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Sample records for leptin receptor-deficient mice

  1. Genetics Home Reference: leptin receptor deficiency

    Science.gov (United States)

    ... People with leptin receptor deficiency also have hypogonadotropic hypogonadism, which is a condition caused by reduced production ... weight gain associated with this disorder. Because hypogonadotropic hypogonadism occurs in leptin receptor deficiency , researchers suggest that ...

  2. Validity of leptin receptor-deficiency (db/db) type 2 diabetes mellitus mice as a model of secondary osteoporosis

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    Huang, Le; You, Yong-Ke; Zhu, Tracy Y.; Zheng, Li-Zhen; Huang, Xiao-Ru; Chen, Hai-Yong; Yao, Dong; Lan, Hui-Yao; Qin, Ling

    2016-06-01

    This study aimed to evaluate the validation of the leptin receptor-deficient mice model for secondary osteoporosis associated with type 2 diabetes mellitus (T2DM) at bone micro-architectural level. Thirty three 36-week old male mice were divided into four groups: normal control (db/m) (n = 7), leptin receptor-deficient T2DM (db/db) (n = 8), human C-reactive protein (CRP) transgenic normal control (crp/db/m) (n = 7), and human CRP transgenic T2DM (crp/db/db) (n = 11). Lumber vertebrae (L5) and bilateral lower limbs were scanned by micro-CT to analyze trabecular and cortical bone quality. Right femora were used for three-point bending to analyze the mechanical properties. Trabecular bone quality at L5 was better in db/db or crp/db/db group in terms of bone mineral density (BMD), bone volume fraction, connectivity density, trabecular number and separation (all p  0.05). Maximum loading and energy yield in mechanical test were similar among groups while the elastic modulus in db/db and crp/db/db significantly lower than db/m. The leptin-receptor mice is not a proper model for secondary osteoporosis associated with T2DM.

  3. Whole-Body Vibration Mimics the Metabolic Effects of Exercise in Male Leptin Receptor-Deficient Mice.

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    McGee-Lawrence, Meghan E; Wenger, Karl H; Misra, Sudipta; Davis, Catherine L; Pollock, Norman K; Elsalanty, Mohammed; Ding, Kehong; Isales, Carlos M; Hamrick, Mark W; Wosiski-Kuhn, Marlena; Arounleut, Phonepasong; Mattson, Mark P; Cutler, Roy G; Yu, Jack C; Stranahan, Alexis M

    2017-05-01

    Whole-body vibration (WBV) has gained attention as a potential exercise mimetic, but direct comparisons with the metabolic effects of exercise are scarce. To determine whether WBV recapitulates the metabolic and osteogenic effects of physical activity, we exposed male wild-type (WT) and leptin receptor-deficient (db/db) mice to daily treadmill exercise (TE) or WBV for 3 months. Body weights were analyzed and compared with WT and db/db mice that remained sedentary. Glucose and insulin tolerance testing revealed comparable attenuation of hyperglycemia and insulin resistance in db/db mice following TE or WBV. Both interventions reduced body weight in db/db mice and normalized muscle fiber diameter. TE or WBV also attenuated adipocyte hypertrophy in visceral adipose tissue and reduced hepatic lipid content in db/db mice. Although the effects of leptin receptor deficiency on cortical bone structure were not eliminated by either intervention, exercise and WBV increased circulating levels of osteocalcin in db/db mice. In the context of increased serum osteocalcin, the modest effects of TE and WBV on bone geometry, mineralization, and biomechanics may reflect subtle increases in osteoblast activity in multiple areas of the skeleton. Taken together, these observations indicate that WBV recapitulates the effects of exercise on metabolism in type 2 diabetes.

  4. Impaired clearance of influenza A virus in obese, leptin receptor deficient mice is independent of leptin signaling in the lung epithelium and macrophages.

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    Kathryn A Radigan

    Full Text Available During the recent H1N1 outbreak, obese patients had worsened lung injury and increased mortality. We used a murine model of influenza A pneumonia to test the hypothesis that leptin receptor deficiency might explain the enhanced mortality in obese patients.We infected wild-type, obese mice globally deficient in the leptin receptor (db/db and non-obese mice with tissue specific deletion of the leptin receptor in the lung epithelium (SPC-Cre/LepR fl/fl or macrophages and alveolar type II cells (LysM-Cre/Lepr fl/fl with influenza A virus (A/WSN/33 [H1N1] (500 and 1500 pfu/mouse and measured mortality, viral clearance and several markers of lung injury severity.The clearance of influenza A virus from the lungs of mice was impaired in obese mice globally deficient in the leptin receptor (db/db compared to normal weight wild-type mice. In contrast, non-obese, SP-C-Cre+/+/LepR fl/fl and LysM-Cre+/+/LepR fl/fl had improved viral clearance after influenza A infection. In obese mice, mortality was increased compared with wild-type mice, while the SP-C-Cre+/+/LepR fl/fl and LysM-Cre+/+/LepR fl/fl mice exhibited improved survival.Global loss of the leptin receptor results in reduced viral clearance and worse outcomes following influenza A infection. These findings are not the result of the loss of leptin signaling in lung epithelial cells or macrophages. Our results suggest that factors associated with obesity or with leptin signaling in non-myeloid populations such as natural killer and T cells may be associated with worsened outcomes following influenza A infection.

  5. Mechanical Vibration Mitigates the Decrease of Bone Quantity and Bone Quality of Leptin Receptor-Deficient Db/Db Mice by Promoting Bone Formation and Inhibiting Bone Resorption.

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    Jing, Da; Luo, Erping; Cai, Jing; Tong, Shichao; Zhai, Mingming; Shen, Guanghao; Wang, Xin; Luo, Zhuojing

    2016-09-01

    Leptin, a major hormonal product of adipocytes, is involved in regulating appetite and energy metabolism. Substantial studies have revealed the anabolic actions of leptin on skeletons and bone cells both in vivo and in vitro. Growing evidence has substantiated that leptin receptor-deficient db/db mice exhibit decreased bone mass and impaired bone microstructure despite several conflicting results previously reported. We herein systematically investigated bone microarchitecture, mechanical strength, bone turnover and its potential molecular mechanisms in db/db mice. More importantly, we also explored an effective approach for increasing bone mass in leptin receptor-deficient animals in an easy and noninvasive manner. Our results show that deterioration of trabecular and cortical bone microarchitecture and decreases of skeletal mechanical strength-including maximum load, yield load, stiffness, energy, tissue-level modulus and hardness-in db/db mice were significantly ameliorated by 12-week, whole-body vibration (WBV) with 0.5 g, 45 Hz via micro-computed tomography (μCT), three-point bending, and nanoindentation examinations. Serum biochemical analysis shows that WBV significantly decreased serum tartrate-resistant acid phosphatase 5b (TRACP5b) and CTx-1 levels and also mitigated the reduction of serum osteocalcin (OCN) in db/db mice. Bone histomorphometric analysis confirmed that decreased bone formation-lower mineral apposition rate, bone formation rate, and osteoblast numbers in cancellous bone-in db/db mice were suppressed by WBV. Real-time PCR assays show that WBV mitigated the reductions of tibial alkaline phosphatase (ALP), OCN, Runt-related transcription factor 2 (RUNX2), type I collagen (COL1), BMP2, Wnt3a, Lrp6, and β-catenin mRNA expression, and prevented the increases of tibial sclerostin (SOST), RANK, RANKL, RANL/osteoprotegerin (OPG) gene levels in db/db mice. Our results show that WBV promoted bone quantity and quality in db/db mice with obvious

  6. Diet-induced obese mice retain endogenous leptin action.

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    Ottaway, Nickki; Mahbod, Parinaz; Rivero, Belen; Norman, Lee Ann; Gertler, Arieh; D'Alessio, David A; Perez-Tilve, Diego

    2015-06-02

    Obesity is characterized by hyperleptinemia and decreased response to exogenous leptin. This has been widely attributed to the development of leptin resistance, a state of impaired leptin signaling proposed to contribute to the development and persistence of obesity. To directly determine endogenous leptin activity in obesity, we treated lean and obese mice with a leptin receptor antagonist. The antagonist increased feeding and body weight (BW) in lean mice, but not in obese models of leptin, leptin receptor, or melanocortin-4 receptor deficiency. In contrast, the antagonist increased feeding and BW comparably in lean and diet-induced obese (DIO) mice, an increase associated with decreased hypothalamic expression of Socs3, a primary target of leptin. These findings demonstrate that hyperleptinemic DIO mice retain leptin suppression of feeding comparable to lean mice and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Early childhood BMI trajectories in monogenic obesity due to leptin, leptin receptor, and melanocortin 4 receptor deficiency.

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    Kohlsdorf, Katja; Nunziata, Adriana; Funcke, Jan-Bernd; Brandt, Stephanie; von Schnurbein, Julia; Vollbach, Heike; Lennerz, Belinda; Fritsch, Maria; Greber-Platzer, Susanne; Fröhlich-Reiterer, Elke; Luedeke, Manuel; Borck, Guntram; Debatin, Klaus-Michael; Fischer-Posovszky, Pamela; Wabitsch, Martin

    2018-02-27

    To evaluate whether early childhood body mass index (BMI) is an appropriate indicator for monogenic obesity. A cohort of n = 21 children living in Germany or Austria with monogenic obesity due to congenital leptin deficiency (group LEP, n = 6), leptin receptor deficiency (group LEPR, n = 6) and primarily heterozygous MC4 receptor deficiency (group MC4R, n = 9) was analyzed. A control group (CTRL) was defined that consisted of n = 22 obese adolescents with no mutation in the above mentioned genes. Early childhood (0-5 years) BMI trajectories were compared between the groups at selected time points. The LEP and LEPR group showed a tremendous increase in BMI during the first 2 years of life with all patients displaying a BMI >27 kg/m 2 (27.2-38.4 kg/m 2 ) and %BMI P95 (percentage of the 95th percentile BMI for age and sex) >140% (144.8-198.6%) at the age of 2 years and a BMI > 33 kg/m 2 (33.3-45.9 kg/m 2 ) and %BMI P95  > 184% (184.1-212.6%) at the age of 5 years. The MC4R and CTRL groups had a later onset of obesity with significantly lower BMI values at both time points (p BMI trajectories in this pediatric cohort with monogenic obesity we suggest that BMI values >27.0 kg/m 2 or %BMI P95  > 140% at the age of 2 years and BMI values >33.0 kg/m 2 or %BMI P95  > 184% at the age of 5 years may be useful cut points to identify children who should undergo genetic screening for monogenic obesity due to functionally relevant mutations in the leptin gene or leptin receptor gene.

  8. Dihydromyricetin ameliorates atherosclerosis in LDL receptor deficient mice.

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    Liu, Ting Ting; Zeng, Yi; Tang, Kun; Chen, XueMeng; Zhang, Wei; Xu, Xiao Le

    2017-07-01

    Dihydromyricetin, the most abundant flavonoid in Ampelopsis grossedentata, exerts numerous pharmacological activities, including anti-inflammatory, antioxidant, hepatoprotective, and lipid regulatory activities; however, its protective effect against atherosclerosis remains poorly understood. The aim of the present study was to evaluate the effects of dihydromyricetin on high fat diet (HFD)-induced atherosclerosis using LDL receptor deficient (LDLr -/- ) mice. Blood samples were collected for determination of serum lipid profiles, oxidized LDL (ox-LDL) and pro-inflammatory cytokines. Histology, hepatic lipid content, quantification of atherosclerosis, assessment of oxidative stress and inflammation were performed on liver and aorta samples by molecular biology methods. The effects of dihydromyricetin on ox-LDL-induced human umbilical vein endothelial cells (HUVECs) dysfunction and foam cell formation were further studied. (1) Dihydromyricetin ameliorated hyperlipidemia, reduced serum ox-LDL, IL-6 and TNF-α levels in HFD-fed LDLr -/- mice. Moreover, (2) dihydromyricetin suppressed hepatic lipid accumulation and increased protein expressions of PPARα, LXRα and ABCA1. (3) It inhibited atherosclerotic lesion formation and favoured features of plaque stability. (4) Dihydromyricetin prevented hepatic and aortic inflammation as evidenced by the reduced IL-6 and TNF-α mRNA expression; (5) it prevented hepatic and aortic oxidative stress by normalizing activities of antioxidant enzymes in the liver and suppressing reactive oxygen species generation and NOX2 protein expression in both liver and aorta; (6) it inhibited oxLDL-induced injury, monocytes adhesion and oxidative stress in HUVECs and (7) inhibited macrophage foam cell formation and enhanced cholesterol efflux. These findings suggest that dihydromyricetin could reduce atherosclerosis via its pleiotropic effects, including improvement of endothelial dysfunction, inhibition of macrophage foam cell formation

  9. Leptin Increases Striatal Dopamine D2 Receptor Binding in Leptin-Deficient Obese (ob/ob) Mice

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    Pfaffly, J.; Michaelides, M.; Wang, G-J.; Pessin, J.E.; Volkow, N.D.; Thanos, P.K.

    2010-06-01

    Peripheral and central leptin administration have been shown to mediate central dopamine (DA) signaling. Leptin-receptor deficient rodents show decreased DA D2 receptor (D2R) binding in striatum and unique DA profiles compared to controls. Leptin-deficient mice show increased DA activity in reward-related brain regions. The objective of this study was to examine whether basal D2R-binding differences contribute to the phenotypic behaviors of leptin-deficient ob/ob mice, and whether D2R binding is altered in response to peripheral leptin treatment in these mice. Leptin decreased body weight, food intake, and plasma insulin concentration in ob/ob mice but not in wild-type mice. Basal striatal D2R binding (measured with autoradiography [{sup 3}H] spiperone) did not differ between ob/ob and wild-type mice but the response to leptin did. In wild-type mice, leptin decreased striatal D2R binding, whereas, in ob/ob mice, leptin increased D2R binding. Our findings provide further evidence that leptin modulates D2R expression in striatum and that these effects are genotype/phenotype dependent.

  10. Leptin Receptor Deficiency is Associated With Upregulation of Cannabinoid 1 Receptors in Limbic Brain Regions

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    THANOS, PANAYOTIS K.; RAMALHETE, ROBERTO C.; MICHAELIDES, MICHAEL; PIYIS, YIANNI K.; WANG, GENE-JACK; VOLKOW, NORA D.

    2009-01-01

    Leptin receptor dysfunction results in overeating and obesity. Leptin regulates hypothalamic signaling that underlies the motivation to hyperphagia, but the interaction between leptin and cannabinoid signaling is poorly understood. We evaluated the role of cannabinoid 1 receptors (CB1R) in overeating and the effects of food deprivation on CB1R in the brain. One-month-old Zucker rats were divided into unrestricted and restricted (fed 70% of unrestricted rats) diet groups and maintained until adulthood (4 months). Levels of relative binding sites of CB1R (CB1R binding levels) were assessed using [3H] SR141716A in vitro autoradiography. These levels were higher (except cerebellum and hypothalamus) at 4 months than at 1 month of age. One month CB1R binding levels for most brain regions did not differ between Ob and Lean (Le) rats (except in frontal and cingulate cortices in Le and in the hypothalamus in Ob). Four month Ob rats had higher CB1R binding levels than Le in most brain regions and food restriction was associated with higher CB1R levels in all brain regions in Ob, but not in Le rats. CB1R binding levels increased between adolescence and young adulthood which we believe was influenced by leptin and food availability. The high levels of CB1R in Ob rats suggest that leptin's inhibition of food-intake is in part mediated by downregulation of CB1R and that leptin interferes with CB1R upregulation under food-deprivation conditions. These results are consistent with prior findings showing increased levels of endogenous cannabinoids in the Ob rats corroborating the regulation of cannabinoid signaling by leptin. PMID:18563836

  11. Increased vascular sympathetic modulation in mice with Mas receptor deficiency

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    Rabello Casali, Karina; Ravizzoni Dartora, Daniela; Moura, Marina; Bertagnolli, Mariane; Bader, Michael; Haibara, Andrea; Alenina, Natalia; Irigoyen, Maria Claudia; Santos, Robson A

    2016-01-01

    Introduction: The angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1–7)/Mas axis could modulate the heart rate (HR) and blood pressure variabilities (BPV) which are important predictors of cardiovascular risk and provide information about the autonomic modulation of the cardiovascular system. Therefore we investigated the effect of Mas deficiency on autonomic modulation in wild type and Mas-knockout (KO) mice. Methods: Blood pressure was recorded at high sample rate (4000 Hz). Stationary sequences of 200–250 beats were randomly chosen. Frequency domain analysis of HR and BPV was performed with an autoregressive algorithm on the pulse interval sequences and on respective systolic sequences. Results: The KO group presented an increase of systolic arterial pressure (SAP; 127.26±11.20 vs 135.07±6.98 mmHg), BPV (3.54±1.54 vs 5.87±2.12 mmHg2), and low-frequency component of systolic BPV (0.12±0.11 vs 0.47±0.34 mmHg2). Conclusions: The deletion of Mas receptor is associated with an increase of SAP and with an increased BPV, indicating alterations in autonomic control. Increase of sympathetic vascular modulation in absence of Mas evidences the important role of Ang-(1–7)/Mas on cardiovascular regulation. Moreover, the absence of significant changes in HR and HRV can indicate an adaptation of autonomic cardiac balance. Our results suggest that the Ang-(1–7)/Mas axis seems more important in autonomic modulation of arterial pressure than HR. PMID:27080540

  12. The daidzein- and estradiol- induced anorectic action in CCK or leptin receptor deficiency rats.

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    Fujitani, Mina; Mizushige, Takafumi; Bhattarai, Keshab; Iwahara, Asami; Aida, Ryojiro; Kishida, Taro

    2015-01-01

    We investigated the effect of daidzein feeding and estradiol treatment on food intake in cholecystokinin-1 receptor (CCK1R) deficiency, leptin receptor (ObRb) deficiency rats and their wild-type rats. These rats underwent an ovariectomy or a sham operation. For the 5 week experiment, each rat was divided in three groups: control, daidzein (150 mg/kg diet), and estradiol (4.2 μg/rat/day) groups. In both CCK1R+ and CCK1R- rats, daidzein feeding and estradiol treatment significantly decreased food intake. Daidzein feeding significantly reduced food intake in ovariectomized ObRb- rats, although not in ObRb+ rats. Estradiol treatment significantly lowered food intake in ovariectomized ObRb+ and ObRb- rats. In the ovariectomized rats, estradiol treatment significantly increases uterine weight, while daidzein feeding did not change it, suggesting that daidzein might have no or weak estrogenic effect in our experiment. These results suggest that CCK1R and ObRb signalings were not essential for the daidzein- and estradiol-induced anorectic action.

  13. P2X7 receptor-deficient mice are susceptible to bone cancer pain

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    Hansen, RR; Nielsen, CK; Nasser, A

    2011-01-01

    The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice...... of the P2X7R KO mouse. Further experiments are needed to elucidate the exact role of the P2X7 receptors in bone cancer pain. Pain-related behaviours had an earlier onset in bone cancer-bearing, P2X7 receptor-deficient mice, and treatment with A-438079 failed to alleviate pain-related behaviours....

  14. Modulation of sweet taste sensitivities by endogenous leptin and endocannabinoids in mice.

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    Niki, Mayu; Jyotaki, Masafumi; Yoshida, Ryusuke; Yasumatsu, Keiko; Shigemura, Noriatsu; DiPatrizio, Nicholas V; Piomelli, Daniele; Ninomiya, Yuzo

    2015-06-01

    Potential roles of endogenous leptin and endocannabinoids in sweet taste were examined by using pharmacological antagonists and mouse models including leptin receptor deficient (db/db) and diet-induced obese (DIO) mice. Chorda tympani (CT) nerve responses of lean mice to sweet compounds were increased after administration of leptin antagonist (LA) but not affected by administration of cannabinoid receptor antagonist (AM251). db/db mice showed clear suppression of CT responses to sweet compounds after AM251, increased endocannabinoid levels in the taste organ, and enhanced expression of a biosynthesizing enzyme of endocannabinoids in taste cells. The effect of LA was gradually decreased and that of AM251 was increased during the course of obesity in DIO mice. These findings suggest that circulating leptin, but not local endocannabinoids, is a dominant modulator for sweet taste in lean mice and endocannabinoids become more effective modulators of sweet taste under conditions of deficient leptin signalling. Leptin is an anorexigenic mediator that reduces food intake by acting on hypothalamic receptor Ob-Rb. In contrast, endocannabinoids are orexigenic mediators that act via cannabinoid CB1 receptors in hypothalamus, limbic forebrain, and brainstem. In the peripheral taste system, leptin administration selectively inhibits behavioural, taste nerve and taste cell responses to sweet compounds. Opposing the action of leptin, endocannabinoids enhance sweet taste responses. However, potential roles of endogenous leptin and endocannabinoids in sweet taste remain unclear. Here, we used pharmacological antagonists (Ob-Rb: L39A/D40A/F41A (LA), CB1 : AM251) and examined the effects of their blocking activation of endogenous leptin and endocannabinoid signalling on taste responses in lean control, leptin receptor deficient db/db, and diet-induced obese (DIO) mice. Lean mice exhibited significant increases in chorda tympani (CT) nerve responses to sweet compounds after LA

  15. Deficiency of leptin receptor in myeloid cells disrupts hypothalamic metabolic circuits and causes body weight increase

    Directory of Open Access Journals (Sweden)

    Yuanqing Gao

    2018-01-01

    Conclusions: Myeloid cell leptin receptor deficient mice partially replicate the db/db phenotype. Leptin signaling in hypothalamic microglia is important for microglial function and a correct formation of the hypothalamic neuronal circuit regulating metabolism.

