soluble protein, shares homology with members of the cytokine type I receptor family.

    Science.gov (United States)

    Elson, G C; Graber, P; Losberger, C; Herren, S; Gretener, D; Menoud, L N; Wells, T N; Kosco-Vilbois, M H; Gauchat, J F

    1998-08-01

    In this report we describe the identification, cloning, and expression pattern of human cytokine-like factor 1 (hCLF-1) and the identification and cloning of its murine homologue. They were identified from expressed sequence tags using amino acid sequences from conserved regions of the cytokine type I receptor family. Human CLF-1 and murine CLF-1 shared 96% amino acid identity and significant homology with many cytokine type I receptors. CLF-1 is a secreted protein, suggesting that it is either a soluble subunit within a cytokine receptor complex, like the soluble form of the IL-6R alpha-chain, or a subunit of a multimeric cytokine, e.g., IL-12 p40. The highest levels of hCLF-1 mRNA were observed in lymph node, spleen, thymus, appendix, placenta, stomach, bone marrow, and fetal lung, with constitutive expression of CLF-1 mRNA detected in a human kidney fibroblastic cell line. In fibroblast primary cell cultures, CLF-1 mRNA was up-regulated by TNF-alpha, IL-6, and IFN-gamma. Western blot analysis of recombinant forms of hCLF-1 showed that the protein has the tendency to form covalently linked di- and tetramers. These results suggest that CLF-1 is a novel soluble cytokine receptor subunit or part of a novel cytokine complex, possibly playing a regulatory role in the immune system and during fetal development.

  2. Serum ghrelin in female patients with rheumatoid arthritis during treatment with infliximab

    OpenAIRE

    Magiera, Michal; Kopec-Medrek, Magdalena; Widuchowska, Ma?gorzata; Kotulska, Anna; Dziewit, Tomasz; Ziaja, Damian; Kucharz, Eugene J.; Logiewa-Bazger, Beata; Mazur, Wlodzimierz

    2011-01-01

    Ghrelin is a gastric hormone that posses multiple functions, including induction of growth hormone release, regulation of proinflammatory cytokines and control of food intake and energy homeostasis. A few reports on serum ghrelin level in chronic inflammatory states revealed contradictory results. The study was undertaken to determine ghrelin in patients with rheumatoid arthritis receiving infliximab, a TNF-? blocking agent. Serum ghrelin was determined in 18 female rheumatoid patients before...

  3. Estimation of gastric ghrelin-positive cells activity in hyperthyroid rats.

    OpenAIRE

    Maria M Winnicka; Bogusław Sawicki; Robert L Zbucki; Jacek Dadan

    2009-01-01

    Ghrelin is a peptide of 28 amino acids that transmits appetite related signals from peripheral organs to the brain. The main source of ghrelin is stomach. The regulation of ghrelin secretion is still unknown. The finding that fasting and food intake, respectively increase and decrease the secretion of ghrelin suggests that this hormone may be a bridge connecting somatic growth with energy metabolism and appears to play an important role in the alteration of energy homeostasis and body weight ...

  4. Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin

    OpenAIRE

    Wang, Qian; Liu, Chen; Uchida, Aki; Chuang, Jen-Chieh; Walker, Angela; Liu, Tiemin; Osborne-Lawrence, Sherri; Mason, Brittany L.; Mosher, Christina; Berglund, Eric D.; Elmquist, Joel K.; Zigman, Jeffrey M.

    2014-01-01

    The hormone ghrelin stimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreERT2 transgenic mouse model that allows spatiotemporally-controlled re-expression of physiologi...

  5. A novel germline mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene in an Italian family with gigantism.

    Science.gov (United States)

    Urbani, C; Russo, D; Raggi, F; Lombardi, M; Sardella, C; Scattina, I; Lupi, I; Manetti, L; Tomisti, L; Marcocci, C; Martino, E; Bogazzi, F

    2014-10-01

    Acromegaly usually occurs as a sporadic disease, but it may be a part of familial pituitary tumor syndromes in rare cases. Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been associated with a predisposition to familial isolated pituitary adenoma. The aim of the present study was to evaluate the AIP gene in a patient with gigantism and in her relatives. Direct sequencing of AIP gene was performed in fourteen members of the family, spanning among three generations. The index case was an 18-year-old woman with gigantism due to an invasive GH-secreting pituitary adenoma and a concomitant tall-cell variant of papillary thyroid carcinoma. A novel germline mutation in the AIP gene (c.685C>T, p.Q229X) was identified in the proband and in two members of her family, who did not present clinical features of acromegaly or other pituitary disorders. Eleven subjects had no mutation in the AIP gene. Two members of the family with clinical features of acromegaly refused either the genetic or the biochemical evaluation. The Q229X mutation was predicted to generate a truncated AIP protein, lacking the last two tetratricopeptide repeat domains and the final C-terminal α-7 helix. We identified a new AIP germline mutation predicted to produce a truncated AIP protein, lacking its biological properties due to the disruption of the C-terminus binding sites for both the chaperones and the client proteins of AIP.

  6. The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy.

    Science.gov (United States)

    Paolino, Magdalena; Penninger, Josef M

    2016-10-21

    The TAM receptor protein tyrosine kinases-Tyro3, Axl, and Mer-are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy.

  7. Brain Mapping of Ghrelin O-Acyltransferase in Goldfish (Carassius Auratus): Novel Roles for the Ghrelinergic System in Fish?

    Science.gov (United States)

    Blanco, Ayelén M; Sánchez-Bretaño, Aída; Delgado, María J; Valenciano, Ana I

    2016-06-01

    Ghrelin O-acyltransferase (GOAT) is the enzyme responsible for acylation of ghrelin, a gut-brain hormone with important roles in many physiological functions in vertebrates. Many aspects of GOAT remain to be elucidated, especially in fish, and particularly its anatomical distribution within the different brain areas has never been reported to date. The present study aimed to characterize the brain mapping of GOAT using RT-qPCR and immunohistochemistry in a teleost, the goldfish (Carassius auratus). Results show that goat transcripts are expressed in different brain areas of the goldfish, with the highest levels in the vagal lobe. Using immunohistochemistry, we also report the presence of GOAT immunoreactive cells in different encephalic areas, including the telencephalon, some hypothalamic nuclei, pineal gland, optic tectum and cerebellum, although they are especially abundant in the hindbrain. Particularly, an important signal is observed in the vagal lobe and some fiber tracts of the brainstem, such as the medial longitudinal fasciculus, Mauthneri fasciculus, secondary gustatory tract and spinothalamic tract. Most of the forebrain areas where GOAT is detected, particularly the hypothalamic nuclei, also express the ghs-r1a ghrelin receptor and other appetite-regulating hormones (e.g., orexin and NPY), supporting the role of ghrelin as a modulator of food intake and energy balance in fish. Present results are the first report on the presence of GOAT in the brain using imaging techniques. The high presence of GOAT in the hindbrain is a novelty, and point to possible new functions for the ghrelinergic system in fish. Anat Rec, 299:748-758, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. Stress does not affect ghrelin secretion in obese and normal weight women.