  16. Citrullus lanatus `Sentinel' (Watermelon) Extract Reduces Atherosclerosis in LDL Receptor Deficient Mice

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    Poduri, Aruna; Rateri, Debra L.; Saha, Shubin K.; Saha, Sibu; Daugherty, Alan

    2012-01-01

    Watermelon (Citrullus lanatus or C. lanatus) has many potentially bioactive compounds including citrulline, which may influence atherosclerosis. In this study, we determined the effects of C. lanatus, provided as an extract of the cultivar `sentinel', on hypercholesterolemia-induced atherosclerosis in mice. Male LDL receptor deficient mice at 8 weeks old were given either C. lanatus `sentinel' extract (2% vol/vol; n=10) or a mixture of matching carbohydrates (2% vol/vol; n=8) as the control in drinking water, while fed a saturated fat-enriched diet for 12 weeks ad libitum. Mice consuming C. lanatus `sentinel' extract had significantly increased plasma citrulline concentrations. Systolic blood pressure was comparable between the two groups. Consumption of C. lanatus `sentinel' extract led to lower body weight and fat mass without influencing lean mass. There were no differences in food and water intake, and urine output between the two groups. C. lanatus `sentinel' extract administration decreased plasma cholesterol concentrations that were attributed to reductions of intermediate/low density lipoprotein cholesterol. Plasma concentrations of MCP-1 and IFN-γ were decreased and IL-10 increased in mice consuming C. lanatus `sentinel' extract. Intake of C. lanatus `sentinel' extract resulted in reductions of atherosclerosis in both aortic arch and thoracic regions. In conclusion, consumption of C. lanatus `sentinel' extract led to reduced body weight gain, decreased plasma cholesterol concentrations, improved homeostasis of pro- and anti-inflammatory cytokines, and attenuated development of atherosclerosis without affecting systolic blood pressure in hypercholesterolemic mice. PMID:22902326

  17. Citrullus lanatus 'sentinel' (watermelon) extract reduces atherosclerosis in LDL receptor-deficient mice.

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    Poduri, Aruna; Rateri, Debra L; Saha, Shubin K; Saha, Sibu; Daugherty, Alan

    2013-05-01

    Watermelon (Citrullus lanatus or C. lanatus) has many potentially bioactive compounds including citrulline, which may influence atherosclerosis. In this study, we determined the effects of C. lanatus, provided as an extract of the cultivar 'sentinel,' on hypercholesterolemia-induced atherosclerosis in mice. Male low-density lipoprotein receptor-deficient mice at 8 weeks old were given either C. lanatus 'sentinel' extract (2% vol/vol; n=10) or a mixture of matching carbohydrates (2% vol/vol; n=8) as the control in drinking water while being fed a saturated fat-enriched diet for 12 weeks ad libitum. Mice consuming C. lanatus 'sentinel' extract had significantly increased plasma citrulline concentrations. Systolic blood pressure was comparable between the two groups. Consumption of C. lanatus 'sentinel' extract led to lower body weight and fat mass without influencing lean mass. There were no differences in food and water intake and in urine output between the two groups. C. lanatus 'sentinel' extract administration decreased plasma cholesterol concentrations that were attributed to reductions of intermediate-/low-density lipoprotein cholesterol. Plasma concentrations of monocyte chemoattractant protein-1 and interferon-gamma were decreased and those of interleukin-10 were increased in mice consuming C. lanatus 'sentinel' extract. Intake of C. lanatus 'sentinel' extract resulted in reductions of atherosclerosis in both aortic arch and thoracic regions. In conclusion, consumption of C. lanatus 'sentinel' extract led to reduced body weight gain, decreased plasma cholesterol concentrations, improved homeostasis of pro- and anti-inflammatory cytokines, and attenuated development of atherosclerosis without affecting systolic blood pressure in hypercholesterolemic mice. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Hematopoietic sphingosine 1-phosphate lyase deficiency decreases atherosclerotic lesion development in LDL-receptor deficient mice.

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    Martine Bot

    Full Text Available AIMS: Altered sphingosine 1-phosphate (S1P homeostasis and signaling is implicated in various inflammatory diseases including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we investigated the impact of hematopoietic S1P lyase (Sgpl1(-/- deficiency on leukocyte subsets relevant to atherosclerosis. METHODS AND RESULTS: LDL receptor deficient mice that were transplanted with Sgpl1(-/- bone marrow showed disrupted S1P gradients translating into lymphopenia and abrogated lymphocyte mitogenic and cytokine response as compared to controls. Remarkably however, Sgpl1(-/- chimeras displayed mild monocytosis, due to impeded stromal retention and myelopoiesis, and plasma cytokine and macrophage expression patterns, that were largely compatible with classical macrophage activation. Collectively these two phenotypic features of Sgpl1 deficiency culminated in diminished atherogenic response. CONCLUSIONS: Here we not only firmly establish the critical role of hematopoietic S1P lyase in controlling S1P levels and T cell trafficking in blood and lymphoid tissue, but also identify leukocyte Sgpl1 as critical factor in monocyte macrophage differentiation and function. Its, partly counterbalancing, pro- and anti-inflammatory activity spectrum imply that intervention in S1P lyase function in inflammatory disorders such as atherosclerosis should be considered with caution.

  19. Endogenous androgen deficiency enhances diet-induced hypercholesterolemia and atherosclerosis in low-density lipoprotein receptor-deficient mice.

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    Hatch, Nicholas W; Srodulski, Sarah J; Chan, Huei-Wei; Zhang, Xuan; Tannock, Lisa R; King, Victoria L

    2012-10-01

    Despite numerous clinical and animal studies, the role of sex steroid hormones on lipoprotein metabolism and atherosclerosis remain controversial. We sought to determine the effects of endogenous estrogen and testosterone on lipoprotein levels and atherosclerosis using mice fed a low-fat diet with no added cholesterol. Male and female low-density lipoprotein receptor-deficient mice were fed an open stock low-fat diet (10% of kcals from fat) for 2, 4, or 17 weeks. Ovariectomy, orchidectomy, or sham surgeries were performed to evaluate the effects of the presence or absence of endogenous hormones on lipid levels, lipoprotein distribution, and atherosclerosis development. Female mice fed the study diet for 17 weeks had a marked increase in levels of total cholesterol, triglycerides, apolipoprotein-B containing lipoproteins, and atherosclerosis compared with male mice. Surprisingly, ovariectomy in female mice had no effect on any of these parameters. In contrast, castration of male mice markedly increased total cholesterol concentrations, triglycerides, apolipoprotein B-containing lipoproteins, and atherosclerotic lesion formation compared with male and female mice. These data suggest that endogenous androgens protect against diet-induced increases in cholesterol concentrations, formation of proatherogenic lipoproteins, and atherosclerotic lesions formation. Conversely orchidectomy, which decreases androgen concentrations, promotes increases in cholesterol concentrations, proatherogenic lipoprotein formation, and atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice in response to a low-fat diet. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

  20. Hematopoietic androgen receptor deficiency promotes visceral fat deposition in male mice without impairing glucose homeostasis.

    Science.gov (United States)

    Rubinow, K B; Wang, S; den Hartigh, L J; Subramanian, S; Morton, G J; Buaas, F W; Lamont, D; Gray, N; Braun, R E; Page, S T

    2015-07-01

    Androgen deficiency in men increases body fat, but the mechanisms by which testosterone suppresses fat deposition have not been elucidated fully. Adipose tissue macrophages express the androgen receptor (AR) and regulate adipose tissue remodeling. Thus, testosterone signaling in macrophages could alter the paracrine function of these cells and thereby contribute to the metabolic effects of androgens in men. A metabolic phenotyping study was performed to determine whether the loss of AR signaling in hematopoietic cells results in greater fat accumulation in male mice. C57BL/6J male mice (ages 12-14 weeks) underwent bone marrow transplant from either wild-type (WT) or AR knockout (ARKO) donors (n = 11-13 per group). Mice were fed a high-fat diet (60% fat) for 16 weeks. At baseline, 8 and 16 weeks, glucose and insulin tolerance tests were performed, and body composition was analyzed with fat-water imaging by MRI. No differences in body weight were observed between mice transplanted with WT bone marrow [WT(WTbm)] or ARKO bone marrow [WT(ARKObm)] prior to initiation of the high-fat diet. After 8 weeks of high-fat feeding, WT(ARKObm) mice exhibited significantly more visceral and total fat mass than WT(WTbm) animals. Despite this, no differences between groups were observed in glucose tolerance, insulin sensitivity, or plasma concentrations of insulin, glucose, leptin, or cholesterol, although WT(ARKObm) mice had higher plasma levels of adiponectin. Resultant data indicate that AR signaling in hematopoietic cells influences body fat distribution in male mice, and the absence of hematopoietic AR plays a permissive role in visceral fat accumulation. These findings demonstrate a metabolic role for AR signaling in marrow-derived cells and suggest a novel mechanism by which androgen deficiency in men might promote increased adiposity. The relative contributions of AR signaling in macrophages and other marrow-derived cells require further investigation. © 2015 American

  1. Group 1B phospholipase A₂ inactivation suppresses atherosclerosis and metabolic diseases in LDL receptor-deficient mice.

    Science.gov (United States)

    Hollie, Norris I; Konaniah, Eddy S; Goodin, Colleen; Hui, David Y

    2014-06-01

    Previous studies have shown that inactivation of the group 1B phospholipase A2 (Pla2g1b) suppresses diet-induced obesity, hyperglycemia, insulin resistance, and hyperlipidemia in C57BL/6 mice. A possible influence of Pla2g1b inactivation on atherosclerosis has not been addressed previously. The current study utilized LDL receptor-deficient (Ldlr(-/-)) mice with plasma lipid levels and distribution similar to hyperlipidemic human subjects as a preclinical animal model to test the effectiveness of Pla2g1b inactivation on atherosclerosis. The Pla2g1b(+/+)Ldlr(-/-) and Pla2g1b(-/-)Ldlr(-/-) mice were fed a low fat chow diet or a hypercaloric diet with 58.5 kcal% fat and 25 kcal% sucrose for 10 weeks. Minimal differences were observed between Pla2g1b(+/+)Ldlr(-/-) and Pla2g1b(-/-)Ldlr(-/-) mice when the animals were maintained on the low fat chow diet. However, when the animals were maintained on the hypercaloric diet, the Pla2g1(+/+)Ldlr(-/-) mice showed the expected body weight gain but the Pla2g1b(-/-)Ldlr(-/-) mice were resistant to diet-induced body weight gain. The Pla2g1b(-/-)Ldlr(-/-) mice also displayed lower fasting glucose, insulin, and plasma lipid levels compared to the Pla2g1b(+/+)Ldlr(-/-) mice, which displayed robust hyperglycemia, hyperinsulinemia, and hyperlipidemia in response to the hypercaloric diet. Importantly, atherosclerotic lesions in the aortic roots were also reduced 7-fold in the Pla2g1b(-/-)Ldlr(-/-) mice. The effectiveness of Pla2g1b inactivation to suppress diet-induced body weight gain and reduce diabetes and atherosclerosis in LDL receptor-deficient mice suggests that pharmacological inhibition of Pla2g1b may be a viable strategy to decrease diet-induced obesity and the risk of diabetes and atherosclerosis in humans. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  2. Atherosclerosis and cardiac function assessment in low-density lipoprotein receptor-deficient mice undergoing body weight cycling.

    Science.gov (United States)

    McMillen, T S; Minami, E; Leboeuf, R C

    2013-06-24

    Obesity has become an epidemic in many countries and is supporting a billion dollar industry involved in promoting weight loss through diet, exercise and surgical procedures. Because of difficulties in maintaining body weight reduction, a pattern of weight cycling often occurs (so called 'yo-yo' dieting) that may result in deleterious outcomes to health. There is controversy about cardiovascular benefits of yo-yo dieting, and an animal model is needed to better understand the contributions of major diet and body weight changes on heart and vascular functions. Our purpose is to determine the effects of weight cycling on cardiac function and atherosclerosis development in a mouse model. We used low-density lipoprotein receptor-deficient mice due to their sensitivity to metabolic syndrome and cardiovascular diseases when fed high-fat diets. Alternating ad libitum feeding of high-fat and low-fat (rodent chow) diets was used to instigate weight cycling during a 29-week period. Glucose tolerance and insulin sensitivity tests were done at 22 and 24 weeks, echocardiograms at 25 weeks and atherosclerosis and plasma lipoproteins assessed at 29 weeks. Mice subjected to weight cycling showed improvements in glucose homeostasis during the weight loss cycle. Weight-cycled mice showed a reduction in the severity of atherosclerosis as compared with high-fat diet-fed mice. However, atherosclerosis still persisted in weight-cycled mice as compared with mice fed rodent chow. Cardiac function was impaired in weight-cycled mice and matched with that of mice fed only the high-fat diet. This model provides an initial structure in which to begin detailed studies of diet, calorie restriction and surgical modifications on energy balance and metabolic diseases. This model also shows differential effects of yo-yo dieting on metabolic syndrome and cardiovascular diseases.

  3. The peroxisome proliferator activated receptor gamma (PPARgamma) ligand rosiglitazone modulates bronchoalveolar lavage levels of leptin, adiponectin, and inflammatory cytokines in lean and obese mice.

    Science.gov (United States)

    Holguin, Fernando; Rojas, Mauricio; Hart, C Michael

    2007-12-01

    Obese mice that lack leptin receptor (db (-) /db (-)) have been shown to have innate bronchial hyperresponsiveness (BHR). It has been proposed that the obesity-mediated BHR may involve a combination of increased leptin and reduced systemic adiponectin levels. The aim of this study was to determine if obesity modifies the airway concentration of leptin and adiponectin and whether treatment with a synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) ligand can reduce airway leptin and increase airway adiponectin. In this study, obese, leptin receptor-deficient (db (-) /db (-)), or lean (db ( + ) /db (-)) mice were treated with rosiglitazone (3 mg/kg/day) or vehicle by gavage daily for 1 week. Bronchioalveolar lavage (BAL) was subsequently performed to determine levels of leptin, adiponectin, and inflammatory cytokines. Treatment with rosiglitazone increased BAL adiponectin levels in lean (p = 0.04) and to a lesser extent in obese mice (p = 0.07). Rosiglitazone treatment lowered leptin levels in lean mice, but increased leptin levels in BAL fluid of obese mice (p < 0.01). The BAL levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were lower in the lean rosiglitazone-treated group compared with the obese vehicle-treated group and lower in the obese rosiglitazone-treated group compared with the obese vehicle-treated group. These results demonstrate that obesity is associated with alterations in adipokine and cytokine levels in the airways that can be modulated by treatment with roziglitazone.

  4. Leptin controls hair follicle cycling.

    Science.gov (United States)

    Watabe, Reiko; Yamaguchi, Takashi; Kabashima-Kubo, Rieko; Yoshioka, Manabu; Nishio, Daisuke; Nakamura, Motonobu

    2014-04-01

    Leptin is a cytokine well known for its ability to control body weight and energy metabolism. Several lines of evidence have recently revealed that leptin also plays an important role in wound healing and immune modulation in skin. Sumikawa et al. Exp Dermatol 2014 evaluated the effect of leptin on hair follicle cycling using mutant and wild-type mice. They report that leptin is produced in dermal papilla cells in hair follicles and that leptin receptor-deficient db/db mice show an abnormality in hair follicle cycling. Moreover, leptin injection induced the transition into the growth stage of the hair cycle (anagen). On this basis, it now deserves exploration whether leptin-mediated signalling is a key stimulus for anagen induction and whether this may be targeted to manage human hair disorders with defect in the control of hair follicle cycling. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice.

    Science.gov (United States)

    Konuma, Kuniha; Itoh, Michiko; Suganami, Takayoshi; Kanai, Sayaka; Nakagawa, Nobutaka; Sakai, Takeru; Kawano, Hiroyuki; Hara, Mitsuko; Kojima, Soichi; Izumi, Yuichi; Ogawa, Yoshihiro

    2015-01-01

    Many attempts have been made to find novel therapeutic strategies for non-alcoholic steatohepatitis (NASH), while their clinical efficacy is unclear. We have recently reported a novel rodent model of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice, which exhibit the sequence of events that comprise hepatic steatosis, liver fibrosis, and hepatocellular carcinoma with obesity-related phenotypes. In the liver of MC4R-KO mice, there is a unique histological feature termed hepatic crown-like structures (hCLS), where macrophages interact with dead hepatocytes and fibrogenic cells, thereby accelerating inflammation and fibrosis. In this study, we employed MC4R-KO mice to examine the effect of highly purified eicosapentaenoic acid (EPA), a clinically available n-3 polyunsaturated fatty acid, on the development of NASH. EPA treatment markedly prevented the development of hepatocyte injury, hCLS formation and liver fibrosis along with lipid accumulation. EPA treatment was also effective even after MC4R-KO mice developed NASH. Intriguingly, improvement of liver fibrosis was accompanied by the reduction of hCLS formation and plasma kallikrein-mediated transforming growth factor-β activation. Moreover, EPA treatment increased the otherwise reduced serum concentrations of adiponectin, an adipocytokine with anti-inflammatory and anti-fibrotic properties. Collectively, EPA treatment effectively prevents the development and progression of NASH in MC4R-KO mice along with amelioration of hepatic steatosis. This study unravels a novel anti-fibrotic mechanism of EPA, thereby suggesting a clinical implication for the treatment of NASH.

  6. Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice.

    Directory of Open Access Journals (Sweden)

    Kuniha Konuma

    Full Text Available Many attempts have been made to find novel therapeutic strategies for non-alcoholic steatohepatitis (NASH, while their clinical efficacy is unclear. We have recently reported a novel rodent model of NASH using melanocortin 4 receptor-deficient (MC4R-KO mice, which exhibit the sequence of events that comprise hepatic steatosis, liver fibrosis, and hepatocellular carcinoma with obesity-related phenotypes. In the liver of MC4R-KO mice, there is a unique histological feature termed hepatic crown-like structures (hCLS, where macrophages interact with dead hepatocytes and fibrogenic cells, thereby accelerating inflammation and fibrosis. In this study, we employed MC4R-KO mice to examine the effect of highly purified eicosapentaenoic acid (EPA, a clinically available n-3 polyunsaturated fatty acid, on the development of NASH. EPA treatment markedly prevented the development of hepatocyte injury, hCLS formation and liver fibrosis along with lipid accumulation. EPA treatment was also effective even after MC4R-KO mice developed NASH. Intriguingly, improvement of liver fibrosis was accompanied by the reduction of hCLS formation and plasma kallikrein-mediated transforming growth factor-β activation. Moreover, EPA treatment increased the otherwise reduced serum concentrations of adiponectin, an adipocytokine with anti-inflammatory and anti-fibrotic properties. Collectively, EPA treatment effectively prevents the development and progression of NASH in MC4R-KO mice along with amelioration of hepatic steatosis. This study unravels a novel anti-fibrotic mechanism of EPA, thereby suggesting a clinical implication for the treatment of NASH.

  7. Accelerated Central Nervous System Autoimmunity in BAFF-Receptor-Deficient Mice

    OpenAIRE

    Kim, Susan S.; Richman, David P.; Zamvil, Scott S.; Agius, Mark A.

    2011-01-01

    B cell activating factor (BAFF) is critical for B cell survival, a function that is mediated by BAFF receptor, (BAFF-R). The role of BAFF (or BAFF-R) in the multiple sclerosis model, experimental autoimmune encephalomyelitis (EAE), was examined using BAFF-R-deficient mice. BAFF-R deficiency resulted in paradoxically increased severity of EAE induced by myelin-oligodendrocyte glycoprotein (MOG) peptide 35-55. Inflammatory foci in BAFF-R-deficient mice comprised increased numbers of activated m...

  8. D4 receptor deficiency in mice has limited effects on impulsivity and novelty seeking.

    Science.gov (United States)

    Helms, C M; Gubner, N R; Wilhelm, C J; Mitchell, S H; Grandy, D K

    2008-09-01

    Alleles of the human dopamine D(4) receptor (D(4)R) gene (DRD4.7) have repeatedly been found to correlate with novelty seeking, substance abuse, pathological gambling, and attention-deficit hyperactivity disorder (ADHD). If these various psychopathologies are a result of attenuated D(4)R-mediated signaling, mice lacking D(4)Rs (D(4)KO) should be more impulsive than wild-type (WT) mice and exhibit more novelty seeking. However, in our study, D(4)KO and WT mice showed similar levels of impulsivity as measured by delay discounting performance and response inhibition on a Go/No-go test, suggesting that D(4)R-mediated signaling may not affect impulsivity. D(4)KO mice were more active than WT mice in the first 5 min of a novel open field test, suggesting greater novelty seeking. For both genotypes, more impulsive mice habituated less in the novel open field. These data suggest that the absence of D(4)Rs is not sufficient to cause psychopathologies associated with heightened impulsivity and novelty seeking.

  9. Scavenger receptor deficiency leads to more complex atherosclerotic lesions in APOE3Leiden transgenic mice

    NARCIS (Netherlands)

    de Winther, M. P.; Gijbels, M. J.; van Dijk, K. W.; van Gorp, P. J.; Suzuki, H.; Kodama, T.; Frants, R. R.; Havekes, L. M.; Hofker, M. H.

    1999-01-01

    Apolipoprotein (apo) E3Leiden is a dysfunctional apo E variant associated with familial dysbetalipoproteinemia in humans. Transgenic mice carrying the APOE3Leiden gene develop hyperlipidemia and are highly susceptible to diet-induced atherosclerosis. An early step in atherosclerosis is foam cell

  10. Melanocortin 1 Receptor Deficiency Promotes Atherosclerosis in Apolipoprotein E−/− Mice

    Science.gov (United States)

    Kadiri, James J.; Velasco-Delgado, Mauricio; Nuutinen, Salla; Viitala, Miro; Hollmén, Maija; Rami, Martina; Savontaus, Eriika; Steffens, Sabine

    2018-01-01

    Objective— The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transporter subfamily G member 1). In this study, we aimed to investigate whether global deficiency in MC1-R signaling affects the development of atherosclerosis. Approach and Results— Apoe−/− (apolipoprotein E deficient) mice were crossed with recessive yellow (Mc1re/e) mice carrying dysfunctional MC1-R and fed a high-fat diet to induce atherosclerosis. Apoe−/− Mc1re/e mice developed significantly larger atherosclerotic lesions in the aortic sinus and in the whole aorta compared with Apoe−/− controls. In terms of plaque composition, MC1-R deficiency was associated with less collagen and smooth muscle cells and increased necrotic core, indicative of more vulnerable lesions. These changes were accompanied by reduced Abca1 and Abcg1 expression in the aorta. Furthermore, Apoe−/− Mc1re/e mice showed a defect in bile acid metabolism that aggravated high-fat diet–induced hypercholesterolemia and hepatic lipid accumulation. Flow cytometric analysis of leukocyte profile revealed that dysfunctional MC1-R enhanced arterial accumulation of classical Ly6Chigh monocytes and macrophages, effects that were evident in mice fed a normal chow diet but not under high-fat diet conditions. In support of enhanced arterial recruitment of Ly6Chigh monocytes, these cells had increased expression of L-selectin and P-selectin glycoprotein ligand 1. Conclusions— The present study highlights the importance of MC1-R in the development of atherosclerosis. Deficiency in MC1-R signaling exacerbates atherosclerosis by disturbing cholesterol handling and by increasing arterial monocyte accumulation. PMID:29284608

  11. Melanocortin 1 Receptor Deficiency Promotes Atherosclerosis in Apolipoprotein E-/-Mice.

    Science.gov (United States)

    Rinne, Petteri; Kadiri, James J; Velasco-Delgado, Mauricio; Nuutinen, Salla; Viitala, Miro; Hollmén, Maija; Rami, Martina; Savontaus, Eriika; Steffens, Sabine

    2018-02-01

    The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transporter subfamily G member 1). In this study, we aimed to investigate whether global deficiency in MC1-R signaling affects the development of atherosclerosis. Apoe -/- (apolipoprotein E deficient) mice were crossed with recessive yellow (Mc1r e/e ) mice carrying dysfunctional MC1-R and fed a high-fat diet to induce atherosclerosis. Apoe -/- Mc1r e/e mice developed significantly larger atherosclerotic lesions in the aortic sinus and in the whole aorta compared with Apoe -/- controls. In terms of plaque composition, MC1-R deficiency was associated with less collagen and smooth muscle cells and increased necrotic core, indicative of more vulnerable lesions. These changes were accompanied by reduced Abca1 and Abcg1 expression in the aorta. Furthermore, Apoe -/- Mc1r e/e mice showed a defect in bile acid metabolism that aggravated high-fat diet-induced hypercholesterolemia and hepatic lipid accumulation. Flow cytometric analysis of leukocyte profile revealed that dysfunctional MC1-R enhanced arterial accumulation of classical Ly6C high monocytes and macrophages, effects that were evident in mice fed a normal chow diet but not under high-fat diet conditions. In support of enhanced arterial recruitment of Ly6C high monocytes, these cells had increased expression of L-selectin and P-selectin glycoprotein ligand 1. The present study highlights the importance of MC1-R in the development of atherosclerosis. Deficiency in MC1-R signaling exacerbates atherosclerosis by disturbing cholesterol handling and by increasing arterial monocyte accumulation. © 2017 The Authors.

  12. Myeloid interferon-γ receptor deficiency does not affect atherosclerosis in LDLR(-/-) mice.

    Science.gov (United States)

    Boshuizen, Marieke C S; Neele, Annette E; Gijbels, Marion J J; van der Velden, Saskia; Hoeksema, Marten A; Forman, Ruth A; Muller, Werner; Van den Bossche, Jan; de Winther, Menno P J

    2016-03-01

    Atherosclerosis is a chronic lipid-driven inflammatory disease of the arterial wall. Interferon gamma (IFNγ) is an important immunomodulatory cytokine and a known pro-atherosclerotic mediator. However, cell-specific targeting of IFNγ or its signaling in atherosclerosis development has not been studied yet. As macrophages are important IFNγ targets, we here addressed the involvement of myeloid IFNγ signaling in murine atherosclerosis. Bone marrow was isolated from interferon gamma receptor 2 chain (IFNγR2) wildtype and myeloid IFNγR2 deficient mice and injected into lethally irradiated LDLR(-/-) mice. After recovery mice were put on a high fat diet for 10 weeks after which atherosclerotic lesion analysis was performed. In addition, the accompanying liver inflammation was assessed. Even though absence of myeloid IFNγ signaling attenuated the myeloid IFNγ response, no significant differences in atherosclerotic lesion size or phenotype were found. Also, when examining the liver inflammatory state no effects of IFNγR2 deficiency could be observed. Overall, our data argue against a role for myeloid IFNγR2 in atherosclerosis development. Since myeloid IFNγ signaling seems to be nonessential throughout atherogenesis, it is important to understand the mechanisms by which IFNγ acts in atherogenesis. In the future new studies should be performed considering other cell-specific targets. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Diazepam improves aspects of social behaviour and neuron activation in NMDA receptor-deficient mice

    Science.gov (United States)

    Mielnik, C. A.; Horsfall, W.; Ramsey, A. J.

    2017-01-01

    NR1 knockdown (NR1KD) mice are genetically modified to express low levels of the NR1 subunit of N-methyl-D-aspartate (NMDA) receptors, and show deficits in affiliative social behaviour. In this study, we determined which brain regions were selectively activated in response to social stimulation and asked whether differences in neuronal activation could be observed in mice with reduced sociability. Furthermore, we aimed to determine whether brain activation patterns correlated with the amelioration of social deficits through pharmacological intervention. The cingulate cortex, lateral septal nuclei, hypothalamus, thalamus and amygdala showed an increase in c-Fos immunoreactivity that was selective for exposure to social stimuli. NR1KD mice displayed a reduction in social behaviour and a reduction in c-Fos immunoreactivity in the cingulate cortex and septal nuclei. Acute clozapine did not significantly alter sociability; however, diazepam treatment did increase sociability and neuronal activation in the lateral septal region. This study has identified the lateral septal region as a neural substrate of social behaviour and the GABA system as a potential therapeutic target for social dysfunction. PMID:25040071

  14. P2X7 receptor-deficient mice are susceptible to bone cancer pain

    DEFF Research Database (Denmark)

    Hansen, Rikke Rie; Nielsen, Christian K.; Nasser, Arafat

    2011-01-01

    The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice...... were susceptible to bone cancer pain and moreover had an earlier onset of pain-related behaviours compared with cancer-bearing, wild-type mice. Furthermore, acute treatment with the selective P2X7 receptor antagonist, A-438079, failed to alleviate pain-related behaviours in models of bone cancer pain...... with and without astrocyte activation (BALB/cJ or C3H mice inoculated with 4T1 mammary cancer cells or NCTC 2472 osteosarcoma cells, respectively), suggesting that astrocytic P2X7 receptors play a negligible role in bone cancer pain. The results support the hypothesis that bone cancer pain is a separate pain state...

  15. Effect of everolimus on pre-existing atherosclerosis in LDL-receptor deficient mice.

    Science.gov (United States)

    Beutner, Frank; Brendel, Désiré; Teupser, Daniel; Sass, Kristina; Baber, Ronny; Mueller, Marc; Ceglarek, Uta; Thiery, Joachim

    2012-06-01

    Proliferation signal inhibitors/mTOR-inhibitors have been shown to reduce de novo development of hypercholesterolemic atherosclerosis in animal models. However, their effect on pre-existing atherosclerosis has not yet been studied. Feeding LDL-R-KO mice a high cholesterol diet for 12 weeks resulted in formation of moderate fibroatheroma (induction phase). Sixty mice received either everolimus (1 or 5 mg/kg) or no everolimus for further 12 weeks (treatment phase). Everolimus significantly enhanced hypercholesterolemia (plasma cholesterol +45%, pAtherosclerosis progressed obstructively in treated and non-treated mice. Everolimus (5 mg/kg) tended to reduced progression in aortic root lesions (0.28±0.02 vs. 0.33±0.03 mm(2), p=ns) and brachiocephalic lesions (0.044±0.006 vs. 0.066±0.012 mm(2), p=ns) but without significance. Everolimus (5mg/kg) resulted in an arrest of CD68 positive plaque area (p=0.03) and nearly halved CD68 fraction (p=0.05) in aortic root lesions but not in brachiocephalic lesions. Taken together, despite a trend to reduced progression and inflammatory cell content there was less conclusive net effect of everolimus treatment than expected. A higher potential of everolimus in the treatment of atherosclerosis might be obscured by its concomitant hypercholesterolemia. Considering stronger effects in previous studies we suggest that everolimus might exert more potent anti-atherogenic properties in earlier stages of atherogenesis than in advanced atherosclerosis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  16. State-dependent alterations in hippocampal oscillations in serotonin 1A receptor-deficient mice.

    Science.gov (United States)

    Gordon, Joshua A; Lacefield, Clay O; Kentros, Clifford G; Hen, Rene

    2005-07-13

    Mice lacking the serotonin 1A receptor (5-HT(1A)R) show increased levels of anxiety-related behavior across multiple tests and background strains. Tissue-specific rescue experiments, lesion studies, and neurophysiological findings all point toward the hippocampus as a potential mediator of the phenotype. Serotonin, acting through 5-HT(1A)Rs, can suppress hippocampal theta-frequency oscillations, suggesting that theta oscillations might be increased in the knock-outs. To test this hypothesis, local field potential recordings were obtained from the hippocampus of awake, behaving knock-outs and wild-type littermates. The magnitude of theta oscillations was increased in the knock-outs, specifically in the anxiety-provoking elevated plus maze and not in a familiar environment or during rapid eye movement sleep. Theta power correlated with the fraction of time spent in the open arms, an anxiety-related behavioral variable. These results suggest a possible role for the hippocampus, and theta oscillations in particular, in the expression of anxiety in 5-HT(1A)R-deficient mice.

  17. CD1d deficiency inhibits the development of abdominal aortic aneurysms in LDL receptor deficient mice.

    Directory of Open Access Journals (Sweden)

    Gijs H M van Puijvelde

    Full Text Available An abdominal aortic aneurysm (AAA is a dilatation of the abdominal aorta leading to serious complications and mostly to death. AAA development is associated with an accumulation of inflammatory cells in the aorta including NKT cells. An important factor in promoting the recruitment of these inflammatory cells into tissues and thereby contributing to the development of AAA is angiotensin II (Ang II. We demonstrate that a deficiency in CD1d dependent NKT cells under hyperlipidemic conditions (LDLr-/-CD1d-/- mice results in a strong decline in the severity of angiotensin II induced aneurysm formation when compared with LDLr-/- mice. In addition, we show that Ang II amplifies the activation of NKT cells both in vivo and in vitro. We also provide evidence that type I NKT cells contribute to AAA development by inducing the expression of matrix degrading enzymes in vSMCs and macrophages, and by cytokine dependently decreasing vSMC viability. Altogether, these data prove that CD1d-dependent NKT cells contribute to AAA development in the Ang II-mediated aneurysm model by enhancing aortic degradation, establishing that therapeutic applications which target NKT cells can be a successful way to prevent AAA development.

  18. Validation of dopamine receptor DRD1 and DRD2 antibodies using receptor deficient mice.

    Science.gov (United States)

    Stojanovic, Tamara; Orlova, Michaela; Sialana, Fernando J; Höger, Harald; Stuchlik, Stanislav; Milenkovic, Ivan; Aradska, Jana; Lubec, Gert

    2017-06-01

    Dopamine receptors 1 and 2 (DRD1, DRD2) are essential for signaling in the brain for a multitude of brain functions. Previous work using several antibodies against these receptors is abundant but only the minority of antibodies used have been validated and, therefore, the results of these studies remain uncertain. Herein, antibodies against DRD1 (Merck Millipore AB1765P, Santa Cruz Biotechnology sc-14001, Sigma Aldrich D2944, Alomone Labs ADR-001) and DRD2 (Abcam ab21218, Merck Millipore AB5084P, Santa Cruz Biotechnology sc-5303) have been tested using western blotting and immunohistochemistry on mouse striatum (wild type and corresponding knock-out mice) and when specific, they were further evaluated on rat and human striatum. Moreover, a DRD1 antibody and a DRD2 antibody that were found specific in our tests were used for immunoprecipitation with subsequent mass spectrometrical identification of the immunoprecipitate. Two out of nine antibodies (anti DRD1 Sigma Aldrich D2944 and anti DRD2 Merck Millipore AB5084P) against the abovementioned dopamine receptors were specific for DRD1 and DRD2 as evaluated by western blotting and immunohistochemistry and the immunoprecipitate indeed contained DRD1 and DRD2 as revealed by mass spectrometry. The observed findings may question the use of so far non-validated antibodies against the abovementioned dopamine receptors. Own observations may be valuable for the interpretation of previous results and the design of future studies using dopamine receptors DRD1 or DRD2.

  19. CD8+ T Cell Response to Gammaherpesvirus Infection Mediates Inflammation and Fibrosis in Interferon Gamma Receptor-Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Brigid M O'Flaherty

    Full Text Available Idiopathic pulmonary fibrosis (IPF, one of the most severe interstitial lung diseases, is a progressive fibrotic disorder of unknown etiology. However, there is growing appreciation for the role of viral infection in disease induction and/or progression. A small animal model of multi-organ fibrosis, which involves murine gammaherpesvirus (MHV68 infection of interferon gamma receptor deficient (IFNγR-/- mice, has been utilized to model the association of gammaherpesvirus infections and lung fibrosis. Notably, several MHV68 mutants which fail to induce fibrosis have been identified. Our current study aimed to better define the role of the unique MHV68 gene, M1, in development of pulmonary fibrosis. We have previously shown that the M1 gene encodes a secreted protein which possesses superantigen-like function to drive the expansion and activation of Vβ4+ CD8+ T cells. Here we show that M1-dependent fibrosis is correlated with heightened levels of inflammation in the lung. We observe an M1-dependent cellular infiltrate of innate immune cells with most striking differences at 28 days-post infection. Furthermore, in the absence of M1 protein expression we observed reduced CD8+ T cells and MHV68 epitope specific CD8+ T cells to the lungs-despite equivalent levels of viral replication between M1 null and wild type MHV68. Notably, backcrossing the IFNγR-/- onto the Balb/c background, which has previously been shown to exhibit weak MHV68-driven Vβ4+ CD8+ T cell expansion, eliminated MHV68-induced fibrosis-further implicating the activated Vβ4+ CD8+ T cell population in the induction of fibrosis. We further addressed the role that CD8+ T cells play in the induction of fibrosis by depleting CD8+ T cells, which protected the mice from fibrotic disease. Taken together these findings are consistent with the hypothesized role of Vβ4+ CD8+ T cells as mediators of fibrotic disease in IFNγR-/- mice.

  20. The effect of leptin receptor deficiency and fasting on cannabinoid receptor 1 mRNA expression in the rat hypothalamus, brainstem and nodose ganglion.

    Science.gov (United States)

    Jelsing, Jacob; Larsen, Philip Just; Vrang, Niels

    2009-10-02

    Despite ample evidence for the involvement of the endocannabinoid system in the control of appetite, food intake and energy balance, relatively little is known about the regulation of cannabinoid receptor 1 (CB(1)R) expression in respect to leptin signalling and fasting. In the present study, we examined CB(1)R mRNA levels in lean (Fa/?) and obese (fa/fa) male Zucker rats under basal and food-restricted conditions. Using stereological sampling principles coupled with semi-quantitative radioactive in situ hybridization we provide semi-quantitative estimates of CB(1)R mRNA expression in key appetite regulatory hypothalamic and brainstem areas, as well as in the nodose ganglia. Whereas no effect of fasting were determined on CB(1)R mRNA levels in the paraventricular (PVN) and ventromedial hypothalamic (VMH) nucleus, in the brainstem dorsal vagal complex or nodose ganglion of lean Zucker rats, CB(1)R mRNA levels were consistently elevated in obese Zucker rats pointing to a direct influence of disrupted leptin signalling on CB(1)R mRNA regulation.

  1. Leptin levels in free ranging striped mice (Rhabdomys pumilio) increase when food decreases: the ecological leptin hypothesis.

    Science.gov (United States)

    Schradin, Carsten; Raynaud, Julien; Arrivé, Mathilde; Blanc, Stéphane

    2014-09-15

    Leptin is a hormone informing the body about its fat stores, reducing appetite and foraging and as such reducing fattening of individuals. In laboratory rodents, leptin secretion is highly correlated to the amount of adipose tissue. We compared this to the alternative ecological leptin hypothesis, which based on the behavioural effects of leptin predicts that leptin levels are disassociated from adipose tissue when fattening is of evolutionary advantage to survive coming periods of low food availability. Studying a species that has to survive a dry season with low food availability, we tested the ecological leptin hypothesis, predicting low leptin levels when food availability and thus adiposity is high promoting foraging and fattening, but high leptin levels in the seasons of low food availability, reducing energetic costs due to foraging. We measured leptin levels in 154 samples of free living African striped mice (Rhabdomys pumilio). Striped mice gain significant body mass during the moist season to survive the following dry season with low food availability. We found a strong seasonal effect, with higher leptin levels in the dry season with low food availability, which was in contrast to the hypothesis deriving from studies on laboratory rodents, but in agreement with ecological leptin hypothesis: leptin levels remained low in the period of high food availability, allowing fattening, but increased during periods of low food availability, possibly suppressing energetically costly foraging in an environment where foraging success would have been very low. Leptin correlated significantly and negatively with testosterone levels, and high testosterone levels in the moist season could explain why leptin levels were low even though food availability was high. However, analysing samples from an experimental laboratory study where testosterone levels were increased via implants found no support for a suppressive role of testosterone on leptin. In sum, our study

  2. SKI-II--a sphingosine kinase 1 inhibitor--exacerbates atherosclerosis in low-density lipoprotein receptor-deficient (LDL-R-/-) mice on high cholesterol diet.

    Science.gov (United States)

    Potì, Francesco; Ceglarek, Uta; Burkhardt, Ralph; Simoni, Manuela; Nofer, Jerzy-Roch

    2015-05-01

    Sphingosine 1-phosphate (S1P) is a lysosphingolipid associated with high-density lipoproteins (HDL) that contributes to their anti-atherogenic potential. We investigated whether a reduction in S1P plasma levels affects atherosclerosis in low-density lipoprotein receptor deficient (LDL-R-/-) mice. LDL-R-/- mice on Western diet containing low (0.25% w/w) or high (1.25% w/w) cholesterol were treated for 16 weeks with SKI-II, a sphingosine kinase 1 inhibitor that significantly reduced plasma S1P levels. SKI-II treatment increased atherosclerotic lesions in the thoracic aorta in mice on high but not low cholesterol diet. This compound did not affect body weight, blood cell counts and plasma total and HDL cholesterol, but decreased triglycerides. In addition, mice on high cholesterol diet receiving SKI-II showed elevated levels of tumor necrosis factor-α and endothelial adhesion molecules (sICAM-1, sVCAM-1). Prolonged lowering of plasma S1P produces pro-atherogenic effects in LDL-R-/- mice that are evident under condition of pronounced hypercholesterolemia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. Left ventricular dysfunction with reduced functional cardiac reserve in diabetic and non-diabetic LDL-receptor deficient apolipoprotein B100-only mice

    Directory of Open Access Journals (Sweden)

    Bosch Fatima

    2011-06-01

    Full Text Available Abstract Background Lack of suitable mouse models has hindered the studying of diabetic macrovascular complications. We examined the effects of type 2 diabetes on coronary artery disease and cardiac function in hypercholesterolemic low-density lipoprotein receptor-deficient apolipoprotein B100-only mice (LDLR-/-ApoB100/100. Methods and results 18-month-old LDLR-/-ApoB100/100 (n = 12, diabetic LDLR-/-ApoB100/100 mice overexpressing insulin-like growth factor-II (IGF-II in pancreatic beta cells (IGF-II/LDLR-/-ApoB100/100, n = 14 and age-matched C57Bl/6 mice (n = 15 were studied after three months of high-fat Western diet. Compared to LDLR-/-ApoB100/100 mice, diabetic IGF-II/LDLR-/-ApoB100/100 mice demonstrated more calcified atherosclerotic lesions in aorta. However, compensatory vascular enlargement was similar in both diabetic and non-diabetic mice with equal atherosclerosis (cross-sectional lesion area ~60% and consequently the lumen area was preserved. In coronary arteries, both hypercholesterolemic models showed significant stenosis (~80% despite positive remodeling. Echocardiography revealed severe left ventricular systolic dysfunction and anteroapical akinesia in both LDLR-/-ApoB100/100 and IGF-II/LDLR-/-ApoB100/100 mice. Myocardial scarring was not detected, cardiac reserve after dobutamine challenge was preserved and ultrasructural changes revealed ischemic yet viable myocardium, which together with coronary artery stenosis and slightly impaired myocardial perfusion suggest myocardial hibernation resulting from chronic hypoperfusion. Conclusions LDLR-/-ApoB100/100 mice develop significant coronary atherosclerosis, severe left ventricular dysfunction with preserved but diminished cardiac reserve and signs of chronic myocardial hibernation. However, the cardiac outcome is not worsened by type 2 diabetes, despite more advanced aortic atherosclerosis in diabetic animals.

  4. CER-001, a HDL-mimetic, stimulates the reverse lipid transport and atherosclerosis regression in high cholesterol diet-fed LDL-receptor deficient mice.

    Science.gov (United States)

    Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Ackermann, Rose; Sy, Gavin; Bluteau, Alice; Cholez, Guy; Keyserling, Constance; Lalwani, Narendra; Paolini, John F; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

    2014-01-01

    CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and phospholipids that was designed to mimic the beneficial properties of nascent pre-β HDL. In this study, we have evaluated the capacity of CER-001 to perform reverse lipid transport in single dose studies as well as to regress atherosclerosis in LDLr(-/-) mice after short-term multiple-dose infusions. CER-001 induced cholesterol efflux from macrophages and exhibited anti-inflammatory response similar to natural HDL. Studies with HUVEC demonstrated CER-001 at a concentration of 500 μg/mL completely suppressed the secretion of cytokines IL-6, IL-8, GM-CSF and MCP-1. Following infusion of CER-001 (10mg/kg) in C57Bl/6J mice, we observed a transient increase in the mobilization of unesterified cholesterol in HDL particles containing recombinant human apoA-I. Finally we show that cholesterol elimination was stimulated in CER-001 treated animals as demonstrated by the increased cholesterol concentration in liver and feces. In a familial hypercholesterolemia mouse model (LDL-receptor deficient mice), the infusion of CER-001 caused 17% and 32% reductions in plaque size, 17% and 23% reductions in lipid content after 5 and 10 doses given every 2 days, respectively. Also, there was an 80% reduction in macrophage content in the plaque following 5 doses, and decreased VCAM-1 expression by 16% and 22% in the plaque following 5 and 10 intravenous doses of CER-001, respectively. These data demonstrate that CER-001 rapidly enhances reverse lipid transport in the mouse, reducing vascular inflammation and promoting regression of diet-induced atherosclerosis in LDLr(-/-) mice upon a short-term multiple dose treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Weibin; Liu, Xijun; Peng, Xiaomin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Xue, Ruyi [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Ji, Lingling [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Shen, Xizhong [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Chen, She, E-mail: shechen@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhang, Si, E-mail: zhangsi@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China)

    2014-05-23

    Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR{sup −/−}) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR{sup −/−} mice fed MCD diet (FXR{sup −/−}/MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR{sup −/−}/MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR{sup −/−}/MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR{sup −/−}/MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection.