    Science.gov (United States)

    Kiessl, Gundula R R; Laessle, Reinhold G

    2017-03-01

    Stress has been supposed to increase appetite. The biological basis of this phenomenon may be a stress-induced alteration of the secretion of GUT peptides such as ghrelin. Stress-induced changes in ghrelin secretion could be a biological basis of overeating and a factor contributing to the development of obesity. Aim of the study was to analyze the effect of acute psychosocial stress on ghrelin secretion in obese and normal weight women. We compared pre- and postprandial plasma ghrelin secretion of 42 obese and 43 normal weight women in a randomized crossover design. Ghrelin and cortisol concentrations were measured and ratings of stress were also recorded in response to a psychological stressor (Trier Social Stress Test, TSST). Ghrelin samples were collected in the fasting state one time before participating in the TSST and one time before a control session. After the TSST, respectively, control session participants had a standardized ad libitum meal. 30 and 60 min after the TSST, respectively, control session preprandial ghrelin was measured again. Obese women showed lower pre- and postprandial release of ghrelin than normal weight controls. Moreover, obese women showed inhibited postprandial decrease of ghrelin secretion. Stress did not affect postprandial ghrelin secretion, but inhibited food intake in all subjects. The present data provide further evidence of altered ghrelin release in obesity. Acute stress did not affect postprandial ghrelin secretion, but inhibited food intake in all subjects. Results are discussed with regard to biological and psychological regulation of hunger and satiety in obesity.

  9. Rise of plasma ghrelin with weight loss is not sustained during weight maintenance

    Science.gov (United States)

    Ghrelin is postulated to be an orexigenic signal that promotes weight regain after weight loss (WL). However, it is not known whether this putative effect of ghrelin is sustained after weight stabilization. The objective of this study was to investigate the relationship of plasma ghrelin concentrati...

  10. Ghrelin level negatively predicts quality of life in obese women.

    Science.gov (United States)

    Lu, P H; Song, Y L; Hsu, C H

    2017-02-01

    A cross-sectional cohort study was conducted to investigate whether ghrelin level in obese women predicts the quality of life (QOL). A total of 307 subjects fulfilled the criteria: (1) age between 20 and 65 years old, (2) body mass index ≥27 kg/m 2 (3) waist circumference ≥80 cm were enrolled in the study. All subjects were assigned to one of the plasma ghrelin level categories according to the quartiles. The median of age and BMI of the 307 obese women were 45 ± 18 years and 29.9 ± 4.1 kg/m 2 , respectively. The main outcome evaluated is the associations of plasma ghrelin level and QOL, which were evaluated using multiple linear regression analysis. Results of linear trend test show significant statistical difference in plasma lipoproteins (triglyceride, cholesterol, HDL-cholestero and LDL-cholesterol = and levels of obesity-related hormone peptides, including leptin, adiponectin, insulin among quartiles of ghrelin. Multiple liner regression analysis of serum obesity-related hormone peptide level and QOL using stepwise method shows ghrelin concentration was the only predictor of QOL, including PCS-12 level (β = -0.18, p = 0.001), MCS-12 level (β = -0.14, p = 0.009), WHOQOL-BREF scores: physical (β = -0.13, p = 0.03), psychological (β = -0.16, p = 0.007), social (β = -0.21, p =  ghrelin concentration is strongly associated with QOL level among obese women. Hence, ghrelin concentration might be a valuable marker to be monitored in obese women.

  11. Lateral septum growth hormone secretagogue receptor affects food intake and motivation for sucrose reinforcement.

    Science.gov (United States)

    Terrill, Sarah J; Wall, Kaylee D; Medina, Nelson D; Maske, Calyn B; Williams, Diana L

    2018-03-28

    The hormone ghrelin promotes eating and is widely considered to be a hunger signal. Ghrelin receptors, growth hormone secretagogue receptors (GHSRs), are found in a number of specific regions throughout the brain, including the lateral septum (LS), an area not traditionally associated with the control of feeding. Here we investigated whether GHSRs in the LS play a role in the control of food intake. We examined the feeding effects of ghrelin and the GHSR antagonists ([D-Lys3]-GHRP-6 and JMV 2959), at doses subthreshold for effect when delivered to the lateral ventricle. Intra-LS ghrelin significantly increased chow intake during the mid-light phase, suggesting that pharmacologic activation of LS GHSRs promotes feeding. Conversely, GHSR antagonist delivered to the LS shortly before dark onset significantly reduced chow intake. These data support the hypothesis that exogenous and endogenous stimulation of GHSRs in the LS influence feeding. Ghrelin is known to affect motivation for food, and the dorsal subdivision of LS (dLS) has been shown to play a role in motivation. Thus, we investigated the role of dLS GHSRs in motivation for food reward by examining operant responding for sucrose on a progressive ratio (PR) schedule. Intra-dLS ghrelin increased PR responding for sucrose, while blockade of LS GHSRs did not affect responding in either a fed or fasted state. Together these findings for the first time substantiate the LS as a site of action for ghrelin signaling in the control of food intake.

  12. THYROID HORMONE RECEPTOR BETA GENE MUTATION (P453A) IN A TURKISH FAMILY PRODUCING RESISTANCE TO THYROID HORMONE

    Science.gov (United States)

    Bayraktaroglu, Taner; Noel, Janet; Mukaddes, Nahit Motavalli; Refetoff, Samuel

    2018-01-01

    Two members of a Turkish family, a mother and son, had thyroid function tests suggestive of resistance to thyroid hormone (RTH). The clinical presentation was, however, different. The mother (proposita) had palpitation, weakness, tiredness, nervousness, dry mouth and was misdiagnosed as having multinodular toxic goiter which was treated with antithyroid drugs and partial thyroidectomy. Her younger son had attention deficit hyperactivity disorder and primary encopresis, but normal intellectual quotient. Both had elevated serum iodothyronine levels with nonsuppressed thyrotropin. A mutation in one allele of the thyroid hormone receptor beta gene (P453A) was identified, providing a genetic confirmation for the diagnosis of RTH. PMID:18561095

  13. Association of ghrelin Leu72Met polymorphism with type 2 diabetes mellitus in Chinese population.

    Science.gov (United States)

    Liu, Jing; Liu, Jia; Tian, Li-min; Liu, Ju-xiang; Bing, Ya-jun; Zhang, Ji-ping; Wang, Yun-Fang; Zhang, Lu-yan