  6. Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

    International Nuclear Information System (INIS)

    Wu, Weibin; Liu, Xijun; Peng, Xiaomin; Xue, Ruyi; Ji, Lingling; Shen, Xizhong; Chen, She; Gu, Jianxin; Zhang, Si

    2014-01-01

    Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR −/− ) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR −/− mice fed MCD diet (FXR −/− /MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR −/− /MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR −/− /MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR −/− /MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection

  7. Involvement of leptin in hypophagia induced by the serotonin precursor 5-hydroxytryptophan (5-HTP) in mice.

    Science.gov (United States)

    Yamada, Jun; Sugimoto, Yumi; Ujikawa, Masanori

    2006-03-01

    We previously demonstrated that a serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP) increases serum leptin levels in mice. It was reported that administration of 5-HTP elicits hypophagia in rodents and humans. In the present study, we examined involvement of leptin in 5-HTP-elicited decreases in the milk intake of fasted mice. Serum leptin levels increased with increases in milk intake in mice, while 5-HTP strongly decreased milk intake in fasted mice compared to that in the control group. Serum leptin levels in fasted mice treated with 5-HTP were similar to those control mice after milk intake. As leptin is a powerful anorectic signal, 5-HTP-induced anorexia may be mediated by facilitation of leptin secretion.

  8. [Leptin].

    Science.gov (United States)

    Nedvídková, J

    1997-12-01

    Leptin (ob-protein), a previously unknown protein signal, is secreted from adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks, that regulate weight and energy homeostasis. Leptin provides a communication link between fat tissue and the brain. Ob protein appears to play a major role in the control of body fat stores through coordinated regulation of feeding behavior, metabolism, autonomic nervous system and body energy balance in rodents, primates and humans. Leptin levels have pulsative and diurnal character. In lean subjects with relatively low adipose tissue, the majority of circulating leptin is in the bound form. On other hand, in obese individuals the majority of leptin circulates in free form presumably bioactive protein, and thus obese subjects are resistant to free leptin. Leptin's resistance is often coupled with insuline resistance postreceptor type. Leptin receptor is product of db genes. Ob-protein receptor belongs to the cytokine superfamily of receptors and has several variants. Leptin-receptor gene is expressed in abundant degree in ovary, uterus, testes, less in hypothalamus, hypophysis, and little in kidney. Leptin stimulates the reproductive endocrine system and may serve as a permissive signal to the reproductive system of normal animals. Ob-gene product, leptin is regulated by feedings patterns and hormones, such as insulin and glucocorticoids. There is assumed that neuropeptide Y (NPY) and melanocyte-stimulating hormone (MSH) and its receptor (MCR) are a critical components of the biological response to leptin levels. MCR in contrast to leptin receptors are coupled with G-transduction system.

  9. Alpha/beta interferon receptor deficiency in mice significantly enhances susceptibility of the animals to pseudorabies virus infection.

    Science.gov (United States)

    Wei, Jingyun; Ma, Yanmei; Wang, Long; Chi, Xiaojuan; Yan, Ruoxiang; Wang, Song; Li, Xinxin; Chen, Xiaoyong; Shao, Wenhan; Chen, Ji-Long

    2017-05-01

    Pseudorabies virus, one of the neurotropic viruses, can infect numerous mammals. In particular, pseudorabies virus infection of swine occurs worldwide, and is a major threat to swine industry. However, the mechanism underlying the interaction between pseudorabies virus and host innate immune system is not fully understood. Here, we investigated the involvement of interferon α/β (IFN-α/β) receptor (IFNAR) in the pathogenesis of pseudorabies virus in a mouse model. The results showed that IFNAR-deficient (IFNAR -/- ) mice were highly susceptible to the virus infection, as evidenced by markedly reduced survival rate of infected animals and increased viral replication. The expression of IFN-α/β and relevant interferon-stimulated genes in IFNAR -/- mice was significantly lower than that in wild-type (WT) littermates after the viral infection. Moreover, in response to the virus challenge, IFNAR -/- mice displayed elevated levels of inflammatory cytokines including interleukin 6 (IL-6) and IL-1β, and IFNAR -/- cells showed increased phosphorylation of STAT3. Collectively, these data reveal that the IFNAR -/- mice are more sensitive to pseudorabies virus infection than WT animals, and excessive IL-6/STAT3 response in IFNAR -/- mice may contribute to the pathogenesis. Our findings suggest that type I IFNs/IFNAR-dependent homeostatic control of the innate immunity is required for host defense against pseudorabies virus infection. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Proximal tubule-dominant transfer of AT1a receptors induces blood pressure responses to intracellular angiotensin II in AT1a receptor-deficient mice

    Science.gov (United States)

    Li, Xiao C.

    2013-01-01

    The role of intracellular ANG II in proximal tubules of the kidney remains poorly understood. We tested the hypothesis that proximal tubule-dominant transfer of AT1a receptors in the cortex mediates intracellular ANG II-induced blood pressure responses in AT1a receptor-deficient (Agtr1a-/-) mice. A GFP-tagged AT1a receptor, AT1aR/GFP, and an enhanced cyan fluorescent intracellular ANG II fusion protein, ECFP/ANG II, were expressed in proximal tubules of Agtr1a-/- mouse kidneys via the adenoviral transfer using a sodium and glucose cotransporter 2 promoter. Transfer of AT1aR/GFP alone or with ECFP/ANG II induced proximal tubule-dominant expression of AT1aR/GFP and/or ECFP/ANG II with a peak response at 2 wk. No significant AT1aR/GFP and/or ECFP/ANG II expression was observed in the glomeruli, medulla, or extrarenal tissues. Transfer of AT1aR/GFP alone, but not ECFP/ANG II, increased systolic blood pressure by 12 ± 2 mmHg by day 14 (n = 9, P tubule-dominant transfer of AT1aR/GFP alone (P tubules (P tubules had no effect on all indices. These results suggest that AT1a receptors and intracellular ANG II in proximal tubules of the kidney play an important physiological role in blood pressure regulation. PMID:23427083

  11. Dioxin-like PCB 126 increases systemic inflammation and accelerates atherosclerosis in lean LDL receptor deficient mice.

    Science.gov (United States)

    Petriello, Michael C; Brandon, J Anthony; Hoffman, Jessie; Wang, Chunyan; Tripathi, Himi; Abdel-Latif, Ahmed; Ye, Xiang; Li, Xiangan; Yang, Liping; Lee, Eun; Soman, Sony; Barney, Jazmyne; Wahlang, Banrida; Hennig, Bernhard; Morris, Andrew J

    2017-12-01

    Exposure to dioxins and related persistent organic pollutants likely contributes to cardiovascular disease (CVD) risk through multiple mechanisms including the induction of chronic inflammation. Epidemiological studies have shown that leaner individuals may be more susceptible to the detrimental effects of lipophilic toxicants because they lack large adipose tissue depots that can accumulate and sequester these pollutants. This phenomenon complicates efforts to study mechanisms of pollutant-accelerated atherosclerosis in experimental animal models where high-fat feeding and adipose expansion limit the bioavailability of lipophilic pollutants. Here, we investigated whether a model dioxin-like pollutant, PCB 126, could increase inflammation and accelerate atherosclerosis in Ldlr -/- mice fed a low-fat atherogenic diet. We fed Ldlr -/- mice the Clinton/Cybulsky diet (10% kcal fat, 0.15% cholesterol) and sacrificed mice at 8, 10, or 12 weeks post PCB (2 doses of 1 μmol/kg) or vehicle gavage. To characterize this novel model, we examined the effects of PCB 126 on markers of systemic inflammation, hematological indices, fatty livers, and atherosclerotic lesion size. Mice exposed to PCB 126 exhibited significantly increased plasma inflammatory cytokine levels, increased circulating biomarkers of CVD, altered platelet and red blood cell counts, increased accumulation of hepatic fatty acids, and accelerated atherosclerotic lesion formation in the aortic root. PCB 126 also increased circulating neutrophils, monocytes, and macrophages as determined by flow cytometry analysis. Exposure to dioxin-like PCB 126 increases inflammation and accelerates atherosclerosis in mice. This low-fat atherogenic diet may provide a useful tool to study the mechanisms linking exposure to lipophilic pollutants to increased risk of CVD. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  12. Leptin increases skeletal muscle lipoprotein lipase and postprandial lipid metabolism in mice.

    Science.gov (United States)

    Donahoo, William T; Stob, Nicole R; Ammon, Stefen; Levin, Nancy; Eckel, Robert H

    2011-03-01

    The ability of leptin to preserve lean tissue during weight loss may be in part due to differences in nutrient partitioning. Because lipoprotein lipase (LPL) plays a key role in partitioning lipid nutrients, this study was conducted to test the hypothesis that leptin would modify the tissue-specific regulation of LPL and result in increased lipid oxidation and decreased storage. The effects of daily intraperitoneal leptin injections (2 mg/kg body weight) over 2 weeks on LPL activity and postprandial lipid metabolism were tested in both wild-type (WT), leptin-deficient ob/ob obese mice and mice pair fed to the leptin-treated mice. On the experimental day, mice were given food by gavage, blood was drawn periodically, and adipose tissue and skeletal muscle were harvested for measurements of LPL activity at 240 minutes. After 2 weeks of leptin administration, skeletal muscle LPL (SMLPL) activity was increased in leptin-treated compared with pair-fed (P = .012) and WT (P = .002) mice. There was no effect of leptin or pair feeding on postprandial adipose tissue LPL activity. In ob/ob mice, leptin treatment normalized the decrease in postprandial free fatty acid concentration (P = .066). Leptin had no effect on either the area under the triglyceride (TG) excursion or the integrated area under the TG excursion in WT mice. In ob/ob mice, however, the TG excursion was lower in the leptin-treated than the pair-fed mice by area under the TG excursion (P = .012) and was lower than in the WT mice by integrated area under the TG excursion (P = .027). As expected, 2 weeks of leptin treatment decreased body weight in both the WT and ob/ob mice (-2.6% and -10.4%, respectively). Leptin treatment increased SMLPL, an effect that may have contributed to the leptin-induced weight loss. The leptin-induced decreased postprandial TG excursion in ob/ob mice suggests that leptin acts to augment clearance of postprandial TG-rich lipoprotein lipid and that this increase may in part be secondary

  13. Detection of early stage atherosclerotic plaques using PET and CT fusion imaging targeting P-selectin in low density lipoprotein receptor-deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Ikuko, E-mail: nakamuri@riken.jp [RIKEN Center for Molecular Imaging Science, Kobe (Japan); Department of Cardiovascular Medicine, Saga University, Saga (Japan); Hasegawa, Koki [RIKEN Center for Molecular Imaging Science, Kobe (Japan); Department of Pathology and Experimental Medicine, Kumamoto University, Kumamoto (Japan); Wada, Yasuhiro [RIKEN Center for Molecular Imaging Science, Kobe (Japan); Hirase, Tetsuaki; Node, Koichi [Department of Cardiovascular Medicine, Saga University, Saga (Japan); Watanabe, Yasuyoshi, E-mail: yywata@riken.jp [RIKEN Center for Molecular Imaging Science, Kobe (Japan)

    2013-03-29

    Highlights: ► P-selectin regulates leukocyte recruitment as an early stage event of atherogenesis. ► We developed an antibody-based molecular imaging probe targeting P-selectin for PET. ► This is the first report on successful PET imaging for delineation of P-selectin. ► P-selectin is a candidate target for atherosclerotic plaque imaging by clinical PET. -- Abstract: Background: Sensitive detection and qualitative analysis of atherosclerotic plaques are in high demand in cardiovascular clinical settings. The leukocyte–endothelial interaction mediated by an adhesion molecule P-selectin participates in arterial wall inflammation and atherosclerosis. Methods and results: A {sup 64}Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid conjugated anti-P-selectin monoclonal antibody ({sup 64}Cu-DOTA-anti-P-selectin mAb) probe was prepared by conjugating an anti-P-selectin monoclonal antibody with DOTA followed by {sup 64}Cu labeling. Thirty-six hours prior to PET and CT fusion imaging, 3 MBq of {sup 64}Cu-DOTA-anti-P-selectin mAb was intravenously injected into low density lipoprotein receptor-deficient Ldlr-/- mice. After a 180 min PET scan, autoradiography and biodistribution of {sup 64}Cu-DOTA-anti-P-selectin monoclonal antibody was examined using excised aortas. In Ldlr-/- mice fed with a high cholesterol diet for promotion of atherosclerotic plaque development, PET and CT fusion imaging revealed selective and prominent accumulation of the probe in the aortic root. Autoradiography of aortas that demonstrated probe uptake into atherosclerotic plaques was confirmed by Oil red O staining for lipid droplets. In Ldlr-/- mice fed with a chow diet to develop mild atherosclerotic plaques, probe accumulation was barely detectable in the aortic root on PET and CT fusion imaging. Probe biodistribution in aortas was 6.6-fold higher in Ldlr-/- mice fed with a high cholesterol diet than in those fed with a normal chow diet. {sup 64}Cu-DOTA-anti-P-selectin m

  14. Kefir improves fatty liver syndrome by inhibiting the lipogenesis pathway in leptin-deficient ob/ob knockout mice.

    Science.gov (United States)

    Chen, H-L; Tung, Y-T; Tsai, C-L; Lai, C-W; Lai, Z-L; Tsai, H-C; Lin, Y-L; Wang, C-H; Chen, C-M

    2014-09-01

    Fatty liver disease is commonly associated with obesity, insulin resistance and diabetes. Severe fatty liver is sometimes accompanied by steatohepatitis and may lead to the development of hepatocellular carcinoma. At present, there is no effective treatment for non-alcoholic fatty liver disease (NAFLD); thus, recent investigations have focused on developing effective therapeutics to treat this condition. This study aimed to evaluate the effects of kefir on the hepatic lipid metabolism of ob/ob mice, which are commonly used to model fatty liver disease. In this study, we used leptin receptor-deficient ob/ob mice as an animal disease model of NAFLD. Six-week-old ob/ob mice were orally administered the dairy product kefir (140 mg kg(-1) of body weight (BW) per day) for 4 weeks. The data demonstrated that kefir improved fatty liver syndrome on BW, energy expenditure and basal metabolic rate by inhibiting serum glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) activities (Pkefir administration also significantly reduced the macrovesicular fat quantity in liver tissue. In addition, kefir markedly decreased the expression of the genes sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) (Pkefir improves NAFLD on BW, energy expenditure and basal metabolic rate by inhibiting the lipogenesis pathway and that kefir may have the potential for clinical application to the prevention or treatment of NAFLD.

  15. 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...

  16. GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Chabenne, Joseph; Finan, Brian

    2014-01-01

    We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically optimized, polyethylene-glycolated (PEG)-leptin analog in combination with exendin-4 or FGF21. However, the return of leptin action required discontinuation of high-fat diet (HFD......) exposure. Here we assess whether a single peptide possessing balanced coagonism at the glucagon-like peptide 1 (GLP-1) and glucagon receptors can restore leptin responsiveness in DIO mice maintained on a HFD. DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce an ∼15% body...

  17. Effects of leptin treatment and Western diet on wheel running in selectively bred high runner mice.

    Science.gov (United States)

    Meek, Thomas H; Dlugosz, Elizabeth M; Vu, Kim T; Garland, Theodore

    2012-05-15

    The role of leptin in regulating physical activity is varied. The behavioral effects of leptin signaling depend on the type of activity and the animal's physiological state. We used mice from lines selectively bred for high voluntary wheel running to further study how leptin regulates volitional exercise. Mice from four replicate high runner (HR) lines typically run ~3-fold more revolutions per day than those from four non-selected control (C) lines. HR mice have altered dopamine function and differences from C in brain regions known to be important in leptin-mediated behavior. Furthermore, male HR mice have been found to dramatically increase running when administered Western diet, an effect possibly mediated through leptin signaling. Male mice from generation 61 (representing three HR lines and one C line) were allowed wheel access at 24 days of age and given either Western diet (high in fat and with added sucrose) or standard chow. After four weeks, Western diet significantly increased circulating leptin, insulin, C-peptide, gastric inhibitory polypeptide, and inflammatory hormone resistin concentrations in HR mice (C mice not measured). Western diet increased running in HR mice, but did not significantly affect running in C mice. During the fifth week, all mice received two days of intra-peritoneal sham injections (physiological saline) followed by three days of murine recombinant leptin injections, and then another six days of sham injections. Leptin treatment significantly decreased caloric intake (adjusted for body mass) and body mass in all groups. Wheel running significantly increased with leptin injections in HR mice (fed Western or standard diet), but was unaffected in C mice. Whether Western diet and leptin treatment stimulate wheel running in HR mice through the same physiological pathways awaits future study. These results have implications for understanding the neural and endocrine systems that control locomotor activity, food consumption, and body

  18. Neonatal exposure to leptin augments diet-induced obesity in leptin-deficient Ob/Ob mice.

    Science.gov (United States)

    Yura, Shigeo; Itoh, Hiroaki; Sagawa, Norimasa; Yamamoto, Hiroshi; Masuzaki, Hiroaki; Nakao, Kazuwa; Kawamura, Makoto; Mogami, Haruta; Ogawa, Yoshihiro; Fujii, Shingo

    2008-06-01

    Epidemiological evidence has revealed that undernutrition in utero is closely associated with obesity and related detrimental metabolic sequelae in adulthood. Recently, using a wild-type (wt) mouse model in which offspring were exposed to intrauterine undernutrition (UN offspring), we reported that the premature leptin surge during neonatal growth promotes lifelong changes in energy regulating circuitry in the hypothalamus, thus playing an important role in the development of pronounced obesity on a high-fat diet (HFD) in adulthood. Here, we further evaluate the essential involvement of leptin in the developmental origins of obesity using leptin-deficient ob/ob mice. We assessed the progression of obesity on an HFD in adult leptin-deficient ob/ob male mice that were exposed to intrauterine undernutrition by maternal food restriction (ob/ob UN offspring) or to leptin treatment during the neonatal period; this treatment is comparable to the premature leptin surge observed in the wt-UN offspring. On an HFD, the body weight of the male ob/ob UN offspring paralleled that of the ob/ob offspring exposed to normal intrauterine nutrition (ob/ob NN offspring). In contrast, early exposure to leptin in the ob/ob NN offspring during early neonatal growth reproduced the development of pronounced obesity on an HFD in adulthood. The presence of leptin and associated energy regulation are indispensable in the acceleration of obesity on an HFD caused by undernutrition in utero. The premature leptin surge plays an essential role in the developmental origins of obesity as a programming signal during the early neonatal period.

  19. Obesity, diabetes and leptin: lessons learned from obese hyperglycemic mice

    Directory of Open Access Journals (Sweden)

    Meftun Ahmed

    2008-07-01

    Full Text Available The recent epidemic nature of obesity and association of obesity with the development of type 2 diabetes demands dissection of the pathophysiology of this morbid disorder which is essential for better understanding of the process of evolution of insulin resistance. Different animal models have been used to explore the mechanism linking obesity to insulin resistance and type 2 diabetes. The discovery of ob gene and its product, leptin, has revealed the signaling system regulating energy balance in rodents. The mice lacking this ob gene, ob/ob mice, display obesity, hyperglycemia and hyperinsulinemia and has been extensively used for the study of type 2 diabetes and for potential drug development. In this review, the features and development of obese hyperglycemic syndrome, the role of leptin in the pathogenesis of the syndrome and finally the applicability of the findings in rodents to body weight regulation and pathogenesis of insulin resistance in humans have been summarized. Ibrahim Med. Coll. J. 2008; 2(2: 72-84

  20. Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lep(ob)) mice

    Science.gov (United States)

    Winters, B.; Mo, Z.; Brooks-Asplund, E.; Kim, S.; Shoukas, A.; Li, D.; Nyhan, D.; Berkowitz, D. E.

    2000-01-01

    Obesity is a major health care problem and is associated with significant cardiovascular morbidity. Leptin, a neuroendocrine hormone released by adipose tissue, is important in modulating obesity by signaling satiety and increasing metabolism. Moreover, leptin receptors are expressed on vascular endothelial cells (ECs) and mediate angiogenesis. We hypothesized that leptin may also play an important role in vasoregulation. We investigated vasoregulatory mechanisms in the leptin-deficient obese (ob/ob) mouse model and determined the influence of leptin replacement on endothelial-dependent vasorelaxant responses. The direct effect of leptin on EC nitric oxide (NO) production was also tested by using 4, 5-diaminofluorescein-2 diacetate staining and measurement of nitrate and nitrite concentrations. Vasoconstrictor responses to phenylephrine, norepinephrine, and U-46619 were markedly enhanced in aortic rings from ob/ob mice and were modulated by NO synthase inhibition. Vasorelaxant responses to ACh were markedly attenuated in mesenteric microvessels from ob/ob mice. Leptin replacement resulted in significant weight loss and reversal of the impaired endothelial-dependent vasorelaxant responses observed in ob/ob mice. Preincubation of ECs with leptin enhanced the release of NO production. Thus leptin-deficient ob/ob mice demonstrate marked abnormalities in vasoregulation, including impaired endothelial-dependent vasodilation, which is reversed by leptin replacement. These findings may be partially explained by the direct effect of leptin on endothelial NO production. These vascular abnormalities are similar to those observed in obese, diabetic, leptin-resistant humans. The ob/ob mouse may, therefore, be an excellent new model for the study of the cardiovascular effects of obesity.

  1. Astrocytes Modulate Distribution and Neuronal Signaling of Leptin in the Hypothalamus of Obese Avy Mice

    OpenAIRE

    Pan, Weihong; Hsuchou, Hung; Xu, Changlei; Wu, Xiaojun; Bouret, Sebastien G.; Kastin, Abba J.

    2010-01-01

    We tested the hypothesis that astrocytic activity modulates neuronal uptake and signaling of leptin in the adult-onset obese agouti viable yellow (Avy) mouse. In the immunohistochemical study, Avy mice were pretreated with the astrocyte metabolic inhibitor fluorocitrate or phosphate-buffered saline (PBS) vehicle intracerebroventricularly (icv) followed 1 h later by Alexa568-leptin. Confocal microscopy showed that fluorocitrate pretreatment reduced astrocytic uptake of Alexa568-leptin 30 min a...

  2. Leptin Is Required for Glucose Homeostasis after Roux-en-Y Gastric Bypass in Mice.

    Science.gov (United States)

    Mokadem, Mohamad; Zechner, Juliet F; Uchida, Aki; Aguirre, Vincent

    2015-01-01

    Leptin, the protein product of the ob gene, increases energy expenditure and reduces food intake, thereby promoting weight reduction. Leptin also regulates glucose homeostasis and hepatic insulin sensitivity via hypothalamic proopiomelanocortin neurons in mice. Roux-en-Y gastric bypass (RYGB) induces weight loss that is substantial and sustained despite reducing plasma leptin levels. In addition, patients who fail to undergo diabetes remission after RYGB are hypoletinemic compared to those who do and to lean controls. We have previously demonstrated that the beneficial effects of RYGB in mice require the melanocortin-4 receptor, a downstream effector of leptin action. Based on these observations, we hypothesized that leptin is required for sustained weight reduction and improved glucose homeostasis observed after RYGB. To investigate this hypothesis, we performed RYGB or sham operations on leptin-deficient ob/ob mice maintained on regular chow. To investigate whether leptin is involved in post-RYGB weight maintenance, we challenged post-surgical mice with high fat diet. RYGB reduced total body weight, fat and lean mass and caused reduction in calorie intake in ob/ob mice. However, it failed to improve glucose tolerance, glucose-stimulated plasma insulin, insulin tolerance, and fasting plasma insulin. High fat diet eliminated the reduction in calorie intake observed after RYGB in ob/ob mice and promoted weight regain, although not to the same extent as in sham-operated mice. We conclude that leptin is required for the effects of RYGB on glucose homeostasis but not body weight or composition in mice. Our data also suggest that leptin may play a role in post-RYGB weight maintenance.

  3. Leptin Is Required for Glucose Homeostasis after Roux-en-Y Gastric Bypass in Mice.

    Directory of Open Access Journals (Sweden)

    Mohamad Mokadem

    Full Text Available Leptin, the protein product of the ob gene, increases energy expenditure and reduces food intake, thereby promoting weight reduction. Leptin also regulates glucose homeostasis and hepatic insulin sensitivity via hypothalamic proopiomelanocortin neurons in mice. Roux-en-Y gastric bypass (RYGB induces weight loss that is substantial and sustained despite reducing plasma leptin levels. In addition, patients who fail to undergo diabetes remission after RYGB are hypoletinemic compared to those who do and to lean controls. We have previously demonstrated that the beneficial effects of RYGB in mice require the melanocortin-4 receptor, a downstream effector of leptin action. Based on these observations, we hypothesized that leptin is required for sustained weight reduction and improved glucose homeostasis observed after RYGB.To investigate this hypothesis, we performed RYGB or sham operations on leptin-deficient ob/ob mice maintained on regular chow. To investigate whether leptin is involved in post-RYGB weight maintenance, we challenged post-surgical mice with high fat diet.RYGB reduced total body weight, fat and lean mass and caused reduction in calorie intake in ob/ob mice. However, it failed to improve glucose tolerance, glucose-stimulated plasma insulin, insulin tolerance, and fasting plasma insulin. High fat diet eliminated the reduction in calorie intake observed after RYGB in ob/ob mice and promoted weight regain, although not to the same extent as in sham-operated mice. We conclude that leptin is required for the effects of RYGB on glucose homeostasis but not body weight or composition in mice. Our data also suggest that leptin may play a role in post-RYGB weight maintenance.

  4. Astrocytes modulate distribution and neuronal signaling of leptin in the hypothalamus of obese A vy mice.

    Science.gov (United States)

    Pan, Weihong; Hsuchou, Hung; Xu, Changlei; Wu, Xiaojun; Bouret, Sebastien G; Kastin, Abba J

    2011-03-01

    We tested the hypothesis that astrocytic activity modulates neuronal uptake and signaling of leptin in the adult-onset obese agouti viable yellow (A vy) mouse. In the immunohistochemical study, A vy mice were pretreated with the astrocyte metabolic inhibitor fluorocitrate or phosphate-buffered saline (PBS) vehicle intracerebroventricularly (icv) followed 1 h later by Alexa568-leptin. Confocal microscopy showed that fluorocitrate pretreatment reduced astrocytic uptake of Alexa568-leptin 30 min after icv while increasing neuronal uptake in the arcuate nucleus and dorsomedial hypothalamus. Fluorocitrate also induced mild astrogliosis and moderately increased pSTAT3 immunopositive neurons in response to Alexa568-leptin in the dorsomedial hypothalamus. In the Western blotting study, A vy mice were pretreated with either PBS or fluorocitrate, and received PBS or leptin 1 h later followed by determination of pSTAT3 and GFAP expression an additional 30 min afterward. The results show that fluorocitrate induced a mild pSTAT3 activation but attenuated leptin-induced pSTAT3 activation and decreased GFAP expression independently of leptin treatment. We conclude that inhibition of astrocytic activity resulted in enhanced neuronal leptin uptake and signaling. This suggests opposite roles of astrocytes and neurons in leptin's actions in the A vy mouse with adult-onset obesity.

  5. Behavioral changes induced by cocaine in mice are modified by a hyperlipidic diet or recombinant leptin

    Directory of Open Access Journals (Sweden)

    E. Erhardt

    2006-12-01

    Full Text Available The objective of the present study was to determine if the acute behavioral effects of cocaine acutely administered intraperitoneally (ip at doses of 5, 10 and 20 mg/kg on white male CF1 mice, 90 days of age, would be influenced by leptin acutely administered ip (at doses of 5, 10 and 20 µg/kg or by endogenous leptin production enhanced by a high-fat diet. The acute behavioral effects of cocaine were evaluated in open-field, elevated plus-maze and forced swimming tests. Results were compared between a group of 80 mice consuming a balanced diet and a high-fat diet, and a group of 80 mice fed a commercially available rodent chow formula (Ralston Purina but receiving recombinant leptin (rLeptin or saline ip. Both the high-fat-fed and rLeptin-treated mice showed decreased locomotion in the open-field test, spent more time in the open arms of the elevated plus-maze and showed less immobility time in the forced swimming test (F(1,68 = 7.834, P = 0.007. There was an interaction between diets and cocaine/saline treatments in locomotion (F(3,34 = 3.751, P = 0.020 and exploration (F(3,34 = 3.581, P = 0.024. These results suggest that anxiolytic effects and increased general activity were induced by leptin in cocaine-treated mice and that low leptin levels are associated with behavioral depression. Chronic changes in diet composition producing high leptin levels or rLeptin treatment may result in an altered response to cocaine in ethologic tests that measure degrees of anxiety and depression, which could be attributed to an antagonistic effect of leptin.

  6. Causation of Acute Flaccid Paralysis by Myelitis and Myositis in Enterovirus-D68 Infected Mice Deficient in Interferon αβ/γ Receptor Deficient Mice

    Science.gov (United States)

    Morrey, John D.; Wang, Hong; Hurst, Brett L.; Zukor, Katherine; Siddharthan, Venkatraman; Tarbet, E. Bart

    2018-01-01

    Enterovirus D68 (EV-D68) caused a large outbreak in the summer and fall of 2014 in the United States. It causes serious respiratory disease, but causation of associated paralysis is controversial, because the virus is not routinely identified in cerebrospinal fluid. To establish clinical correlates with human disease, we evaluated EV-D68 infection in non-lethal paralysis mouse models. Ten-day-old mice lacking interferon responses were injected intraperitoneally with the virus. Paralysis developed in hindlimbs. After six weeks of paralysis, the motor neurons were depleted due to viral infection. Hindlimb muscles were also infected and degenerating. Even at the earliest stage of paralysis, muscles were still infected and were degenerating, in addition to presence of virus in the spinal cord. To model natural respiratory infection, five-day-old mice were infected intranasally with EV-D68. Two of the four infected mice developed forelimb paralysis. The affected limbs had muscle disease, but no spinal cord infection was detected. The unique contributions of this study are that EV-D68 causes paralysis in mice, and that causation by muscle disease, with or without spinal cord disease, may help to resolve the controversy that the virus can cause paralysis, even if it cannot be identified in cerebrospinal fluid. PMID:29329211

  7. Causation of Acute Flaccid Paralysis by Myelitis and Myositis in Enterovirus-D68 Infected Mice Deficient in Interferon αβ/γ Receptor Deficient Mice

    Directory of Open Access Journals (Sweden)

    John D. Morrey

    2018-01-01

    Full Text Available Enterovirus D68 (EV-D68 caused a large outbreak in the summer and fall of 2014 in the United States. It causes serious respiratory disease, but causation of associated paralysis is controversial, because the virus is not routinely identified in cerebrospinal fluid. To establish clinical correlates with human disease, we evaluated EV-D68 infection in non-lethal paralysis mouse models. Ten-day-old mice lacking interferon responses were injected intraperitoneally with the virus. Paralysis developed in hindlimbs. After six weeks of paralysis, the motor neurons were depleted due to viral infection. Hindlimb muscles were also infected and degenerating. Even at the earliest stage of paralysis, muscles were still infected and were degenerating, in addition to presence of virus in the spinal cord. To model natural respiratory infection, five-day-old mice were infected intranasally with EV-D68. Two of the four infected mice developed forelimb paralysis. The affected limbs had muscle disease, but no spinal cord infection was detected. The unique contributions of this study are that EV-D68 causes paralysis in mice, and that causation by muscle disease, with or without spinal cord disease, may help to resolve the controversy that the virus can cause paralysis, even if it cannot be identified in cerebrospinal fluid.

  8. Teasaponin improves leptin sensitivity in the prefrontal cortex of obese mice.

    Science.gov (United States)

    Yu, Yinghua; Wu, Yizhen; Szabo, Alexander; Wang, Sen; Yu, Shijia; Wang, Qing; Huang, Xu-Feng

    2015-12-01

    Obesity impairs cognition, and the leptin-induced increase of brain-derived neurotrophic factor (BDNF) and neurogenesis. Tea consumption improves cognition and increases brain activation in the prefrontal cortex. This study examined whether teasaponin, an active ingredient in tea, could improve memory and central leptin effects on neurogenesis in the prefrontal cortex of obese mice, and in vitro in cultured prefrontal cortical neurons. Teasaponin (10 mg/kg, intraperitoneal) for 21 days improved downstream leptin signaling (JAK2 and STAT3), and leptin's effect on BDNF, in the prefrontal cortex of high-fat diet (HFD) fed mice. Prefrontal cortical neurons were cultured with teasaponin and palmitic acid (the most abundant dietary saturated fatty acid) to examine their effects on neurogenesis and BDNF expression in response to leptin. Palmitic acid decreased leptin's effect on neurite outgrowth, postsynaptic density protein 95, and BDNF expression in cultured cortical neurons, which was reversed by teasaponin. Teasaponin improved the leptin sensitivity of prefrontal cortical neurons in obese mice or when treated by palmitic acid. This in turn increased BDNF expression and neurite growth. Therefore, teasaponin supplementation may be used to prevent obesity-associated neurodegeneration and improve cognitive function. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Leptin deficiency in mice counteracts imiquimod (IMQ)-induced psoriasis-like skin inflammation while leptin stimulation induces inflammation in human keratinocytes.

    Science.gov (United States)

    Stjernholm, Theresa; Ommen, Pernille; Langkilde, Ane; Johansen, Claus; Iversen, Lars; Rosada, Cecilia; Stenderup, Karin

    2017-04-01

    Leptin is an adipocyte-derived cytokine secreted mostly by adipose tissue. Serum leptin levels are elevated in obese individuals and correlate positively with body mass index (BMI). Interestingly, serum leptin levels are also elevated in patients with psoriasis and correlate positively with disease severity. Psoriasis is associated with obesity; patients with psoriasis have a higher incidence of obesity, and obese individuals have a higher risk of developing psoriasis. Additionally, obese patients with psoriasis experience a more severe degree of psoriasis. In this study, we hypothesised that leptin may link psoriasis and obesity and plays an aggravating role in psoriasis. To investigate leptin's role in psoriasis, we applied the widely accepted imiquimod (IMQ)-induced psoriasis-like skin inflammation mouse model on leptin-deficient (ob/ob) mice and evaluated psoriasis severity. Moreover, we stimulated human keratinocytes with leptin and investigated the effect on proliferation and expression of pro-inflammatory proteins. In ob/ob mice, clinical signs of erythema, infiltration and scales in dorsal skin and inflammation in ear skin, as measured by ear thickness, were attenuated and compared with wt mice. Moreover, IL-17A and IL-22 mRNA expression levels, as well as increased epidermal thickness, were significantly less induced. In vitro, the effect of leptin stimulation on human keratinocytes demonstrated increased proliferation and induced secretion of several pro-inflammatory proteins; two hallmarks of psoriasis. In conclusion, leptin deficiency attenuated IMQ-induced psoriasis-like skin inflammation in a mouse model, and leptin stimulation induced a pro-inflammatory phenotype in human keratinocytes, thus, supporting an aggravating role of leptin in psoriasis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Leptin Signaling in AgRP Neurons Modulates Puberty Onset and Adult Fertility in Mice.

    Science.gov (United States)

    Egan, Olivia K; Inglis, Megan A; Anderson, Greg M

    2017-04-05

    The hormone leptin indirectly communicates metabolic information to brain neurons that control reproduction, using GABAergic circuitry. Agouti-related peptide (AgRP) neurons in the arcuate nucleus are GABAergic, express leptin receptors (LepR), and are known to influence reproduction. This study tested whether leptin actions on AgRP neurons are required and sufficient for puberty onset and subsequent fertility. First, Agrp- Cre and Lepr- flox mice were used to target deletion of LepR to AgRP neurons. AgRP-LepR knock-out female mice exhibited mild obesity and adiposity as described previously, as well as a significant delay in the pubertal onset of estrous cycles compared with control animals. No significant differences in male puberty onset or adult fecundity in either sex were observed. Next, mice with a floxed polyadenylation signal causing premature transcriptional termination of the Lepr gene were crossed with AgRP-Cre mice to generate mice with AgRP neuron-specific rescue of LepR. Lepr-null control males and females were morbidly obese and exhibited delayed puberty onset, no evidence of estrous cycles, and minimal fecundity. Remarkably, AgRP-LepR rescue partially or fully restored all of these reproductive attributes to levels similar to those of LepR-intact controls despite minimal rescue of metabolic function. These results indicate that leptin signaling in AgRP neurons is sufficient for puberty onset and normal adult fecundity in both sexes when leptin signaling is absent in all other cells and that in females, the absence of AgRP neuron leptin signaling delays puberty. These actions appear to be independent of leptin's metabolic effects. SIGNIFICANCE STATEMENT Sexual maturation and fertility are dispensable at the individual level but critical for species survival. Conditions such as nutritional imbalance may therefore suppress puberty onset and fertility in an individual. In societies characterized by widespread obesity, the sensitivity of reproduction to

  11. Magel2 is required for leptin-mediated depolarization of POMC neurons in the hypothalamic arcuate nucleus in mice.

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    Rebecca E Mercer

    Full Text Available Prader-Willi Syndrome is the most common syndromic form of human obesity and is caused by the loss of function of several genes, including MAGEL2. Mice lacking Magel2 display increased weight gain with excess adiposity and other defects suggestive of hypothalamic deficiency. We demonstrate Magel2-null mice are insensitive to the anorexic effect of peripherally administered leptin. Although their excessive adiposity and hyperleptinemia likely contribute to this physiological leptin resistance, we hypothesized that Magel2 may also have an essential role in intracellular leptin responses in hypothalamic neurons. We therefore measured neuronal activation by immunohistochemistry on brain sections from leptin-injected mice and found a reduced number of arcuate nucleus neurons activated after leptin injection in the Magel2-null animals, suggesting that most but not all leptin receptor-expressing neurons retain leptin sensitivity despite hyperleptinemia. Electrophysiological measurements of arcuate nucleus neurons expressing the leptin receptor demonstrated that although neurons exhibiting hyperpolarizing responses to leptin are present in normal numbers, there were no neurons exhibiting depolarizing responses to leptin in the mutant mice. Additional studies demonstrate that arcuate nucleus pro-opiomelanocortin (POMC expressing neurons are unresponsive to leptin. Interestingly, Magel2-null mice are hypersensitive to the anorexigenic effects of the melanocortin receptor agonist MT-II. In Prader-Willi Syndrome, loss of MAGEL2 may likewise abolish leptin responses in POMC hypothalamic neurons. This neural defect, together with increased fat mass, blunted circadian rhythm, and growth hormone response pathway defects that are also linked to loss of MAGEL2, could contribute to the hyperphagia and obesity that are hallmarks of this disorder.

  12. Inhibitory effect of leptin on rosiglitazone-induced differentiation of primary adipocytes prepared from TallyHO/Jng mice

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ki Young; Kim, Joo Young; Sung, Yoon-Young; Jung, Won Hoon; Kim, Hee-Youn; Park, Ji Seon; Cheon, Hyae Gyeong [Medicinal Science Division, Korea Research Institute of Chemical Technology, 100 Jang-dong, Yuseong, 305-600 Daejon (Korea, Republic of); Rhee, Sang Dal, E-mail: sdrhee@krict.re.kr [Medicinal Science Division, Korea Research Institute of Chemical Technology, 100 Jang-dong, Yuseong, 305-600 Daejon (Korea, Republic of)

    2011-03-25

    Research highlights: {yields} In this study, we investigated the effects of leptin on adipocyte differentiation prepared from subcutaneous fat of TallyHo mice. {yields} Leptin inhibited the adipocytes differentiation at physiological concentration via inhibition of PPAR{gamma} expression. {yields} Inhibitors of ERK and STAT1 restored the leptin's inhibitory activity both in vitro and in vivo. -- Abstract: The effects of leptin on rosiglitazone-induced adipocyte differentiation were investigated in the primary adipocytes prepared from subcutaneous fat of TallyHO/Jng (TallyHO) mouse, a recently developed model animal for type 2 diabetes mellitus (T2DM). The treatment of leptin inhibited the rosiglitazone-induced adipocyte differentiation with a decreased expression of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) a key adipogenic transcription factor, both in mRNA and protein levels. Leptin (10 nM) was sufficient to inhibit the adipocyte differentiation, which seemed to come from increased expression of leptin receptor genes in the fat of TallyHO mice. The inhibition of adipogenesis by leptin was restored by the treatment of inhibitors for extracellular-signal-regulated kinase (ERK) (PD98059) and signal transducer and activator of transcription-1 (STAT1) (fludarabine). Furthermore, in vivo intraperitoneal administration of PD98059 and fludarabine increased the PPAR{gamma} expression in the subcutaneous fat of TallyHO mice. These data suggest that leptin could inhibit the PPAR{gamma} expression and adipocyte differentiation in its physiological concentration in TallyHO mice.

  13. Influence of the core circadian gene "Clock" on obesity and leptin resistance in mice.

    Science.gov (United States)

    Xie, Xiaoping; Yang, Shuhong; Zou, Yan; Cheng, Shuting; Wang, Yuhui; Jiang, Zhou; Xiao, Jing; Wang, Zhengrong; Liu, Yanyou

    2013-01-23

    Alterations in metabolism could be due to cell-autonomous effects associated with altered expression of Clock in central nervous system feeding centers and/or peripheral tissues involved in metabolism. Clock mutant mice are hyperphagic and obese, which indicates that Clock is related to obesity. In the present study, we used intracerebroventricular injection of recombinant adenoviral vector harboring Clock genes to explore the role of Clock on diet induced obesity and the mechanisms involved in leptin resistance and leptin signaling in mice. The results demonstrated that expression of Clock in the arcuate nucleus of diet induced obesity mice was down-regulated. The recombinant adenoviral vector harboring Clock genes could reduce obesity indexes of diet induced obesity mice including body weight, BMI and total fat mass, attenuate hyperleptinemia, increase leptin sensitivity and decrease accumulated suppressor of cytokine signaling-3 in the arcuate nucleus. These results indicate that Clock plays an important role on obesity, which may be involved in leptin resistance and regulation of suppressor of cytokine signaling-3 in arcuate nucleus. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Leptin differentially regulates STAT3 activation in the ob/ob mice adipose mesenchymal stem cells

    Science.gov (United States)

    Leptin-deficient genetically obese ob/ob mice exhibit adipocyte hypertrophy and hyperplasia as well as elevated adipose tissue and systemic inflammation. Studies have shown that multipotent stem cells isolated from adult adipose tissue can differentiate into adipocytes ex vivo and thereby contribute...

  15. Long-lived weight-reduced αMUPA mice show higher and longer maternal-dependent postnatal leptin surge.

    Directory of Open Access Journals (Sweden)

    Mariel Pinsky

    Full Text Available We investigated whether long-lived weight-reduced αMUPA mice differ from their wild types in postnatal body composition and leptin level, and whether these differences are affected by maternal-borne factors. Newborn αMUPA and wild type mice had similar body weight and composition up to the third postnatal week, after which αMUPA mice maintained lower body weight due to lower fat-free mass. Both strains showed a surge in leptin levels at the second postnatal week, initiating earlier in αMUPA mice, rising higher and lasting longer than in the wild types, mainly in females. Leptin level in dams' serum and breast milk, and in their pup's stomach content were also higher in αMUPA than in the WT during the surge peak. Leptin surge preceded the strain divergence in body weight, and was associated with an age-dependent decrease in the leptin:fat mass ratio-suggesting that postnatal sex and strain differences in leptin ontogeny are strongly influenced by processes independent of fat mass, such as production and secretion, and possibly outside fat tissues. Dam removal elevated corticosterone level in female pups from both strains similarly, yet mitigated the leptin surge only in αMUPA-eliminating the strain differences in leptin levels. Overall, our results indicate that αMUPA's postnatal leptin surge is more pronounced than in the wild type, more sensitive to maternal deprivation, less related to pup's total adiposity, and is associated with a lower post-weaning fat-free mass. These strain-related postnatal differences may be related to αMUPA's higher milk-borne leptin levels. Thus, our results support the use of αMUPA mice in future studies aimed to explore the relationship between maternal (i.e. milk-borne factors, postnatal leptin levels, and post-weaning body composition and energy homeostasis.

  16. Long-lived weight-reduced αMUPA mice show higher and longer maternal-dependent postnatal leptin surge.

    Science.gov (United States)

    Pinsky, Mariel; Rauch, Maayan; Abbas, Atallah; Sharabi-Nov, Adi; Tamir, Snait; Gutman, Roee

    2017-01-01

    We investigated whether long-lived weight-reduced αMUPA mice differ from their wild types in postnatal body composition and leptin level, and whether these differences are affected by maternal-borne factors. Newborn αMUPA and wild type mice had similar body weight and composition up to the third postnatal week, after which αMUPA mice maintained lower body weight due to lower fat-free mass. Both strains showed a surge in leptin levels at the second postnatal week, initiating earlier in αMUPA mice, rising higher and lasting longer than in the wild types, mainly in females. Leptin level in dams' serum and breast milk, and in their pup's stomach content were also higher in αMUPA than in the WT during the surge peak. Leptin surge preceded the strain divergence in body weight, and was associated with an age-dependent decrease in the leptin:fat mass ratio-suggesting that postnatal sex and strain differences in leptin ontogeny are strongly influenced by processes independent of fat mass, such as production and secretion, and possibly outside fat tissues. Dam removal elevated corticosterone level in female pups from both strains similarly, yet mitigated the leptin surge only in αMUPA-eliminating the strain differences in leptin levels. Overall, our results indicate that αMUPA's postnatal leptin surge is more pronounced than in the wild type, more sensitive to maternal deprivation, less related to pup's total adiposity, and is associated with a lower post-weaning fat-free mass. These strain-related postnatal differences may be related to αMUPA's higher milk-borne leptin levels. Thus, our results support the use of αMUPA mice in future studies aimed to explore the relationship between maternal (i.e. milk-borne) factors, postnatal leptin levels, and post-weaning body composition and energy homeostasis.