    2012-08-10

    Ghrelin, a novel endogenous ligand for the growth hormone secretagogue receptor, is considered to implicate the development of the type 2 diabetes mellitus (T2DM). The Leu72Met (+408C>A) polymorphism of the preproghrelin, has been linked to obesity, insulin resistance and diabetes. To investigate the distribution of ghrelin gene Leu72Met polymorphism and its association with the type 2 diabetes mellitus in Chinese population. We conducted a case-control study on 877 patients with T2DM and 864 controls, which were genotyped by the polymerase chain reaction (PCR) technique, denaturing high performance liquid chromatography (DHPLC) and DNA sequence analysis. Laboratory analyses were carried out in the hospital laboratory. No significant difference in the Leu72Met genotype distributions and allele frequency was observed between type 2 diabetes mellitus and controls (both P>0.05). The polymorphism was not associated with T2DM. However, among the T2DM group, the patients carrying Leu72Leu genotype had significantly increased levels of FPG and serum creatinine compared with variant genotypes (Leu72Met and Met72Met) (Ppolymorphism of the preproghrelin gene was not associated with T2DM in Chinese population. However, it may have some roles in the etiology of insulin resistance. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. The relaxin family peptide receptors and their ligands: new developments and paradigms in the evolution from jawless fish to mammals.

    Science.gov (United States)

    Yegorov, Sergey; Bogerd, Jan; Good, Sara V

    2014-12-01

    Relaxin family peptide receptors (Rxfps) and their ligands, relaxin (Rln) and insulin-like (Insl) peptides, are broadly implicated in the regulation of reproductive and neuroendocrine processes in mammals. Most placental mammals harbour genes for four receptors, namely rxfp1, rxfp2, rxfp3 and rxfp4. The number and identity of rxfps in other vertebrates are immensely variable, which is probably attributable to intraspecific variation in reproductive and neuroendocrine regulation. Here, we highlight several interesting, but greatly overlooked, aspects of the rln/insl-rxfp evolutionary history: the ancient origin, recruitment of novel receptors, diverse roles of selection, differential retention and lineage-specific loss of genes over evolutionary time. The tremendous diversity of rln/insl and rxfp genes appears to have arisen from two divergent receptors and one ligand that were duplicated by whole genome duplications (WGD) in early vertebrate evolution, although several genes, notably relaxin in mammals, were also duplicated via small scale duplications. Duplication and loss of genes have varied across lineages: teleosts retained more WGD-derived genes, dominated by those thought to be involved in neuroendocrine regulation (rln3, insl5 and rxfp 3/4 genes), while eutherian mammals witnessed the diversification and rapid evolution of genes involved in reproduction (rln/insl3). Several genes that arose early in evolutionary history were lost in most mammals, but retained in teleosts and, to a lesser extent, in early diverging tetrapods. To elaborate on their evolutionary history, we provide updated phylogenies of the Rxfp1/2 and Rxfp3/4 receptors and their ligands, including new sequences from early diverging vertebrate taxa such as coelacanth, skate, spotted gar, and lamprey. We also summarize the recent progress made towards understanding the functional biology of Rxfps in non-mammalian taxa, providing a new conceptual framework for research on Rxfp signaling across

  15. Nuclear receptor 4A (NR4A) family - orphans no more.

    Science.gov (United States)

    Safe, Stephen; Jin, Un-Ho; Morpurgo, Benjamin; Abudayyeh, Ala; Singh, Mandip; Tjalkens, Ronald B

    2016-03-01

    The orphan nuclear receptors NR4A1, NR4A2 and NR4A3 are immediate early genes induced by multiple stressors, and the NR4A receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurological functions and also in inflammation and inflammatory diseases and in immune functions and cancer. Despite the similarities of NR4A1, NR4A2 and NR4A3 and their interactions with common cis-genomic elements, they exhibit unique activities and cell-/tissue-specific functions. Although endogenous ligands for NR4A receptors have not been identified, there is increasing evidence that structurally-diverse synthetic molecules can directly interact with the ligand binding domain of NR4A1 and act as agonists or antagonists, and ligands for NR4A2 and NR4A3 have also been identified. Since NR4A receptors are key factors in multiple diseases, there are opportunities for the future development of NR4A ligands for clinical applications in treating multiple health problems including metabolic, neurologic and cardiovascular diseases, other inflammatory conditions, and cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Ghrelin and obestatin plasma levels and ghrelin/obestatin prepropeptide gene polymorphisms in small for gestational age infants.

    Science.gov (United States)

    Zhang, Shulian; Zhai, Guanpeng; Zhang, Jinping; Zhou, Jianguo; Chen, Chao

    2014-12-01

    To investigate plasma ghrelin and obestatin levels, and ghrelin/obestatin prepropeptide gene polymorphisms, in sequentially enrolled small for gestational age (SGA) infants. Neonates were sequentially enrolled into this study and were then subdivided into different groups, according to different study aims and availability of study materials. Consequently, plasma ghrelin and obestatin levels were measured in term SGA, term appropriate for gestational age (AGA), term large for gestational age (LGA), preterm SGA and preterm AGA neonates. Levels of both peptides were also measured in AGA infants of different gestational ages, and in term AGA neonates at different days following birth. Three ghrelin/obestatin prepropeptide gene single nucleotide polymorphisms (SNPs), Arg51Gln, Leu72Met, and Gln90Leu, were measured in neonates. The study involved a total cohort of 581 neonates. Out of 150 neonates (30 term AGA, 30 term SGA, 30 term LGA, 30 preterm AGA, and 30 preterm SGA), plasma obestatin levels were significantly higher in term SGA versus term LGA neonates (0.21 ± 0.02 ng/ml versus 0.17 ± 0.01 ng/ml, respectively). Out of a wider cohort, there were no significant differences in genotypes and allele frequencies of Arg51Gln, Leu72Met, and Gln90Leu SNPs between term SGA and AGA neonates, or between preterm SGA and AGA neonates. Ghrelin/obestatin prepropeptide polymorphisms were not found to be associated with SGA status in neonates; however, ghrelin and obestatin levels may be involved in growth and development. Further studies are required to understand the relationship between ghrelin, obestatin and prenatal development. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  17. An Integrative Review on Role and Mechanisms of Ghrelin in Stress, Anxiety and Depression.