  17. Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice.

    Directory of Open Access Journals (Sweden)

    Florian Willecke

    Full Text Available We tested whether a high fat diet (HFD containing the inflammatory dietary fatty acid palmitate or insulin deficient diabetes altered the remodeling of atherosclerotic plaques in LDL receptor knockout (Ldlr-/- mice. Cholesterol reduction was achieved by using a helper-dependent adenovirus (HDAd carrying the gene for the low-density lipoprotein receptor (Ldlr; HDAd-LDLR. After injection of the HDAd-LDLR, mice consuming either HFD, which led to insulin resistance but not hyperglycemia, or low fat diet (LFD, showed regression compared to baseline. However there was no difference between the two groups in terms of atherosclerotic lesion size, or CD68+ cell and lipid content. Because of the lack of effects of these two diets, we then tested whether viral-mediated cholesterol reduction would lead to defective regression in mice with greater hyperglycemia. In both normoglycemic and streptozotocin (STZ-treated hyperglycemic mice, HDAd-LDLR significantly reduced plasma cholesterol levels, decreased atherosclerotic lesion size, reduced macrophage area and lipid content, and increased collagen content of plaque in the aortic sinus. However, reductions in anti-inflammatory and ER stress-related genes were less pronounced in STZ-diabetic mice compared to non-diabetic mice. In conclusion, HDAd-mediated Ldlr gene therapy is an effective and simple method to induce atherosclerosis regression in Ldlr-/- mice in different metabolic states.

  18. Sex differences between CRF1 receptor deficient mice following naloxone-precipitated morphine withdrawal in a conditioned place aversion paradigm: implication of HPA axis.

    Directory of Open Access Journals (Sweden)

    Juan-Antonio García-Carmona

    Full Text Available Extinction period of positive affective memory of drug taking and negative affective memory of drug withdrawal, as well as the different response of men and women might be important for the clinical treatment of drug addiction. We investigate the role of corticotropin releasing factor receptor type one (CRF1R and the different response of male and female mice in the expression and extinction of the aversive memory.We used genetically engineered male and female mice lacking functional CRF1R. The animals were rendered dependent on morphine by intraperitoneally injection of increasing doses of morphine (10-60 mg/kg. Negative state associated with naloxone (1 mg/kg s.c.-precipitated morphine withdrawal was examined by using conditioned place aversion (CPA paradigm. No sex differences for CPA expression were found in wild-type (n = 29 or CRF1R knockout (KO mice (n = 29. However, CRF1R KO mice presented less aversion score than wild-type mice, suggesting that CRF1R KO mice were less responsive than wild-type to continuous associations between drug administration and environmental stimuli. In addition, CPA extinction was delayed in wild-type and CRF1R KO male mice compared with females of both genotypes. The genetic disruption of the CRF1R pathway decreased the period of extinction in males and females suggesting that CRF/CRF1R is implicated in the duration of aversive memory. Our results also showed that the increase in adrenocorticotropic hormone (ACTH levels observed in wild-type (n = 11 mice after CPA expression, were attenuated in CRF1R KO mice (n = 10. In addition, ACTH returned to the baseline levels in males and females once CPA extinction was finished.These results suggest that, at least, CPA expression is partially due to an increase in plasma ACTH levels, through activation of CRF1R, which can return when CPA extinction is finished.

  19. Leptin Suppresses Mouse Taste Cell Responses to Sweet Compounds.

    Science.gov (United States)

    Yoshida, Ryusuke; Noguchi, Kenshi; Shigemura, Noriatsu; Jyotaki, Masafumi; Takahashi, Ichiro; Margolskee, Robert F; Ninomiya, Yuzo

    2015-11-01

    Leptin is known to selectively suppress neural and behavioral responses to sweet-tasting compounds. However, the molecular basis for the effect of leptin on sweet taste is not known. Here, we report that leptin suppresses sweet taste via leptin receptors (Ob-Rb) and KATP channels expressed selectively in sweet-sensitive taste cells. Ob-Rb was more often expressed in taste cells that expressed T1R3 (a sweet receptor component) than in those that expressed glutamate-aspartate transporter (a marker for Type I taste cells) or GAD67 (a marker for Type III taste cells). Systemically administered leptin suppressed taste cell responses to sweet but not to bitter or sour compounds. This effect was blocked by a leptin antagonist and was absent in leptin receptor-deficient db/db mice and mice with diet-induced obesity. Blocking the KATP channel subunit sulfonylurea receptor 1, which was frequently coexpressed with Ob-Rb in T1R3-expressing taste cells, eliminated the effect of leptin on sweet taste. In contrast, activating the KATP channel with diazoxide mimicked the sweet-suppressing effect of leptin. These results indicate that leptin acts via Ob-Rb and KATP channels that are present in T1R3-expressing taste cells to selectively suppress their responses to sweet compounds. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  20. Growth hormone receptor deficiency in mice results in reduced systolic blood pressure and plasma renin, increased aortic eNOS expression, and altered cardiovascular structure and function

    DEFF Research Database (Denmark)

    Egecioglu, E; Andersson, I J; Bollano, E

    2007-01-01

    To study the role of the growth hormone receptor (GHR) in the development of cardiovascular structure and function, female GHR gene-disrupted or knockout (KO) and wild-type (WT) mice at age 18 wk were used. GHR KO mice had lower plasma renin levels (12 +/- 2 vs. 20 +/- 4 mGU/ml, P ... to acetylcholine (P functional and morphological changes in both heart and vasculature that are beyond the observed alterations in body size...

  1. Angiotensin II type 1a receptor-deficient mice develop angiotensin II-induced oxidative stress and DNA damage without blood pressure increase.

    Science.gov (United States)

    Zimnol, Anna; Amann, Kerstin; Mandel, Philipp; Hartmann, Christina; Schupp, Nicole

    2017-12-01

    Hypertensive patients have an increased risk of developing kidney cancer. We have shown in vivo that besides elevating blood pressure, angiotensin II causes DNA damage dose dependently. Here, the role of blood pressure in the formation of DNA damage is studied. Mice lacking one of the two murine angiotensin II type 1 receptor (AT1R) subtypes, AT1aR, were equipped with osmotic minipumps, delivering angiotensin II during 28 days. Parameters of oxidative stress and DNA damage of kidneys and hearts of AT1aR-knockout mice were compared with wild-type (C57BL/6) mice receiving angiotensin II, and additionally, with wild-type mice treated with candesartan, an antagonist of both AT1R subtypes. In wild-type mice, angiotensin II induced hypertension, reduced kidney function, and led to a significant formation of reactive oxygen species (ROS). Furthermore, genomic damage was markedly increased in this group. All these responses to angiotensin II could be attenuated by concurrent administration of candesartan. In AT1aR-deficient mice treated with angiotensin II, systolic pressure was not increased, and renal function was not affected. However, angiotensin II still led to an increase of ROS in kidneys and hearts of these animals. Additionally, genomic damage in the form of double-strand breaks was significantly induced in kidneys of AT1aR-deficient mice. Our results show that angiotensin II induced ROS production and DNA damage even without the presence of AT1aR and independently of blood pressure changes. Copyright © 2017 the American Physiological Society.

  2. Obese Neuronal PPARγ Knockout Mice Are Leptin Sensitive but Show Impaired Glucose Tolerance and Fertility.

    Science.gov (United States)

    Fernandez, Marina O; Sharma, Shweta; Kim, Sun; Rickert, Emily; Hsueh, Katherine; Hwang, Vicky; Olefsky, Jerrold M; Webster, Nicholas J G

    2017-01-01

    The peroxisome-proliferator activated receptor γ (PPARγ) is expressed in the hypothalamus in areas involved in energy homeostasis and glucose metabolism. In this study, we created a deletion of PPARγ brain-knockout (BKO) in mature neurons in female mice to investigate its involvement in metabolism and reproduction. We observed that there was no difference in age at puberty onset between female BKOs and littermate controls, but the BKOs gave smaller litters when mated and fewer oocytes when ovulated. The female BKO mice had regular cycles but showed an increase in the number of cycles with prolonged estrus. The mice also had increased luteinizing hormone (LH) levels during the LH surge and histological examination showed hemorrhagic corpora lutea. The mice were challenged with a 60% high-fat diet (HFD). Metabolically, the female BKO mice showed normal body weight, glucose and insulin tolerance, and leptin levels but were protected from obesity-induced leptin resistance. The neuronal knockout also prevented the reduction in estrous cycles due to the HFD. Examination of ovarian histology showed a decrease in the number of primary and secondary follicles in both genotypes due to the HFD, but the BKO ovaries showed an increase in the number of hemorrhagic follicles. In summary, our results show that neuronal PPARγ is required for optimal female fertility but is also involved in the adverse effects of diet-induced obesity by creating leptin resistance potentially through induction of the repressor Socs3. Copyright © 2017 by the Endocrine Society.

  3. α7 nicotinic ACh receptor-deficient mice exhibit sustained attention impairments that are reversed by β2 nicotinic ACh receptor activation.

    Science.gov (United States)

    Kolisnyk, Benjamin; Al-Onaizi, Mohammed A; Prado, Vania F; Prado, Marco A M

    2015-10-01

    Disruptions of executive function, including attentional deficits, are a hallmark of a number of diseases. ACh in the prefrontal cortex regulates attentive behaviour; however, the role of α7 nicotinic ACh receptor (α7nAChR) in attention is contentious. In order to probe attention, we trained both wild-type and α7nAChR knockout mice on a touch screen-based five-choice serial reaction time task (5-CSRT). Following training procedures, we then tested sustained attention using a probe trial experiment. To further differentiate the role of specific nicotinic receptors in attention, we then tested the effects of both α7nAChR and β2nAChR agonists on the performance of both wild-type and knockout mice on the 5-CSRT task. At low doses, α7nAChR agonists improved attentional performance of wild-type mice, while high doses had deleterious effects on attention. α7nAChR knockout mice displayed deficits in sustained attention that were not ameliorated by α7nAChR agonists. However, these deficits were completely reversed by the administration of a β2nAChR agonist. Furthermore, administration of a β2nAChR agonist in α7nAChR knockout mice elicited similar biochemical response in the prefrontal cortex as the administration of α7nAChR agonists in wild-type mice. Our experiments reveal an intricate relationship between distinct nicotinic receptors to regulate attentional performance and provide the basis for targeting β2nAChRs pharmacologically to decrease attentional deficits due to a dysfunction in α7nAChRs. © 2015 The British Pharmacological Society.

  4. Gamma interferon (IFN-γ) receptor restricts systemic dengue virus replication and prevents paralysis in IFN-α/β receptor-deficient mice.

    Science.gov (United States)

    Prestwood, Tyler R; Morar, Malika M; Zellweger, Raphaël M; Miller, Robyn; May, Monica M; Yauch, Lauren E; Lada, Steven M; Shresta, Sujan

    2012-12-01

    We previously reported that mice lacking alpha/beta and gamma interferon receptors (IFN-α/βR and -γR) uniformly exhibit paralysis following infection with the dengue virus (DENV) clinical isolate PL046, while only a subset of mice lacking the IFN-γR alone and virtually no mice lacking the IFN-α/βR alone develop paralysis. Here, using a mouse-passaged variant of PL046, strain S221, we show that in the absence of the IFN-α/βR, signaling through the IFN-γR confers approximately 140-fold greater resistance against systemic vascular leakage-associated dengue disease and virtually complete protection from dengue-induced paralysis. Viral replication in the spleen was assessed by immunohistochemistry and flow cytometry, which revealed a reduction in the number of infected cells due to IFN-γR signaling by 2 days after infection, coincident with elevated levels of IFN-γ in the spleen and serum. By 4 days after infection, IFN-γR signaling was found to restrict DENV replication systemically. Clearance of DENV, on the other hand, occurred in the absence of IFN-γR, except in the central nervous system (CNS) (brain and spinal cord), where clearance relied on IFN-γ from CD8(+) T cells. These results demonstrate the roles of IFN-γR signaling in protection from initial systemic and subsequent CNS disease following DENV infection and demonstrate the importance of CD8(+) T cells in preventing DENV-induced CNS disease.

  5. CRF1 receptor-deficiency increases cocaine reward.

    Science.gov (United States)

    Contarino, Angelo; Kitchener, Pierre; Vallée, Monique; Papaleo, Francesco; Piazza, Pier-Vincenzo

    2017-05-01

    Stimulant drugs produce reward but also activate stress-responsive systems. The corticotropin-releasing factor (CRF) and the related hypothalamus-pituitary-adrenal (HPA) axis stress-responsive systems are activated by stimulant drugs. However, their role in stimulant drug-induced reward remains poorly understood. Herein, we report that CRF 1 receptor-deficient (CRF 1 -/-), but not wild-type, mice show conditioned place preference (CPP) responses to a relatively low cocaine dose (5 mg/kg, i.p.). Conversely, wild-type, but not CRF 1 -/-, mice display CPP responses to a relatively high cocaine dose (20 mg/kg, i.p.), indicating that CRF 1 receptor-deficiency alters the rewarding effects of cocaine. Acute pharmacological antagonism of the CRF 1 receptor by antalarmin also eliminates cocaine reward. Nevertheless, CRF 1 -/- mice display higher stereotypy responses to cocaine than wild-type mice. Despite the very low plasma corticosterone concentration, CRF 1 -/- mice show higher nuclear glucocorticoid receptor (GR) levels in the brain region of the hippocampus than wild-type mice. Full rescue of wild-type-like corticosterone and GR circadian rhythm and level in CRF 1 -/- mice by exogenous corticosterone does not affect CRF 1 receptor-dependent cocaine reward but induces stereotypy responses to cocaine. These results indicate a critical role for the CRF 1 receptor in cocaine reward, independently of the closely related HPA axis activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Three months of high-fructose feeding fails to induce excessive weight gain or leptin resistance in mice.

    Directory of Open Access Journals (Sweden)

    Erik J Tillman

    Full Text Available High-fructose diets have been implicated in obesity via impairment of leptin signaling in humans and rodents. We investigated whether fructose-induced leptin resistance in mice could be used to study the metabolic consequences of fructose consumption in humans, particularly in children and adolescents. Male C57Bl/6 mice were weaned to a randomly assigned diet: high fructose, high sucrose, high fat, or control (sugar-free, low-fat. Mice were maintained on their diets for at least 14 weeks. While fructose-fed mice regularly consumed more kcal and expended more energy, there was no difference in body weight compared to control by the end of the study. Additionally, after 14 weeks, both fructose-fed and control mice displayed similar leptin sensitivity. Fructose-feeding also did not change circulating glucose, triglycerides, or free fatty acids. Though fructose has been linked to obesity in several animal models, our data fail to support a role for fructose intake through food lasting 3 months in altering of body weight and leptin signaling in mice. The lack of impact of fructose in the food of growing mice on either body weight or leptin sensitivity over this time frame was surprising, and important information for researchers interested in fructose and body weight regulation.

  7. Melatonin Efficacy in Obese Leptin-Deficient Mice Heart

    Directory of Open Access Journals (Sweden)

    Alessandra Stacchiotti

    2017-12-01

    Full Text Available Cardiomyocytes are particularly sensitive to oxidative damage due to the link between mitochondria and sarcoplasmic reticulum necessary for calcium flux and contraction. Melatonin, important indoleamine secreted by the pineal gland during darkness, also has important cardioprotective properties. We designed the present study to define morphological and ultrastructural changes in cardiomyocytes and mainly in mitochondria of an animal model of obesity (ob/ob mice, when treated orally or not with melatonin at 100 mg/kg/day for 8 weeks (from 5 up to 13 week of life. We observed that ob/ob mice mitochondria in sub-sarcolemmal and inter-myofibrillar compartments are often devoid of cristae with an abnormally large size, which are called mega-mitochondria. Moreover, in ob/ob mice the hypertrophic cardiomyocytes expressed high level of 4hydroxy-2-nonenal (4HNE, a marker of lipid peroxidation but scarce degree of mitofusin2, indicative of mitochondrial sufferance. Melatonin oral supplementation in ob/ob mice restores mitochondrial cristae, enhances mitofusin2 expression and minimizes 4HNE and p62/SQSTM1, an index of aberrant autophagic flux. At pericardial fat level, adipose tissue depot strictly associated with myocardium infarction, melatonin reduces adipocyte hypertrophy and inversely regulates 4HNE and adiponectin expressions. In summary, melatonin might represent a safe dietary adjuvant to hamper cardiac mitochondria remodeling and the hypoxic status that occur in pre-diabetic obese mice at 13 weeks of life.

  8. Absence of functional leptin receptor isoforms in the POUND (Lepr(db/lb)) mouse is associated with muscle atrophy and altered myoblast proliferation and differentiation.

    Science.gov (United States)

    Arounleut, Phonepasong; Bowser, Matthew; Upadhyay, Sunil; Shi, Xing-Ming; Fulzele, Sadanand; Johnson, Maribeth H; Stranahan, Alexis M; Hill, William D; Isales, Carlos M; Hamrick, Mark W

    2013-01-01

    Leptin receptors are abundant in human skeletal muscle, but the role of leptin in muscle growth, development and aging is not well understood. Here we utilized a novel mouse model lacking all functional leptin receptor isoforms (POUND mouse, Lepr(db/lb)) to determine the role of leptin in skeletal muscle. Skeletal muscle mass and fiber diameters were examined in POUND mice, and primary myoblast cultures were used to determine the effects of altered leptin signaling on myoblast proliferation and differentiation. ELISA assays, integrated pathway analysis of mRNA microarrays, and reverse phase protein analysis were performed to identify signaling pathways impacted by leptin receptor deficiency. Results show that skeletal muscle mass and fiber diameter are reduced 30-40% in POUND mice relative to wild-type controls. Primary myoblast cultures demonstrate decreased proliferation and decreased expression of both MyoD and myogenin in POUND mice compared to normal mice. Leptin treatment increased proliferation in primary myoblasts from muscles of both adult (12 months) and aged (24 months) wild-type mice, and leptin increased expression of MyoD and myogenin in aged primary myoblasts. ELISA assays and protein arrays revealed altered expression of molecules associated with the IGF-1/Akt and MAPK/MEK signaling pathways in muscle from the hindlimbs of mice lacking functional leptin receptors. These data support the hypothesis that the adipokine leptin is a key factor important for the regulation of skeletal muscle mass, and that leptin can act directly on its receptors in peripheral tissues to regulate cell proliferation and differentiation.

  9. Effects of obesity and exercise on testicular leptin signal transduction and testosterone biosynthesis in male mice.

    Science.gov (United States)

    Yi, Xuejie; Gao, Haining; Chen, Dequan; Tang, Donghui; Huang, Wanting; Li, Tao; Ma, Tie; Chang, Bo

    2017-04-01

    To explore the role of the testicular leptin and JAK-STAT[leptin (LEP)-JAK-STAT] pathway in testosterone biosynthesis during juvenile stages and exercise for weight loss, male C57BL/6J mice were randomly divided into normal-diet and high-fat diet groups. After 10 wk, mice in the high-fat diet-fed group were further divided randomly into obese control, obese moderate-volume exercise, and obese high-volume exercise groups. Mice in the obese moderate-volume exercise group were provided with 2 h/day, 6 days/wk swimming exercise for 8 wk, and mice in the obese high-volume exercise group underwent twice the amount of daily exercise intervention as the obese moderate-volume exercise group. The results showed that a high-fat diet causes obesity, leptin resistance, inhibition of the testicular LEP-JAK-STAT pathway, decreased mRNA and protein expression of steroidogenic factor-1, steroidogenic acute regulatory protein, and the P -450 side-chain cleavage enzyme, a decrease in the serum testosterone-to-estradiol ratio, and declines in sperm quality parameters. Both moderate and high-volume exercise were able to reduce body fat and increase the mRNA and protein expression of LEP-JAK-STAT, but only moderate exercise significantly increased the mRNA and protein expression of steroidogenic factor-1, steroidogenic acute regulatory protein, and P -450 side-chain cleavage enzyme and significantly reversed the serum testosterone-to-estradiol ratio and sperm quality parameters. These findings suggest that by impairing the testicular LEP-JAK-STAT pathway, early-stage obesity inhibits the biosynthesis of testosterone and sexual development and reduces male reproductive potential. Long-term moderate and high-volume exercise can effectively reduce body fat and improve obesity-induced abnormalities in testicular leptin signal transduction, whereas only moderate-volume exercise can reverse the negative impacts of obesity on male reproductive function. Copyright © 2017 the American

  10. ROLE OF LEPTIN ON CYTOCHROME P-450 AND SOME LIVER MICROSOMAL ENZYMES ACTIVITIES IN THE OBESE AND LEAN MICE

    International Nuclear Information System (INIS)

    HEBEISHY, M.I.A.; MAZEN, G.M.A.; SHAHIN, M.I

    2008-01-01

    Leptin is a hormone that is secreted by adipocytes and regulates body weight through its effect on satiety and energy metabolism. The obese mouse is deficient in this protein and is characterized by obesity and other metabolic disorders. This study investigated the alterations of several hepatic cytochrome P 4 -5 0 (CYP), conjugation and antioxidant enzymes in lean and obese mice and the role of leptin in the modulation of these enzymes. Lean and obese male mice were injected with leptin (100 μg / rat) for 15 days. The obtained results revealed that administration of leptin to lean mice caused a significant elevation in the level of blood glucose, serum insulin, 6α, 6β, 16α- hydroxylation of testosterone, the activity of CYP 1 A 1 , CYP 4 A and GSH reductase in liver microsomes while serum corticosterone and the activity of total GSH were significantly decreased when compared to lean control mice. Moreover, obese mice treated with leptin recorded significant reduction in body weight, blood glucose concentration, serum levels of insulin and corticosterone, 7α and 16α- hydroxylation of testosterone, the activity of CYP 1A 1, CYP 2 B 1 and CYP 4 A and GST in liver microsomes. On the other hand, 6α, 6β-hydroxylation of testosterone, the activity of CYP 2 E 1 and GSH reductase in liver microsome were significantly increased when compared to obese control mice. The mechanism for the observed alterations may be due to direct leptin effects or via indirect alterations in insulin, corticosterone and/or growth hormone

  11. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

    International Nuclear Information System (INIS)

    Hamrick, Mark W.; Herberg, Samuel; Arounleut, Phonepasong; He, Hong-Zhi; Shiver, Austin; Qi, Rui-Qun; Zhou, Li; Isales, Carlos M.

    2010-01-01

    Research highlights: → Aging is associated with muscle atrophy and loss of muscle mass, known as the sarcopenia of aging. → We demonstrate that age-related muscle atrophy is associated with marked changes in miRNA expression in muscle. → Treating aged mice with the adipokine leptin significantly increased muscle mass and the expression of miRNAs involved in muscle repair. → Recombinant leptin therapy may therefore be a novel approach for treating age-related muscle atrophy. -- Abstract: Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient-related hormones such as leptin

  12. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

    Energy Technology Data Exchange (ETDEWEB)

    Hamrick, Mark W., E-mail: mhamrick@mail.mcg.edu [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Herberg, Samuel; Arounleut, Phonepasong [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); He, Hong-Zhi [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Shiver, Austin [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Qi, Rui-Qun [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Zhou, Li [Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI (United States); Department of Dermatology, Henry Ford Health System, Detroit, MI (United States); Department of Internal Medicine, Henry Ford Health System, Detroit, MI (United States); Isales, Carlos M. [Department of Cellular Biology and Anatomy, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); Department of Orthopaedic Surgery, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA (United States); and others

    2010-09-24

    Research highlights: {yields} Aging is associated with muscle atrophy and loss of muscle mass, known as the sarcopenia of aging. {yields} We demonstrate that age-related muscle atrophy is associated with marked changes in miRNA expression in muscle. {yields} Treating aged mice with the adipokine leptin significantly increased muscle mass and the expression of miRNAs involved in muscle repair. {yields} Recombinant leptin therapy may therefore be a novel approach for treating age-related muscle atrophy. -- Abstract: Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient

  13. Body weight homeostat that regulates fat mass independently of leptin in rats and mice

    Science.gov (United States)

    Jansson, John-Olov; Hägg, Daniel A.; Schéle, Erik; Dickson, Suzanne L.; Anesten, Fredrik; Bake, Tina; Montelius, Mikael; Bellman, Jakob; Johansson, Maria E.; Cone, Roger D.; Drucker, Daniel J.; Wu, Jianyao; Aleksic, Biljana; Törnqvist, Anna E.; Sjögren, Klara; Gustafsson, Jan-Åke; Windahl, Sara H.; Ohlsson, Claes

    2018-01-01

    Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat (“gravitostat”) that regulates fat mass. PMID:29279372

  14. High-fat diet-induced changes in body mass and hypothalamic gene expression in wild-type and leptin-deficient mice.

    Science.gov (United States)

    Townsend, Kristy L; Lorenzi, Magen M; Widmaier, Eric P

    2008-04-01

    We tested whether diet-induced obesity results from increased energy consumption, is associated with changes in expression of genes involved in leptin signal transduction, and is altered by hyperleptinemia. C57BL/6 mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for up to 15 weeks. HFD mice weighed significantly more than LFD controls by 3 weeks, despite consuming less energy. HFD mice had significantly greater leptin, insulin, and glucose levels than LFD mice, suggesting leptin and insulin resistance. Adiponectin levels declined with age but were unaffected by diet. HFD was associated with altered hypothalamic expression of genes whose products regulate the activity or nuclear translocation of STAT3, an important mediator of leptin actions. Expression of two isoforms of the leptin receptor decreased at 15 weeks in hypothalami of HFD mice in a tissue-specific manner. The type of fat (saturated versus unsaturated) did not influence weight gain on an HFD, but animals on LFD gained significantly more weight and adiposity if the dietary fat consisted mostly of saturated fats; this occurred despite no difference in energy consumption or absorption. Replacement of leptin to leptin-deficient ob/ob mice decreased hypothalamic leptin receptor expression and did not prevent HFD-induced weight gain. It is concluded that (1) increased energy consumption is not required for HFD-induced obesity in C57BL/6 mice, (2) HFD results in weight gain partly by modulating hypothalamic leptin-signaling pathways, (3) saturated fats induce weight gain even when total fat content of the diet is low, and (4) the effects of HFD are manifest in the presence or absence of circulating leptin.

  15. Phosphodiesterase-3B-cAMP pathway of leptin signalling in the hypothalamus is impaired during the development of diet-induced obesity in FVB/N mice.

    Science.gov (United States)

    Sahu, M; Anamthathmakula, P; Sahu, A

    2015-04-01

    The phosphodiesterase-3B (PDE3B)-cAMP pathway plays an important role in transducing the action of leptin in the hypothalamus. Obesity is usually associated with hyperleptinaemia and resistance to anorectic and body weight-reducing effects of leptin. To determine whether the hypothalamic PDE3B-cAMP pathway of leptin signalling is impaired during the development of diet-induced obesity (DIO), we fed male FVB/N mice a high-fat diet (HFD: 58% kcal as fat) or low-fat diet (LFD: 6% kcal as fat) for 4 weeks. HFD fed mice developed DIO in association with hyperphagia, hyperleptinaemia and hyperinsulinaemia. Leptin (i.p.) significantly increased hypothalamic PDE3B activity and phosphorylated (p)-Akt levels in LFD-fed but not in HFD-fed mice. However, basal p-Akt levels in hypothalamus were increased in DIO mice. Additionally, amongst six-microdissected brain nuclei examined, leptin selectively decreased cAMP levels in the arcuate nucleus (ARC) of LFD-fed mice but failed to do so in HFD-fed mice. We next tested whether both the PBE3B and Akt pathways of leptin signalling remained impaired in DIO mice on the HFD for 12 weeks (long-term). DIO mice were hyperinsulinaemic and hyperleptinaemic in association with impaired glucose and insulin tolerance. Although, in LFD-fed mice, leptin significantly increased PDE3B activity and p-Akt levels in the hypothalamus, it failed to do so in HFD-fed mice. Also, basal p-Akt levels in the hypothalamus were increased in DIO mice and leptin had no further effect. Similarly, immunocytochemistry showed that leptin increased the number of p-Akt-positive cells in the ARC of LFD-fed but not in HFD-fed mice, and there was an increased basal number of p-Akt positive cells in the ARC of DIO mice. These results suggest that the PDE3B-cAMP- and Akt-pathways of leptin signalling in the hypothalamus are impaired during the development of DIO. Thus, a defect in the regulation by leptin of the hypothalamic PDE3B-cAMP pathway and Akt signalling may be one

  16. Increased a-series gangliosides positively regulate leptin/Ob receptor-mediated signals in hypothalamus of GD3 synthase-deficient mice.

    Science.gov (United States)

    Ji, Shuting; Tokizane, Kyohei; Ohkawa, Yuki; Ohmi, Yuhsuke; Banno, Ryoichi; Okajima, Tetsuya; Kiyama, Hiroshi; Furukawa, Koichi; Furukawa, Keiko

    2016-10-21

    Gangliosides are widely involved in the regulation of cells and organs. However, little is known about their roles in adipose tissues and hypothalamus. In GD3 synthase-knockout (GD3S KO) mice, deletion of b-series gangliosides resulted in the reduction of serum leptin due to disturbed secretion from adipocytes. To examine whether leptin signals altered, leptin/leptin receptor (ObR)-mediated signaling in hypothalamus was analyzed. Hypothalamus of GD3S KO mouse showed increased expression of GM1 and GD1a, and increased activation of ObR-mediated signals such as pSTAT3 and c-Fos. Leptin stimulation of hypothalamus-derived N-41 cells and their transfectants with GD3S cDNA showed that a-series gangliosides positively regulate leptin/ObR-mediated signals. Co-precipitation analysis revealed that ObR interacts with a-series gangliosides with increased association by leptin stimulation. In brown adipose tissues (BAT) of GD3S KO mice, their weights and adipocyte numbers were increased, and BAT markers such as PGC1α and UCP-1 were also up-regulated. These results suggested that leptin/ObRb-mediated signals were enhanced in hypothalamus of GD3S KO mice due to increased a-series gangliosides, leading to the apparently similar features of energy expenditure between the KO and wild type mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Leptin deficient ob/ob mice and diet-induced obese mice responded differently to Roux-en-Y bypass surgery.

    Science.gov (United States)

    Hao, Z; Münzberg, H; Rezai-Zadeh, K; Keenan, M; Coulon, D; Lu, H; Berthoud, H-R; Ye, J

    2015-05-01

    Weight regain contributes to the therapeutic failure in 15-20% of type 2 diabetic patients after Roux-en-Y gastric bypass surgery (RYGB), and the mechanism remains largely unknown. This study was conducted to explore the mechanism of weight regain. Wild-type (WT) diet-induced obese (DIO) mice were used to mimic human obesity, and ob/ob mice were used for leptin deficiency-induced obesity. Two groups of mice were compared in weight regain for 10 months after RYGB. Weight loss, food intake, fecal energy loss and energy expenditure were monitored in the study of weight regain. Fasting insulin, insulin tolerance and homeostatic model assessment-insulin resistance were tested for insulin sensitivity under the weight regain. Weight loss from RYGB and calorie restriction was compared for the impact in insulin sensitivity. In WT mice, RYGB induced a sustained weight loss and insulin sensitization over the sham operation in this 10-month study. However, RYGB failed to generate the same effects in leptin-deficient ob/ob mice, which suffered a weight regain over the pre-surgery level. In ob/ob mice, body weight was reduced by RYGB transiently in the first week, recovered in the second week and increased over the baseline thereafter. Weight loss was induced by RYGB relative to that of sham mice, but the loss was not sufficient to keep body weight below the pre-surgery levels. In addition, insulin sensitivity was not improved by the weight loss. The response to RYGB was improved in ob/ob mice by 2 weeks of leptin treatment. Weight loss from calorie restriction had an equivalent effect on insulin sensitization compared with that of RYGB. Those data demonstrate that ob/ob mice and DIO mice responded differently to RYGB surgery, suggesting that leptin may be one of the factors required for RYGB to prevent weight regain and diabetes recurrence.

  18. Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice.

    Science.gov (United States)

    Altintas, Mehmet M; Nayer, Behzad; Walford, Eric C; Johnson, Kevin B; Gaidosh, Gabriel; Reiser, Jochen; De La Cruz-Munoz, Nestor; Ortega, Luis M; Nayer, Ali

    2012-02-07

    Mast cells are implicated in the pathogenesis of obesity and insulin resistance. Here, we explored the effects of leptin deficiency-induced obesity on the density of mast cells in metabolic (abdominal fat depots, skeletal muscle, and liver) and lymphatic (abdominal lymph nodes, spleen, and thymus) organs. Fourteen-week-old male leptin-deficient ob/ob mice and their controls fed a standard chow were studied. Tissue sections were stained with toluidine blue to determine the density of mast cells. CD117/c-kit protein expression analysis was also carried out. Furthermore, mast cells containing immunoreactive tumor necrosis factor-α (TNF-α), a proinflammatory cytokine involved in obesity-linked insulin resistance, were identified by immunostaining. ob/ob mice demonstrated adiposity and insulin resistance. In abdominal fat depots, mast cells were distributed differentially. While most prevalent in subcutaneous fat in controls, mast cells were most abundant in epididymal fat in ob/ob mice. Leptin deficiency-induced obesity was accompanied by a 20-fold increase in the density of mast cells in epididymal fat, but a 13-fold decrease in subcutaneous fat. This finding was confirmed by CD117/c-kit protein expression analysis. Furthermore, we found that a subset of mast cells in epididymal and subcutaneous fat were immunoreactive for TNF-α. The proportion of mast cells immunoreactive for TNF-α was higher in epididymal than in subcutaneous fat in both ob/ob and control mice. Mast cells were also distributed differentially in retroperitoneal, mesenteric, and inguinal lymph nodes. In both ob/ob mice and lean controls, mast cells were more prevalent in retroperitoneal than in mesenteric and inguinal lymph nodes. Leptin deficiency-induced obesity was accompanied by increased mast cell density in all lymph node stations examined. No significant difference in the density of mast cells in skeletal muscle, liver, spleen, and thymus was noted between ob/ob and control mice. This study

  19. Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice

    Directory of Open Access Journals (Sweden)

    Altintas Mehmet M

    2012-02-01

    Full Text Available Abstract Background Mast cells are implicated in the pathogenesis of obesity and insulin resistance. Here, we explored the effects of leptin deficiency-induced obesity on the density of mast cells in metabolic (abdominal fat depots, skeletal muscle, and liver and lymphatic (abdominal lymph nodes, spleen, and thymus organs. Fourteen-week-old male leptin-deficient ob/ob mice and their controls fed a standard chow were studied. Tissue sections were stained with toluidine blue to determine the density of mast cells. CD117/c-kit protein expression analysis was also carried out. Furthermore, mast cells containing immunoreactive tumor necrosis factor-α (TNF-α, a proinflammatory cytokine involved in obesity-linked insulin resistance, were identified by immunostaining. Results ob/ob mice demonstrated adiposity and insulin resistance. In abdominal fat depots, mast cells were distributed differentially. While most prevalent in subcutaneous fat in controls, mast cells were most abundant in epididymal fat in ob/ob mice. Leptin deficiency-induced obesity was accompanied by a 20-fold increase in the density of mast cells in epididymal fat, but a 13-fold decrease in subcutaneous fat. This finding was confirmed by CD117/c-kit protein expression analysis. Furthermore, we found that a subset of mast cells in epididymal and subcutaneous fat were immunoreactive for TNF-α. The proportion of mast cells immunoreactive for TNF-α was higher in epididymal than in subcutaneous fat in both ob/ob and control mice. Mast cells were also distributed differentially in retroperitoneal, mesenteric, and inguinal lymph nodes. In both ob/ob mice and lean controls, mast cells were more prevalent in retroperitoneal than in mesenteric and inguinal lymph nodes. Leptin deficiency-induced obesity was accompanied by increased mast cell density in all lymph node stations examined. No significant difference in the density of mast cells in skeletal muscle, liver, spleen, and thymus was

  20. Leptin administration favors muscle mass accretion by decreasing FoxO3a and increasing PGC-1alpha in ob/ob mice.

    Directory of Open Access Journals (Sweden)

    Neira Sáinz

    2009-09-01

    Full Text Available Absence of leptin has been associated with reduced skeletal muscle mass in leptin-deficient ob/ob mice. The aim of our study was to examine the effect of leptin on the catabolic and anabolic pathways regulating muscle mass. Gastrocnemius, extensor digitorum longus and soleus muscle mass as well as fiber size were significantly lower in ob/ob mice compared to wild type littermates, being significantly increased by leptin administration (P<0.001. This effect was associated with an inactivation of the muscle atrophy-related transcription factor forkhead box class O3 (FoxO3a (P<0.05, and with a decrease in the protein expression levels of the E3 ubiquitin-ligases muscle atrophy F-box (MAFbx (P<0.05 and muscle RING finger 1 (MuRF1 (P<0.05. Moreover, leptin increased (P<0.01 protein expression levels of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha, a regulator of muscle fiber type, and decreased (P<0.05 myostatin protein, a negative regulator of muscle growth. Leptin administration also activated (P<0.01 the regulators of cell cycle progression proliferating cell nuclear antigen (PCNA and cyclin D1, and increased (P<0.01 myofibrillar protein troponin T. The present study provides evidence that leptin treatment may increase muscle mass of ob/ob mice by inhibiting myofibrillar protein degradation as well as enhancing muscle cell proliferation.

  1. The Beneficial Effects of Leptin on REM Sleep Deprivation-Induced Cognitive Deficits in Mice

    Science.gov (United States)

    Chang, Hsiao-Fu; Su, Chun-Lin; Chang, Chih-Hua; Chen, Yu-Wen; Gean, Po-Wu

    2013-01-01

    Leptin, a 167 amino acid peptide, is synthesized predominantly in the adipose tissues and plays a key role in the regulation of food intake and body weight. Recent studies indicate that leptin receptor is expressed with high levels in many brain regions that may regulate synaptic plasticity. Here we show that deprivation of rapid eye movement…

  2. The over-expression of miR-200a in the hypothalamus of ob/ob mice is linked to leptin and insulin signaling impairment.

    Science.gov (United States)

    Crépin, Delphine; Benomar, Yacir; Riffault, Laure; Amine, Hamza; Gertler, Arieh; Taouis, Mohammed

    2014-03-25

    Early in life, leptin plays a crucial role in hypothalamic neural organization. Leptin, most likely, controls neural gene expression conferring then specific phenotype regarding energy homeostasis. MicroRNAs are new regulators for several physiological functions, including the regulation of metabolism. However, the impact of leptin on hypothalamic microRNA patterns remains unknown. Here, we demonstrate that miR-200a, miR-200b and miR-429 are up-regulated in the hypothalamus of genetically obese and leptin deficient ob/ob mice. Leptin treatment down-regulates these miRNAs in ob/ob hypothalamus. The hypothalamic silencing of miR-200a increased the expression level of leptin receptor and insulin receptor substrate 2, reduced body weight gain, and restored liver insulin responsiveness. In addition, the overexpression of pre-miR-200a in a human neuroblastoma cell line impaired insulin and leptin signaling. These findings link the alteration of leptin and insulin signaling to the up-regulation of hypothalamic miR-200a which could be a new target for treatment of obesity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  3. Selective Deletion of Leptin Signaling in Endothelial Cells Enhances Neointima Formation and Phenocopies the Vascular Effects of Diet-Induced Obesity in Mice.

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    Hubert, Astrid; Bochenek, Magdalena L; Schütz, Eva; Gogiraju, Rajinikanth; Münzel, Thomas; Schäfer, Katrin

    2017-09-01

    Obesity is associated with elevated circulating leptin levels and hypothalamic leptin resistance. Leptin receptors (LepRs) are expressed on endothelial cells, and leptin promotes neointima formation in a receptor-dependent manner. Our aim was to examine the importance of endothelial LepR (End.LepR) signaling during vascular remodeling and to determine whether the cardiovascular consequences of obesity are because of hyperleptinemia or endothelial leptin resistance. Mice with loxP-flanked LepR alleles were mated with mice expressing Cre recombinase controlled by the inducible endothelial receptor tyrosine kinase promoter. Obesity was induced with high-fat diet. Neointima formation was examined after chemical carotid artery injury. Morphometric quantification revealed significantly greater intimal hyperplasia, neointimal cellularity, and proliferation in End.LepR knockout mice, and similar findings were obtained in obese, hyperleptinemic End.LepR wild-type animals. Analysis of primary endothelial cells confirmed abrogated signal transducer and activator of transcription-3 phosphorylation in response to leptin in LepR knockout and obese LepR wild-type mice. Quantitative PCR, ELISA, and immunofluorescence analyses revealed increased expression and release of endothelin-1 in End.LepR-deficient and LepR-resistant cells, and ET receptor A/B antagonists abrogated their paracrine effects on murine aortic smooth muscle cell proliferation. Reduced expression of peroxisome proliferator-activated receptor-γ and increased nuclear activator protein-1 staining was observed in End.LepR-deficient and LepR-resistant cells, and peroxisome proliferator-activated receptor-γ antagonization increased endothelial endothelin-1 expression. Our findings suggest that intact endothelial leptin signaling limits neointima formation and that obesity represents a state of endothelial leptin resistance. These observations and the identification of endothelin-1 as soluble mediator of the

  4. Single gene deletions of orexin, leptin, neuropeptide Y, and ghrelin do not appreciably alter food anticipatory activity in mice.

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    Keith M Gunapala

    Full Text Available Timing activity to match resource availability is a widely conserved ability in nature. Scheduled feeding of a limited amount of food induces increased activity prior to feeding time in animals as diverse as fish and rodents. Typically, food anticipatory activity (FAA involves temporally restricting unlimited food access (RF to several hours in the middle of the light cycle, which is a time of day when rodents are not normally active. We compared this model to calorie restriction (CR, giving the mice 60% of their normal daily calorie intake at the same time each day. Measurement of body temperature and home cage behaviors suggests that the RF and CR models are very similar but CR has the advantage of a clearly defined food intake and more stable mean body temperature. Using the CR model, we then attempted to verify the published result that orexin deletion diminishes food anticipatory activity (FAA but observed little to no diminution in the response to CR and, surprisingly, that orexin KO mice are refractory to body weight loss on a CR diet. Next we tested the orexigenic neuropeptide Y (NPY and ghrelin and the anorexigenic hormone, leptin, using mouse mutants. NPY deletion did not alter the behavior or physiological response to CR. Leptin deletion impaired FAA in terms of some activity measures, such as walking and rearing, but did not substantially diminish hanging behavior preceding feeding time, suggesting that leptin knockout mice do anticipate daily meal time but do not manifest the full spectrum of activities that typify FAA. Ghrelin knockout mice do not have impaired FAA on a CR diet. Collectively, these results suggest that the individual hormones and neuropepetides tested do not regulate FAA by acting individually but this does not rule out the possibility of their concerted action in mediating FAA.

  5. Osteoarthitis of leptin-deficient ob/ob mice in response to biomechanical loading in micro-CT.

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    Heep, Hansjoerg; Hilken, Gero; Hofmeister, Sebastian; Wedemeyer, Christian

    2009-01-01

    Mechanotransduction is the mechanism that due to reacting chondrocytes on biomechanical loading of body mass. Higher biomechanical loading lead to increased degeneration of chondrocytes, whereas moderate loading is protecting. This suggests that body fat regulates bone metabolism first by means of hormonal factors and second that the effects of muscle and loading are signaling factors in mechanotransduction. Leptin, a peptide hormone produced predominantly by white fat cells, is one of these hormonal factors. The aim of this study was to investigate and measure the different effects of weight-bearing on trabecular bone formation in mice without the stimulation of leptin and with or without osteoarthritis. 40 C57BL/ 6J ob/ob-mice in the age of 20 weeks have been devided into two groups with an ad-libitum-diet and with reduced diet. The hip- and knee-joints have been examinated in micro-CT-scan and histomorphologically. Animals with an ad-libitum-diet were found to increase body weight significantly at the age of six weeks in comparison with lean mice. At the age of twenty weeks the obese mice were almost twice as heavy as the lean mice. Significant statistical differences are shown between the two groups for body weight and bone mineral density. Examination of trabecular bone in micro-CT revealed that the only statistically significant difference between the two groups was the trabecular number for the proximal femur. High weight-bearing insignificantly improved all trabecular bone parameters in the obese mice. Correlation was found between trabecular number and bone mineral density on the one hand and body weight on the other hand. The correlation between body weight and osteoarthritis shows a significant increase in grade of osteoarthritis as body weight increases in hip-joint and knee-joint but not in osteoarthritis-positive (OP) versus osteoarthritis-negative (ON) mices. The correlation of the hip-joint between micro-CT data and body weight shows an increase in

  6. Taurine supplementation preserves hypothalamic leptin action in normal and protein-restricted mice fed on a high-fat diet.