    Science.gov (United States)

    Bali, Anjana; Jaggi, Amteshwar Singh

    2016-01-01

    Ghrelin is orexigenic hormone primarily synthesized by endocrine X/A-like cells of gastric oxyntic mucosa to stimulate appetite and food intake along with regulation of growth hormone and insulin secretion; glucose and lipid metabolism; gastrointestinal motility; blood pressure, heart rate and neurogenesis. Furthermore, peripherally (after crossing the blood brain barrier) as well as centrally synthesized ghrelin (in the hypothalamus) regulates diverse functions of central nervous system including stress-associated behavioral functions. Exposure to stress alters the ghrelin levels and alteration in ghrelin levels significantly affects neuro-endocrinological parameters; metabolism-related physiology, behavior and mood. Studies have shown both anxiolytic and anxiogenic role of ghrelin suggesting its dual role in modulating anxiety-related behavior. However, it is proposed that increase in ghrelin levels during stress condition is an endogenous stress coping behavior and increased ghrelin levels may be required to prevent excessive anxiety. In preclinical and clinical studies, an elevation in ghrelin levels during depression has been correlated with their antidepressant activities. Ghrelin-induced modulation of stress and associated conditions has been linked to alteration in hypothalamic-pituitary-adrenal (HPA) axis; autonomic nervous system (mainly sympathetic nervous system and serotonergic neurotransmission. A reciprocal relationship has been reported between corticotropin-releasing hormone (CRH) and ghrelin as ghrelin increases the release of CRH, ACTH and corticosteroids; while CRH decreases the expression of ghrelin. Similarly, ghrelin increases the serotonin turnover and in turn, serotonin controls ghrelin signaling to modulate anxiety-related behavior. The present review discusses the dual role of ghrelin in stress and related behavioral disorders along with possible mechanisms.

  18. Altered lipid and salt taste responsivity in ghrelin and GOAT null mice.

    Directory of Open Access Journals (Sweden)

    Huan Cai

    Full Text Available Taste perception plays an important role in regulating food preference, eating behavior and energy homeostasis. Taste perception is modulated by a variety of factors, including gastric hormones such as ghrelin. Ghrelin can regulate growth hormone release, food intake, adiposity, and energy metabolism. Octanoylation of ghrelin by ghrelin O-acyltransferase (GOAT is a specific post-translational modification which is essential for many biological activities of ghrelin. Ghrelin and GOAT are both widely expressed in many organs including the gustatory system. In the current study, overall metabolic profiles were assessed in wild-type (WT, ghrelin knockout (ghrelin(-/-, and GOAT knockout (GOAT(-/- mice. Ghrelin(-/- mice exhibited decreased food intake, increased plasma triglycerides and increased ketone bodies compared to WT mice while demonstrating WT-like body weight, fat composition and glucose control. In contrast GOAT(-/- mice exhibited reduced body weight, adiposity, resting glucose and insulin levels compared to WT mice. Brief access taste behavioral tests were performed to determine taste responsivity in WT, ghrelin(-/- and GOAT(-/- mice. Ghrelin and GOAT null mice possessed reduced lipid taste responsivity. Furthermore, we found that salty taste responsivity was attenuated in ghrelin(-/- mice, yet potentiated in GOAT(-/- mice compared to WT mice. Expression of the potential lipid taste regulators Cd36 and Gpr120 were reduced in the taste buds of ghrelin and GOAT null mice, while the salt-sensitive ENaC subunit was increased in GOAT(-/- mice compared with WT mice. The altered expression of Cd36, Gpr120 and ENaC may be responsible for the altered lipid and salt taste perception in ghrelin(-/- and GOAT(-/- mice. The data presented in the current study potentially implicates ghrelin signaling activity in the modulation of both lipid and salt taste modalities.

  19. The EGFR family of receptors sensitizes cancer cells towards UV light

    DEFF Research Database (Denmark)

    Petersen, Steffen B.; Neves Petersen, Teresa; Olsen, Birgitte

    2008-01-01

    A combination of bioinformatics, biophysical, advanced laser studies and cell biology lead to the realization that laser-pulsed UV light stops cancer growth and induces apoptosis. We have previously shown that laser-pulsed UV (LP-UV) illumination of two different skin-derived cancer cell lines both...... bridges. The EGF receptor is often overexpressed in cancers and other proliferative skin disorders, it might be possible to significantly reduce the proliferative potential of these cells making them good targets for laser-pulsed UV-light treatment. The discovery that UV light can be used to open...... disulphide bridges in proteins upon illumination of nearby aromatic amino acids was the first step that lead to the hypothesis that UV light could modulate the structure and therefore the function of these key receptor proteins. The observation that membrane receptors (EGFR) contained exactly the motifs...

  20. Loneliness predicts postprandial ghrelin and hunger in women.

    Science.gov (United States)

    Jaremka, Lisa M; Fagundes, Christopher P; Peng, Juan; Belury, Martha A; Andridge, Rebecca R; Malarkey, William B; Kiecolt-Glaser, Janice K

    2015-04-01

    Loneliness is strongly linked to poor health. Recent research suggests that appetite dysregulation provides one potential pathway through which loneliness and other forms of social disconnection influence health. Obesity may alter the link between loneliness and appetite-relevant hormones, one unexplored possibility. We examined the relationships between loneliness and both postmeal ghrelin and hunger, and tested whether these links differed for people with a higher versus lower body mass index (BMI; kg/m(2)). During this double-blind randomized crossover study, women (N=42) ate a high saturated fat meal at the beginning of one full-day visit and a high oleic sunflower oil meal at the beginning of the other. Loneliness was assessed once with a commonly used loneliness questionnaire. Ghrelin was sampled before the meal and postmeal at 2 and 7h. Self-reported hunger was measured before the meal, immediately postmeal, and then 2, 4, and 7h later. Lonelier women had larger postprandial ghrelin and hunger increases compared with less lonely women, but only among participants with a lower BMI. Loneliness and postprandial ghrelin and hunger were unrelated among participants with a higher BMI. These effects were consistent across both meals. These data suggest that ghrelin, an important appetite-regulation hormone, and hunger may link loneliness to weight gain and its corresponding negative health effects among non-obese people. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Serum Adipokine and Ghrelin Levels in Nonalcoholic Steatohepatitis

    Directory of Open Access Journals (Sweden)

    Mehmet Yalniz

    2006-01-01

    Full Text Available Adipokines and ghrelin play role in insulin resistance, the key pathophysiological abnormality in patients with nonalcoholic fatty liver diseases. In the present study, relationship between nonalcoholic steatohepatitis (NASH and serum adipokine and ghrelin levels was investigated. Thirty seven patients with biopsy-proven NASH and 25 age- and sex-matched controls were enrolled. Ten of NASH patients (27% had diabetes mellitus (n=5 or impaired glucose tolerance (n=5. Body mass index (BMI was less than 30 kg/m2 in 67.6% of patients, while in the remaining 32.4% it was more than 30 kg/m2. Serum adiponectin, leptin, TNF-α, and ghrelin were determined. Serum leptin (15.49±4.84 vs 10.31±2.53 and TNF-α (12.1±2.7 vs 10.31±2.56 levels were significantly higher in the NASH group compared to in the control group (P30 or glucose tolerance was impaired or not (P>.05. Additionally, neither adipokines nor ghrelin was correlated with histopathological grade and stage (P>.05. In conclusion; there is a significant relationship between NASH and adipokines and ghrelin independent from BMI and status of the glucose metabolism. These cytokines that appear to have role in the pathogenesis of NASH, however, do not have any effect upon the severity of the histopathology.

  2. G-Protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention.

    Science.gov (United States)

    Conrad, Kirk P

    2016-09-01

    Important roles for G-protein-coupled receptors (GPCRs) have been identified in the maternal physiological adaptations to pregnancy and in the pathogenesis of preeclampsia. On this basis, GPCRs are potential therapeutic targets for preeclampsia. In this review, vasopressin and apelin are initially considered in this context before the focus on the hormone relaxin and its cognate receptor, the relaxin/insulin-like family peptide receptor 1 (RXFP1). Based on both compelling scientific rationale and a promising safety profile, the relaxin ligand-receptor system is comprehensively evaluated as a potential therapeutic endpoint in preeclampsia. The published literature relating to the topic was searched through January 2016 using PubMed. Relaxin is a peptide hormone secreted by the corpus luteum; it circulates in the luteal phase and during pregnancy. Activation of RXFP1 is vasodilatory; thus, relaxin supplementation is expected to at least partly restore the fundamental vasodilatory changes of normal pregnancy, thereby alleviating maternal organ hypoperfusion, which is a major pathogenic manifestation of severe preeclampsia. Specifically, by exploiting its pleiotropic hemodynamic attributes in preeclampsia, relaxin administration is predicted to (i) reverse robust arterial myogenic constriction; (ii) blunt systemic and renal vasoconstriction in response to activation of the angiotensin II receptor, type 1; (iii) mollify the action of endogenous vasoconstrictors on uterine spiral arteries with failed remodeling and retained smooth muscle; (iv) increase arterial compliance; (v) enhance insulin-mediated glucose disposal by promoting skeletal muscle vasodilation and (vi) mobilize and activate bone marrow-derived angiogenic progenitor cells, thereby repairing injured endothelium and improving maternal vascularity in organs such as breast, uterus, pancreas, skin and fat. By exploiting its pleiotropic molecular attributes in preeclampsia, relaxin supplementation is

  3. Novel nonsense mutation of the endothelin-B receptor gene in a family with Waardenburg-Hirschsprung disease.

    Science.gov (United States)

    Syrris, P; Carter, N D; Patton, M A

    1999-11-05

    Waardenburg syndrome (WS) comprises sensorineural hearing loss, hypopigmentation of skin and hair, and pigmentary disturbances of the irides. Four types of WS have been classified to date; in WS type IV (WS4), patients additionally have colonic aganglionosis (Hirschsprung disease, HSCR). Mutations in the endothelin-3 (EDN3), endothelin-B receptor (EDNRB), and Sox10 genes have been identified as causative for WS type IV. We screened a family with a combined WS-HSCR phenotype for mutations in the EDNRB locus using standard DNA mutation analysis and sequencing techniques. We have identified a novel nonsense mutation at codon 253 (CGA-->TGA, Arg-->STOP). This mutation leads to a premature end of the translation of EDNRB at exon 3, and it is predicted to produce a truncated and nonfunctional endothelin-B receptor. All affected relatives were heterozygous for the Arg(253)-->STOP mutation, whereas it was not observed in over 50 unrelated individuals used as controls. These data confirm the role of EDNRB in the cause of the Waardenburg-Hirschsprung syndrome and demonstrate that in WS-HSCR there is a lack of correlation between phenotype and genotype and a variable expression of disease even within the same family. Copyright 1999 Wiley-Liss, Inc.

  4. Microbial receptor assay for rapid detection and identification of seven families of antimicrobial drugs in milk: collaborative study

    International Nuclear Information System (INIS)

    Charm, S.E.; Chi, R.

    1988-01-01

    A microbial competitive receptor assay for detecting residues of antibiotic families in milk was studied collaboratively by 13 laboratories. In this method, microbial cells added to a milk sample provide specific binding sites for which 14 C or 3 H labeled drug competes with drug resides in the sample. The 14 C or 3 H binding to the specific binding sites is measured in a scintillation counter and compared with a zero standard milk. If the sample is statistically different from the zero standard, it is positive. The assay takes about 15 min. The binding reaction occurs between the receptor site and the drug functional group, so all members of a drug family are detected. In this case, beta-lactams, tetracyclines, macrolides, aminoglycosides, novobiocin, chloramphenicol, and sulfonamides, including p-amino-benzoic acid (PABA) and its other analogs, are detectable. The incidence of false negative determinations among samples is about 1%; the incidence of false positives is about 3%. For negative cases, the relative standard deviations for repeatability ranged from 0 to 5% and for reproducibility from 0 to 6%. For positive cases, relative standard deviations ranged from 0 to 13% for repeatability and from 0 to 14% for reproducibility. The method has been adopted official first action

  5. The Leu72Met polymorphism of the ghrelin gene is associated with a decreased risk for type 2 diabetes.

    Science.gov (United States)

    Berthold, Heiner K; Giannakidou, Eleni; Krone, Wilhelm; Mantzoros, Christos S; Gouni-Berthold, Ioanna

    2009-01-01

    Ghrelin is involved in several metabolic and cardiovascular processes. The Leu72Met polymorphism of its gene was associated with an increased risk of type 2 diabetes (DM2) in some, but not all studies. Its association with atherosclerosis is not known. We investigated 420 Caucasian subjects with DM2 and 430 controls without diabetes (56.6% male, age 62+/-10 years). The Leu72Leu genotype frequencies were 89.76/84.65%, the Leu72Met 9.52/15.12% and the Met72Met 0.71/0.23% (P=0.029) in the DM2 and controls groups, respectively. In subjects with Met72+ genotypes the risk of DM2 was significantly decreased (univariate OR 0.63, 95% CI 0.42-0.95, P=0.026). In a logistic regression model, body mass index, hypertension and a positive family history for diabetes were predictors of diabetes while the polymorphism remained negatively associated with the disease (OR 0.62, 95% CI 0.40-0.97, P=0.036). After adjusting for known risk factors for atherosclerosis, the Met72+ variant was not associated with atherosclerotic disease (OR 1.41, 95% CI 0.78-2.54, P=0.25). Ghrelin concentrations were not associated with the polymorphism, DM2 or atherosclerotic disease. The Leu72Met polymorphism of the ghrelin gene is associated with a decreased risk for DM2. There is no association between the variant and atherosclerotic disease or ghrelin concentrations.

  6. Synthesis and in vitro/in vivo evaluation of novel mono- and trivalent technetium-99m labeled ghrelin peptide complexes as potential diagnostic radiopharmaceuticals

    International Nuclear Information System (INIS)

    Koźmiński, Przemysław; Gniazdowska, Ewa

    2015-01-01

    Introduction: Ghrelin is an endogenous hormone present in blood. It is released from the oxyntic cells (X/A-like cells) of the stomach and fundus and can exist in two forms: as an acylated and des-acylated ghrelin. Ghrelin is an endogenous ligand of the growth hormone receptor (growth hormone secretagogue receptor, GHS-R). Overexpression of GHS-R1a receptor was identified in cells of different types of tumors (e.g. pituitary adenoma, neuroendocrine tumors of the thyroid, lung, breast, gonads, prostate, stomach, colorectal, endocrine and non-endocrine pancreatic tumors). This fact suggests that gamma radionuclide labeled ghrelin peptide may be considered as a potential diagnostic radiopharmaceutical. Methods: Ghrelin peptide labeled with mono- and trivalent technetium-99m complexes, 99m Tc-Lys-GHR, has been prepared on the n.c.a. scale. The physicochemical (stability, charge, shape, lipophilicity) and biological (receptor affinity, biodistribution) properties of the conjugates have been studied relevant to use the conjugates as receptor-based diagnostic radiopharmaceuticals. Results: The obtained conjugates [ 99m Tc(CO) 3 L N,O (CN-Lys-GHR)] + , 99m Tc(CO) 3 L S,O (CN-Lys-GHR) and 99m Tc(NS 3 )(CN-Lys-GHR) show different shape, charge, lipophilicity and two of them, 99m Tc(CO) 3 L S,O (CN-Lys-GHR) and 99m Tc(NS 3 )(CN-Lys-GHR), high stability in neutral aqueous solutions, even in the presence of excess concentration of histidine/cysteine competitive standard ligands or human serum. The in vitro binding affinity of 99m Tc-Lys-GHR conjugates with respect to growth hormone secretagogue receptor (GHS-R1a) present on DU-145 cells was in the range of IC 50 from 45 to 54 nM. The conjugate 99m Tc(CO) 3 L S,O (CN-Lys-GHR) exhibited excretion route by the liver and kidney in comparable degree, while the more lipophilic conjugate 99m Tc(NS 3 )(CN-Lys-GHR)—mainly by the liver. Conclusions: Basing on the results concerning physicochemical and biochemical properties, the

  7. En route to new blockbuster antihistamines:surveying the offspring of the expanding histamine receptor family

    NARCIS (Netherlands)

    Leurs, R.; Vischer, H.F.; Wijtmans, M.; De Esch, I.J.

    2011-01-01

    With the recognition of two new histamine receptors at the start of the new millennium, the field of histamine research has seen a clear revival. In the last 10 years, many academic and industrial groups have taken up the challenge to target these new members of the aminergic G-protein-coupled

  8. Ionotropic glutamate receptors (iGluRs) of the delta family (GluD1 ...

    African Journals Online (AJOL)

    Muhammad Zahid Khan

    2016-10-20

    Oct 20, 2016 ... GluD1 knockout mice (GluD1 KO) have normal learning in the Morris water maze .... could bind and activate the receptor.5,6 D-Ser and glycine have now been identified as .... English editing of this manuscript. References. 1.

  9. Ionotropic glutamate receptors (iGluRs) of the delta family (GluD1 ...

    African Journals Online (AJOL)

    ... such as Neurexin1. This review presents current knowledge regarding the expression, structure and function of Glu delta receptors (GluD1, GluD2) in brain, focusing on synapse formation, function and dysfunction. Keywords: iGluRs; GluD1; GluD2; Synaptogenesis; Autism spectrum disorder (ASD); Schizophrenia (SCZ) ...

  10. Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphoma.

    Directory of Open Access Journals (Sweden)

    Christine F Skibola

    Full Text Available BACKGROUND: Non-Hodgkin lymphoma (NHL is the fifth most common cancer in the U.S. and few causes have been identified. Genetic association studies may help identify environmental risk factors and enhance our understanding of disease mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: 768 coding and haplotype tagging SNPs in 146 genes were examined using Illumina GoldenGate technology in a large population-based case-control study of NHL in the San Francisco Bay Area (1,292 cases 1,375 controls are included here. Statistical analyses were restricted to HIV- participants of white non-Hispanic origin. Genes involved in steroidogenesis, immune function, cell signaling, sunlight exposure, xenobiotic metabolism/oxidative stress, energy balance, and uptake and metabolism of cholesterol, folate and vitamin C were investigated. Sixteen SNPs in eight pathways and nine haplotypes were associated with NHL after correction for multiple testing at the adjusted q<0.10 level. Eight SNPs were tested in an independent case-control study of lymphoma in Germany (494 NHL cases and 494 matched controls. Novel associations with common variants in estrogen receptor 1 (ESR1 and in the vitamin C receptor and matrix metalloproteinase gene families were observed. Four ESR1 SNPs were associated with follicular lymphoma (FL in the U.S. study, with rs3020314 remaining associated with reduced risk of FL after multiple testing adjustments [odds ratio (OR = 0.42, 95% confidence interval (CI = 0.23-0.77 and replication in the German study (OR = 0.24, 95% CI = 0.06-0.94. Several SNPs and haplotypes in the matrix metalloproteinase-3 (MMP3 and MMP9 genes and in the vitamin C receptor genes, solute carrier family 23 member 1 (SLC23A1 and SLC23A2, showed associations with NHL risk. CONCLUSIONS/SIGNIFICANCE: Our findings suggest a role for estrogen, vitamin C and matrix metalloproteinases in the pathogenesis of NHL that will require further validation.

  11. Characterization of a family of gamma-ray-induced CHO mutants demonstrates that the ldlA locus is diploid and encodes the low-density lipoprotein receptor

    International Nuclear Information System (INIS)

    Sege, R.D.; Kozarsky, K.F.; Krieger, M.

    1986-01-01

    The ldlA locus is one of four Chinese hamster ovary (CHO) cell loci which are known to be required for the synthesis of functional low-density lipoprotein (LDL) receptors. Previous studies have suggested that the ldlA locus is diploid and encodes the LDL receptor. To confirm this assignment, we have isolated a partial genomic clone of the Chinese hamster LDL receptor gene and used this and other nucleic acid and antibody probes to study a family of ldlA mutants isolated after gamma-irradiation. Our analysis suggests that there are two LDL receptor alleles in wild-type CHO cells. Each of the three mutants isolated after gamma-irradiation had detectable deletions affecting one of the two LDL receptor alleles. One of the mutants also had a disruption of the remaining allele, resulting in the synthesis of an abnormal receptor precursor which was not subject to Golgi-associated posttranslational glycoprotein processing. The correlation of changes in the expression, structure, and function of LDL receptors with deletions in the LDL receptor genes in these mutants directly demonstrated that the ldlA locus in CHO cells is diploid and encodes the LDL receptor. In addition, our analysis suggests that CHO cells in culture may contain a partial LDL receptor pseudogene

  12. Estimation of gastric ghrelin-positive cells activity in hyperthyroid rats.

    Science.gov (United States)

    Dadan, Jacek; Zbucki, Robert L; Sawicki, Bogusław; Winnicka, Maria M

    2008-01-01

    Ghrelin is a peptide of 28 amino acids that transmits appetite related signals from peripheral organs to the brain. The main source of ghrelin is stomach. The regulation of ghrelin secretion is still unknown. The finding that fasting and food intake, respectively increase and decrease the secretion of ghrelin suggests that this hormone may be a bridge connecting somatic growth with energy metabolism and appears to play an important role in the alteration of energy homeostasis and body weight in pathophisiological conditions. The purpose of this study was the evaluation of gastric ghrelin immunoreactivity and ghrelin plasma concentration in male Wistar rats with hyperthyroidism. Experimental model of hyperthyroidism was induced by intraperitoneal injection of levothyroxine at the dose of 80 microg/kg daily over 21 days. At the end of experiment the animals were anaesthetized, blood was taken from abdominal aorta to determinate plasma ghrelin concentration by RIA and then the animals underwent resection of distal part of stomach. Immunohistochemical study were performed using monoclonal specific antybodies against ghrelin. Hyperthyroidism was a reason of increase of gastric mucosal ghrelin - immunoreactivity, accompanied by a significant decreased of ghrelin plasma concentration. Those observations may indicate, that chronic administration of L-thyroxine cause the change of ghrelin plasma concentration in rats, probably via direct influence on gastric X/A-like cells, but this effect is not responsible for hyperphagia associated with hyperthyroidism.

  13. Estimation of gastric ghrelin-positive cells activity in hyperthyroid rats.

    Directory of Open Access Journals (Sweden)

    Maria M Winnicka

    2009-01-01

    Full Text Available Ghrelin is a peptide of 28 amino acids that transmits appetite related signals from peripheral organs to the brain. The main source of ghrelin is stomach. The regulation of ghrelin secretion is still unknown. The finding that fasting and food intake, respectively increase and decrease the secretion of ghrelin suggests that this hormone may be a bridge connecting somatic growth with energy metabolism and appears to play an important role in the alteration of energy homeostasis and body weight in pathophisiological conditions. The purpose of this study was the evaluation of gastric ghrelin immunoreactivity and ghrelin plasma concentration in male Wistar rats with hyperthyroidism. Experimental model of hyperthyroidism was induced by intraperitoneal injection of levothyroxine at the dose of 80 microg/kg daily over 21 days. At the end of experiment the animals were anaesthetized, blood was taken from abdominal aorta to determinate plasma ghrelin concentration by RIA and then the animals underwent resection of distal part of stomach. Immunohistochemical study were performed using monoclonal specific antybodies against ghrelin. Hyperthyroidism was a reason of increase of gastric mucosal ghrelin - immunoreactivity, accompanied by a significant decreased of ghrelin plasma concentration. Those observations may indicate, that chronic administration of L-thyroxine cause the change of ghrelin plasma concentration in rats, probably via direct influence on gastric X/A-like cells, but this effect is not responsible for hyperphagia associated with hyperthyroidism.

  14. Obesity, food intake and exercise: Relationship with ghrelin

    Directory of Open Access Journals (Sweden)

    Tiryaki-Sonmez Gul

    2015-09-01

    Full Text Available Obesity, a disorder of body composition, is defined by a relative or absolute excess of body fat. In general adult population, obesity has been associated with a diverse array of adverse health outcomes, including major causes of death such as cancer, diabetes, cardiovascular disease, as well as functional impairment from problems such as osteoarthritis and sleep apnea. Ghrelin is a newly discovered peptide hormone which plays an important role in obesity. It is a powerful, endogenous orexigenic peptide and has a crucial function in appetite regulation, as well as short – and long-term energy homeostasis. In the presence of increased obesity, decreased physical activity, and high food consumption, the relationship between exercise, appetite, food intake and ghrelin levels has important implications. In this review, we discuss the effect of acute and chronic exercise performance on appetite, food intake and ghrelin and their relationships.

  15. Leu72Met and Other Intronic Polymorphisms in the and Genes Are Not Associated with Type 2 Diabetes Mellitus, Insulin Resistance, or Serum Ghrelin Levels in a Saudi Population

    OpenAIRE

    Faris Elbahi Joatar; Ali Ahmed Al Qarni; Muhalab E. Ali; Abdulaziz Al Masaud; Abdirashid M. Shire; Nagalla Das; Khalid Gumaa; Hayder A. Giha

    2017-01-01

    Background Ghrelin (GHRL), a gastric peptide encoded by the GHRL gene, is known to be involved in energy homeostasis via its G protein receptor, encoded by the growth hormone secretagogue receptor (GHSR) gene. Some studies have shown associations between plasma GHRL levels and GHRL single-nucleotide polymorphisms (SNPs), namely the Leu72Met polymorphism (rs696217 TG), with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), while others have not. The controversies in these associatio...

  16. Role of ghrelin in the pathophysiology of eating disorders: implications for pharmacotherapy.

    Science.gov (United States)

    Cardona Cano, Sebastian; Merkestein, Myrte; Skibicka, Karolina P; Dickson, Suzanne L; Adan, Roger A H

    2012-04-01

    Ghrelin is the only known circulating orexigenic hormone. It increases food intake by interacting with hypothalamic and brainstem circuits involved in energy balance, as well as reward-related brain areas. A heightened gut-brain ghrelin axis is an emerging feature of certain eating disorders such as anorexia nervosa and Prader-Willi syndrome. In common obesity, ghrelin levels are lowered, whereas post-meal ghrelin levels remain higher than in lean individuals. Agents that interfere with ghrelin signalling have therapeutic potential for eating disorders, including obesity. However, most of these drugs are only in the preclinical phase of development. Data obtained so far suggest that ghrelin agonists may have potential in the treatment of anorexia nervosa, while ghrelin antagonists seem promising for other eating disorders such as obesity and Prader-Willi syndrome. However, large clinical trials are needed to evaluate the efficacy and safety of these drugs.

  17. Lacto-ghrestatin, a novel bovine milk-derived peptide, suppresses ghrelin secretion.

    Science.gov (United States)

    Aoki, Hayato; Nakato, Junya; Mizushige, Takafumi; Iwakura, Hiroshi; Sato, Masaru; Suzuki, Hideyuki; Kanamoto, Ryuhei; Ohinata, Kousaku

    2017-07-01

    Ghrelin, an endogenous peptide isolated from the stomach, is known to stimulate food intake after peripheral administration. We found that the enzymatic digest of β-lactoglobulin decreases ghrelin secretion from the ghrelin-producing cell line MGN3-1. The peptides present in the digest were comprehensively analyzed using the nanoLC-OrbitrapMS. Among them, we identified that the nonapeptide LIVTQTMKG, corresponding to β-lactoglobulin(1-9), suppresses ghrelin secretion from MGN3-1 cells. We named LIVTQTMKG 'lacto-ghrestatin'. We found that lacto-ghrestatin decreases intracellular cAMP levels and mRNA expression levels of ghrelin production-related genes in MGN3-1 cells. Orally administered lacto-ghrestatin decreases plasma ghrelin levels and food intake in fasted mice. Lacto-ghrestatin is the first food-derived peptide to suppress ghrelin secretion in vitro and in vivo. © 2017 Federation of European Biochemical Societies.

  18. On the Emerging Role of the Taste Receptor Type 1 (T1R Family of Nutrient-Sensors in the Musculoskeletal System

    Directory of Open Access Journals (Sweden)

    Shoichiro Kokabu

    2017-03-01

    Full Text Available The special sense of taste guides and guards food intake and is essential for body maintenance. Salty and sour tastes are sensed via ion channels or gated ion channels while G protein-coupled receptors (GPCRs of the taste receptor type 1 (T1R family sense sweet and umami tastes and GPCRs of the taste receptor type 2 (T2R family sense bitter tastes. T1R and T2R receptors share similar downstream signaling pathways that result in the stimulation of phospholipase-C-β2. The T1R family includes three members that form heterodimeric complexes to recognize either amino acids or sweet molecules such as glucose. Although these functions were originally described in gustatory tissue, T1R family members are expressed in numerous non-gustatory tissues and are now viewed as nutrient sensors that play important roles in monitoring global glucose and amino acid status. Here, we highlight emerging evidence detailing the function of T1R family members in the musculoskeletal system and review these findings in the context of the musculoskeletal diseases sarcopenia and osteoporosis, which are major public health problems among the elderly that affect locomotion, activities of daily living, and quality of life. These studies raise the possibility that T1R family member function may be modulated for therapeutic benefit.

  19. Sickness behaviour after lipopolysaccharide treatment in ghrelin deficient mice.

    Science.gov (United States)

    Szentirmai, Éva; Krueger, James M

    2014-02-01

    Ghrelin is an orexigenic hormone produced mainly by the gastrointestinal system and the brain. Much evidence also indicates a role for ghrelin in sleep and thermoregulation. Further, ghrelin was recently implicated in immune system modulation. Administration of bacterial lipopolysaccharide (LPS) induces fever, anorexia, and increased non-rapid-eye movement sleep (NREMS) and these actions are mediated primarily by proinflammatory cytokines. Ghrelin reduces LPS-induced fever, suppresses circulating levels of proinflammatory cytokines and reduces the severity and mortality of various models of experimental endotoxemia. In the present study, we determined the role of intact ghrelin signaling in LPS-induced sleep, feeding, and thermoregulatory responses in mice. Sleep-wake activity was determined after intraperitoneal, dark onset administration of 0.4, 2 and 10 μg LPS in preproghrelin knockout (KO) and wild-type (WT) mice. In addition, body temperature, motor activity and changes in 24-h food intake and body weight were measured. LPS induced dose-dependent increases in NREMS, and suppressed rapid-eye movement sleep, electroencephalographic slow-wave activity, motor activity, food intake and body weight in both Ppg KO and WT mice. Body temperature changes showed a biphasic pattern with a decrease during the dark period followed by an increase in the light phase. The effects of the low and middle doses of LPS were indistinguishable between the two genotypes. Administration of 10 μg LPS, however, induced significantly larger changes in NREMS and wakefulness amounts, body temperature, food intake and body weight in the Ppg KO mice. These findings support a role for ghrelin as an endogenous modulator of inflammatory responses and a central component of arousal and feeding circuits. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Joint association of nicotinic acetylcholine receptor variants with abdominal obesity in American Indians: the Strong Heart Family Study.

    Science.gov (United States)

    Zhu, Yun; Yang, Jingyun; Yeh, Fawn; Cole, Shelley A; Haack, Karin; Lee, Elisa T; Howard, Barbara V; Zhao, Jinying

    2014-01-01

    Cigarette smoke is a strong risk factor for obesity and cardiovascular disease. The effect of genetic variants involved in nicotine metabolism on obesity or body composition has not been well studied. Though many genetic variants have previously been associated with adiposity or body fat distribution, a single variant usually confers a minimal individual risk. The goal of this study is to evaluate the joint association of multiple variants involved in cigarette smoke or nicotine dependence with obesity-related phenotypes in American Indians. To achieve this goal, we genotyped 61 tagSNPs in seven genes encoding nicotine acetylcholine receptors (nAChRs) in 3,665 American Indians participating in the Strong Heart Family Study. Single SNP association with obesity-related traits was tested using family-based association, adjusting for traditional risk factors including smoking. Joint association of all SNPs in the seven nAChRs genes were examined by gene-family analysis based on weighted truncated product method (TPM). Multiple testing was controlled by false discovery rate (FDR). Results demonstrate that multiple SNPs showed weak individual association with one or more measures of obesity, but none survived correction for multiple testing. However, gene-family analysis revealed significant associations with waist circumference (p = 0.0001) and waist-to-hip ratio (p = 0.0001), but not body mass index (p = 0.20) and percent body fat (p = 0.29), indicating that genetic variants are jointly associated with abdominal, but not general, obesity among American Indians. The observed combined genetic effect is independent of cigarette smoking per se. In conclusion, multiple variants in the nAChR gene family are jointly associated with abdominal obesity in American Indians, independent of general obesity and cigarette smoking per se.

  1. Decreased ghrelin and des-acyl ghrelin plasma levels in patients affected by pharmacoresistant epilepsy and maintained on the ketogenic diet.

    Science.gov (United States)

    Marchiò, Maddalena; Roli, Laura; Giordano, Carmela; Trenti, Tommaso; Guerra, Azzurra; Biagini, Giuseppe

    2018-03-23

    The gastric hormones ghreli