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    Camargo, Rafael L; Batista, Thiago M; Ribeiro, Rosane A; Branco, Renato C S; Da Silva, Priscilla M R; Izumi, Clarice; Araujo, Thiago R; Greene, Lewis J; Boschero, Antonio C; Carneiro, Everardo M

    2015-11-01

    Malnutrition programs the neuroendocrine axis by disruption of food-intake control, leading to obesity. Taurine (Tau) is neuroprotective and improves anorexigenic actions in the hypothalamus. We evaluated the hypothalamic gene-expression profile and food-intake control in protein-restricted mice submitted to a high-fat diet (HFD) and Tau supplementation. Mice were fed on a control (14 % protein-C) or a protein-restricted diet (6 % protein-R) for 6 weeks. Thereafter, mice received, or not, HFD for 8 weeks (CH and RH) with or without 5 % Tau supplementation (CHT and RHT). Protein restriction led to higher food intake, but calories were matched to controls. Excessive calorie intake occurred in HFD mice and this was prevented by Tau supplementation only in the CH group. Additionally, RH and CH mice developed hypothalamic leptin resistance, which was prevented by Tau. Global alterations in the expressions of genes involved in hypothalamic metabolism, cellular defense, apoptosis and endoplasmic reticulum stress pathways were induced by dietary manipulations and Tau treatment. The orexigenic peptides NPY and AgRP were increased by protein restriction and lowered by the HFD. The anorexigenic peptide Pomc was increased by HFD, and this was prevented by Tau only in CH mice. Thus, food intake was disrupted by dietary protein restriction and obesity. HFD-induced alterations were not enhanced by previous protein deficiency, but the some beneficial effects of Tau supplementation upon food intake were blunted by protein restriction. Tau effects upon feeding behavior control are complex and involve interactions with a vast gene network, preventing hypothalamic leptin resistance.

  7. Differences in trabecular bone of leptin-deficient ob/ob mice in response to biomechanical loading.

    Science.gov (United States)

    Heep, Hansjoerg; Wedemeyer, Christian; Wegner, Alexander; Hofmeister, Sebastian; von Knoch, Marius

    2008-06-15

    It is known that bone mineral density (BMD) and the strength of bone is predicted by body mass. Fat mass is a significant predictor of bone mineral density which correlates with body weight. This suggests that body fat regulates bone metabolism first by means of hormonal factors and second that the effects of muscle and loading are signaling factors in mechanotransduction. Leptin, a peptide hormone produced predominantly by white fat cells, is one of these hormonal factors. The aim of this study was to investigate and measure by micro-CT the different effects of weight-bearing on trabecular bone formation in mice without the stimulation of leptin. Animals with an ad-libitum-diet (Group A) were found to increase body weight significantly at the age of six weeks in comparison with lean mice (Group B). From this point on, the difference increased constantly. At the age of twenty weeks the obese mice were almost twice as heavy as the lean mice. Significant statistical differences are shown between the two groups for body weight and bone mineral density. Examination of trabecular bone (BV/TV, trabecular number (Tb.N.), trabecular thickness (Tb.Th.)) revealed that the only statistically significant difference between the two groups was the Tb.N. for the proximal femur. High weight-bearing insignificantly improved all trabecular bone parameters in the obese mice. Compared with the control-diet Group B, the BV/TV and Tb.N. were slightly higher in the controlled-diet Group A, but not the Tb.Th.. However, correlation was found between Tb.N. and BMD on the one hand and body weight on the other hand. biomechanical loading led to decreased bone mineral density by a decrease in the number of trabeculae. Trabecular thickness was not increased by biomechanical loading in growing mice. Decreased body weight in leptin-deficient mice protects against bone loss. This finding is consistent with the principle of light-weight construction of bone. Differences in cortical and trabecular

  8. Integration of stress and leptin signaling by CART producing neurons in the rodent midbrain centrally projecting Edinger-Westphal nucleus

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    Lu eXu

    2014-03-01

    Full Text Available Leptin targets the brain to regulate feeding, neuroendocrine function and metabolism. The leptin receptor is present in hypothalamic centers controlling energy metabolism as well as in the centrally projecting Edinger-Westphal nucleus (EWcp, a region implicated in the stress response and in various aspects of stress-related behaviors. We hypothesized that the stress response by cocaine- and amphetamine-regulated transcript (CART-producing EWcp-neurons would depend on the animal’s energy state. To test this hypothesis, we investigated the effects of changes in energy state (mimicked by low, normal and high leptin levels, which were achieved by 24h fasting, normal chow and leptin injection, respectively on the response of CART neurons in the EWcp of rats subjected or not to acute restraint stress. Our data show that leptin treatment alone significantly increases CART mRNA expression in the rat EWcp and that in leptin receptor deficient (db/db mice, the number of CART producing neurons in this nucleus is reduced. This suggests that leptin has a stimulatory effect on the production of CART in the EWcp under non-stressed condition. Under stressed condition, however, leptin blunts stress-induced activation of EWcp neurons and decreases their CART mRNA expression. Interestingly, fasting, does not influence the stress-induced activation of EWcp-neurons, and specifically EWcp-CART neurons are not activated. These results suggest that the stress response by the EWcp depends to some degree on the animal’s energy state, a mechanism that may contribute to a better understanding of the complex interplay between obesity and stress.

  9. Estradiol Supplementation Helps Overcome Central Leptin Resistance of Ovariectomized Mice on a High Fat Diet

    Czech Academy of Sciences Publication Activity Database

    Matyšková, Resha; Železná, Blanka; Maixnerová, Jana; Koutová, Darja; Haluzík, M.; Maletínská, Lenka

    2010-01-01

    Roč. 42, č. 3 (2010), s. 182-186 ISSN 0018-5043 R&D Projects: GA ČR GA305/06/0427; GA ČR GA303/09/0744 Institutional research plan: CEZ:AV0Z40550506 Keywords : leptin * estrogen deficiency * obesity Subject RIV: CE - Biochemistry Impact factor: 2.414, year: 2010

  10. The acute anorexic effect of liraglutide, a GLP-1 receptor agonist, does not require functional leptin receptor, serotonin, and hypothalamic POMC and CART activities in mice.

    Science.gov (United States)

    Nonogaki, Katsunori; Kaji, Takao

    2016-10-01

    The acute anorexic effect of liraglutide, a GLP-1 receptor agonist, did not require functional leptin receptor, serotonin, and hypothalamic proopiomelanocortin and cocaine amphetamine regulated transcript activities in mice, although decrease in functional hypothalamic orexin activity might be involved in the acute anorexic effect of liraglutide. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Long-term correction of obesity and diabetes in genetically obese mice by a single intramuscular injection of recombinant adeno-associated virus encoding mouse leptin.

    Science.gov (United States)

    Murphy, J E; Zhou, S; Giese, K; Williams, L T; Escobedo, J A; Dwarki, V J

    1997-12-09

    The ob/ob mouse is genetically deficient in leptin and exhibits a phenotype that includes obesity and non-insulin-dependent diabetes mellitus. This phenotype closely resembles the morbid obesity seen in humans. In this study, we demonstrate that a single intramuscular injection of a recombinant adeno-associated virus (AAV) vector encoding mouse leptin (rAAV-leptin) in ob/ob mice leads to prevention of obesity and diabetes. The treated animals show normalization of metabolic abnormalities including hyperglycemia, insulin resistance, impaired glucose tolerance, and lethargy. The effects of a single injection have lasted through the 6-month course of the study. At all time points measured the circulating levels of leptin in the serum were similar to age-matched control C57 mice. These results demonstrate that maintenance of normal levels of leptin (2-5 ng/ml) in the circulation can prevent both the onset of obesity and associated non-insulin-dependent diabetes. Thus a single injection of a rAAV vector expressing a therapeutic gene can lead to complete and long-term correction of a genetic disorder. Our study demonstrates the long-term correction of a disease caused by a genetic defect and proves the feasibility of using rAAV-based vectors for the treatment of chronic disorders like obesity.

  12. Long-term correction of obesity and diabetes in genetically obese mice by a single intramuscular injection of recombinant adeno-associated virus encoding mouse leptin

    Science.gov (United States)

    Murphy, John E.; Zhou, Shangzhen; Giese, Klaus; Williams, Lewis T.; Escobedo, Jaime A.; Dwarki, Varavani J.

    1997-01-01

    The ob/ob mouse is genetically deficient in leptin and exhibits a phenotype that includes obesity and non-insulin-dependent diabetes melitus. This phenotype closely resembles the morbid obesity seen in humans. In this study, we demonstrate that a single intramuscular injection of a recombinant adeno-associated virus (AAV) vector encoding mouse leptin (rAAV-leptin) in ob/ob mice leads to prevention of obesity and diabetes. The treated animals show normalization of metabolic abnormalities including hyperglycemia, insulin resistance, impaired glucose tolerance, and lethargy. The effects of a single injection have lasted through the 6-month course of the study. At all time points measured the circulating levels of leptin in the serum were similar to age-matched control C57 mice. These results demonstrate that maintenance of normal levels of leptin (2–5 ng/ml) in the circulation can prevent both the onset of obesity and associated non-insulin-dependent diabetes. Thus a single injection of a rAAV vector expressing a therapeutic gene can lead to complete and long-term correction of a genetic disorder. Our study demonstrates the long-term correction of a disease caused by a genetic defect and proves the feasibility of using rAAV-based vectors for the treatment of chronic disorders like obesity. PMID:9391128

  13. Chronic sleep fragmentation during the sleep period induces hypothalamic endoplasmic reticulum stress and PTP1b-mediated leptin resistance in male mice.

    Science.gov (United States)

    Hakim, Fahed; Wang, Yang; Carreras, Alba; Hirotsu, Camila; Zhang, Jing; Peris, Eduard; Gozal, David

    2015-01-01

    Sleep fragmentation (SF) is highly prevalent and may constitute an important contributing factor to excessive weight gain and the metabolic syndrome. Increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) leading to the attenuation of leptin receptor signaling in the hypothalamus leads to obesity and metabolic dysfunction. Mice were exposed to SF and sleep control (SC) for varying periods of time during which ingestive behaviors were monitored. UPR pathways and leptin receptor signaling were assessed in hypothalami. To further examine the mechanistic role of ER stress, changes in leptin receptor (ObR) signaling were also examined in wild-type mice treated with the ER chaperone tauroursodeoxycholic acid (TUDCA), as well as in CHOP-/+ transgenic mice. Fragmented sleep in male mice induced increased food intake starting day 3 and thereafter, which was preceded by increases in ER stress and activation of all three UPR pathways in the hypothalamus. Although ObR expression was unchanged, signal transducer and activator of transcription 3 (STAT3) phosphorylation was decreased, suggesting reduced ObR signaling. Unchanged suppressor of cytokine signaling-3 (SOCS3) expression and increases in protein-tyrosine phosphatase 1B (PTP1B) expression and activity emerged with SF, along with reduced p-STAT3 responses to exogenous leptin. SF-induced effects were reversed following TUDCA treatment and were absent in CHOP -/+ mice. SF induces hyperphagic behaviors and reduced leptin signaling in hypothalamus that are mediated by activation of ER stress, and ultimately lead to increased PTP1B activity. ER stress pathways are therefore potentially implicated in SF-induced weight gain and metabolic dysfunction, and may represent a viable therapeutic target. © 2014 Associated Professional Sleep Societies, LLC.

  14. Acute sleep fragmentation does not alter pro-inflammatory cytokine gene expression in brain or peripheral tissues of leptin-deficient mice

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    Jennifer E. Dumaine

    2018-02-01

    Full Text Available Obesity and sleep fragmentation (SF are often co-occurring pro-inflammatory conditions in patients with obstructive sleep apnea. Leptin is a peptide hormone produced by adipocytes that has anorexigenic effects upon appetite while regulating immunity. The role of leptin in mediating inflammatory responses to SF is incompletely understood. Male C57BL/6j (lean and ob/ob mice (leptin-deficient mice exhibiting obese phenotype were subjected to SF or control conditions for 24 h using an automated SF chamber. Trunk blood and tissue samples from the periphery (liver, spleen, fat, and heart and brain (hypothalamus, prefrontal cortex, and hippocampus were collected. Quantitative PCR was used to determine relative cytokine gene expression of pro-inflammatory (IL-1β, TNF-α and anti-inflammatory (TGF-β1 cytokines. Enzyme-linked immunosorbent assay (ELISA was used to determine serum corticosterone concentration. Ob/ob mice exhibited elevated cytokine gene expression in liver (TNF-α, TGF-β1, heart (TGF-β1, fat (TNF-α, and brain (hippocampus, hypothalamus, prefrontal cortex: IL-1β, TNF-α compared with wild-type mice. Conversely, leptin deficiency decreased pro-inflammatory cytokine gene expression in heart (IL-1β, TNF-α. SF significantly increased IL-1β and TNF-α gene expression in fat and TGF-β1 expression in spleen relative to controls, but only in wild-type mice. SF increased basal serum corticosterone regardless of genotype. Taken together, these findings suggest that leptin deficiency affects cytokine gene expression differently in the brain compared to peripheral tissues with minimal interaction from acute SF.

  15. 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 ...

  16. Epithelial-microbial crosstalk in polymeric Ig receptor deficient mice

    NARCIS (Netherlands)

    Reikvam, D.H.; Derrien, M.M.N.; Islam, R.; Erofeev, A.; Grcic, V.; Sandvik, A.; Gaustad, P.; Meza-Zepeda, L.A.; Jahnsen, F.L.; Smidt, H.; Johansen, F.E.

    2012-01-01

    Innate and adaptive mucosal defense mechanisms ensure a homeostatic relationship with the large and complex mutualistic gut microbiota. Dimeric IgA and pentameric IgM are transported across the intestinal epithelium via the epithelial polymeric Ig receptor (pIgR) and provide a significant portion of

  17. 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...

  18. Adult exposure to tributyltin affects hypothalamic neuropeptide Y, Y1 receptor distribution, and circulating leptin in mice.

    Science.gov (United States)

    Bo, E; Farinetti, A; Marraudino, M; Sterchele, D; Eva, C; Gotti, S; Panzica, G

    2016-07-01

    Tributyltin (TBT), a pesticide used in antifouling paints, is toxic for aquatic invertebrates. In vertebrates, TBT may act in obesogen- inducing adipogenetic gene transcription for adipocyte differentiation. In a previous study, we demonstrated that acute administration of TBT induces c-fos expression in the arcuate nucleus. Therefore, in this study, we tested the hypothesis that adult exposure to TBT may alter a part of the nervous pathways controlling animal food intake. In particular, we investigated the expression of neuropeptide Y (NPY) immunoreactivity. This neuropeptide forms neural circuits dedicated to food assumption and its action is mediated by Y1 receptors that are widely expressed in the hypothalamic nuclei responsible for the regulation of food intake and energy homeostasis. To this purpose, TBT was orally administered at a dose of 0.025 mg/kg/day/body weight to adult animals [male and female C57BL/6 (Y1-LacZ transgenic mice] for 4 weeks. No differences were found in body weight and fat deposition, but we observed a significant increase in feed efficiency in TBT-treated male mice and a significant decrease in circulating leptin in both sexes. Computerized quantitative analysis of NPY immunoreactivity and Y1-related β-galactosidase activity demonstrated a statistically significant reduction in NPY and Y1 transgene expression in the hypothalamic circuit controlling food intake of treated male mice in comparison with controls. In conclusion, the present results indicate that adult exposure to TBT is profoundly interfering with the nervous circuits involved in the stimulation of food intake. © 2016 American Society of Andrology and European Academy of Andrology.

  19. Genome-wide analysis identifies colonic genes differentially associated with serum leptin and insulin concentrations in C57BL/6J mice fed a high-fat diet.

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    Sung-Eun Kim

    Full Text Available Obesity-induced chronic inflammation is known to increase the risk of ulcerative colitis, Crohn's disease, and colorectal cancer. Accumulating evidence suggests that leptin and insulin are key molecules linking obesity with diseases of the lower intestine. Here, we identified serum phenotype-associated genes in the colon of diet-induced obese mice as early biomarkers of obesity-associated colonic diseases. C57BL/6J mice were fed with either normal diet (ND, 15% of fat calories or high-fat diet (HFD, 45% of fat calories for 8 weeks. Serum concentrations of insulin, insulin-like growth factor-1 (IGF-1, leptin, and adiponectin were measured as obesity-related phenotypic markers. Genome-wide gene expression profiles of colon tissue were determined, followed by statistical analyses to detect differentially expressed and serum phenotype-associated genes. HFD-fed mice showed higher serum concentrations of leptin (P < 0.001 and insulin (P < 0.01 than those in the ND group, whereas serum IGF-1 and adiponectin concentrations did not differ between the two dietary groups. Among differentially expressed genes affected by HFD, 135, 128, 110, and 341 genes were associated with serum levels of leptin, insulin, IGF-1, and adiponectin, respectively. We identified 17 leptin-associated genes and 4 insulin-associated genes that inversely responded to HFD and ND. Among these, leptin-associated Peli3 (Pellino E3 ubiquitin protein ligase family member 3, Creb1 (cAMP responsive element binding protein 1, and Enpp2 (ectonucleotide pyrophosphatase/phosphodiesterase 2, autotaxin and insulin-associated Centg1 (AGAP2, ArfGAP with GTPase domain are reported to play a role either in obesity or colonic diseases. mRNA expression of these genes was validated by RT-qPCR. Our data suggest Peli3, Creb1, Enpp2, and Centg1 as potential early biomarker candidates for obesity-induced pathophysiological changes in the colon. Future studies verifying the function of these candidates are

  20. Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice123

    Science.gov (United States)

    Robertson, Lauren T; Treviño-Villarreal, J Humberto; Mejia, Pedro; Grondin, Yohann; Harputlugil, Eylul; Hine, Christopher; Vargas, Dorathy; Zheng, Hanqiao; Ozaki, C Keith; Kristal, Bruce S; Simpson, Stephen J; Mitchell, James R

    2015-01-01

    Background: Short-term dietary restriction (DR) without malnutrition preconditions against surgical stress in rodents; however, the nutritional basis and underlying nutrient/energy-sensing pathways remain poorly understood. Objectives: We investigated the relative contribution of protein restriction (PR) vs. calorie restriction (CR) to protection from renal ischemia reperfusion injury (IRI) and changes in organ-autonomous nutrient/energy-sensing pathways and hormones underlying beneficial effects. Methods: Mice were preconditioned on experimental diets lacking total calories (0–50% CR) or protein/essential amino acids (EAAs) vs. complete diets consumed ad libitum (AL) for 1 wk before IRI. Renal outcome was assessed by serum markers and histology and integrated over a 2-dimensional protein/energy landscape by geometric framework analysis. Changes in renal nutrient/energy-sensing signal transduction and systemic hormones leptin and adiponectin were also measured. The genetic requirement for amino acid sensing via general control non-derepressible 2 (GCN2) was tested with knockout vs. control mice. The involvement of the hormone leptin was tested by injection of recombinant protein vs. vehicle during the preconditioning period. Results: CR-mediated protection was dose dependent up to 50% with maximal 2-fold effect sizes. PR benefits were abrogated by EAA re-addition and additive with CR, with maximal benefits at any given amount of CR occurring with a protein-free diet. GCN2 was not required for functional benefits of PR. Activation and repression of nutrient/energy-sensing kinases, AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1), respectively, on PR reflected a state of negative energy balance, paralleled by 13% weight loss and an 87% decrease in leptin, independent of calorie intake. Recombinant leptin administration partially abrogated benefits of dietary preconditioning against renal IRI. Conclusions: In male mice, PR

  1. GH Receptor Deficiency in Ecuadorian Adults Is Associated With Obesity and Enhanced Insulin Sensitivity

    Science.gov (United States)

    Rosenbloom, Arlan L.; Balasubramanian, Priya; Teran, Enrique; Guevara-Aguirre, Marco; Guevara, Carolina; Procel, Patricio; Alfaras, Irene; De Cabo, Rafael; Di Biase, Stefano; Narvaez, Luis; Saavedra, Jannette

    2015-01-01

    Context: Ecuadorian subjects with GH receptor deficiency (GHRD) have not developed diabetes, despite obesity. Objective: We sought to determine the metabolic associations for this phenomenon. Design: Four studies were carried out: 1) glucose, lipid, adipocytokine concentrations; 2) metabolomics evaluation; 3) metabolic responses to a high-calorie meal; and 4) oral glucose tolerance tests. Setting: Clinical Research Institute in Quito, Ecuador. Subjects: Adults homozygous for the E180 splice mutation of the GH receptor (GHRD) were matched for age, gender, and body mass index with unaffected control relatives (C) as follows: study 1, 27 GHRD and 35 C; study 2, 10 GHRD and 10 C; study 3, seven GHRD and 11 C; and study 4, seven GHRD and seven C. Results: Although GHRD subjects had greater mean percentage body fat than controls, their fasting insulin, 2-hour blood glucose, and triglyceride levels were lower. The indicator of insulin sensitivity, homeostasis model of assessment 2%S, was greater (P < .0001), and the indicator of insulin resistance, homeostasis model of assessment 2-IR, was lower (P = .0025). Metabolomic differences between GHRD and control subjects were consistent with their differing insulin sensitivity, including postprandial decreases of branched-chain amino acids that were more pronounced in controls. High molecular weight and total adiponectin concentrations were greater in GHRD (P = .0004 and P = .0128, respectively), and leptin levels were lower (P = .02). Although approximately 65% the weight of controls, GHRD subjects consumed an identical high-calorie meal; nonetheless, their mean glucose concentrations were lower, with mean insulin levels one-third those of controls. Results of the 2-hour oral glucose tolerance test were similar. Main Outcome Measures: Measures of insulin sensitivity, adipocytokines, and energy metabolites. Conclusions: Without GH counter-regulation, GHRD is associated with insulin efficiency and obesity. Lower leptin levels

  2. Characterization of the gut microbiota in leptin deficient obese mice - Correlation to inflammatory and diabetic parameters.

    Science.gov (United States)

    Ellekilde, M; Krych, L; Hansen, C H F; Hufeldt, M R; Dahl, K; Hansen, L H; Sørensen, S J; Vogensen, F K; Nielsen, D S; Hansen, A K

    2014-04-01

    Gut microbiota have been implicated as a relevant factor in the development of type 2 diabetes mellitus (T2DM), and its diversity might be a cause of variation in animal models of T2DM. In this study, we aimed to characterise the gut microbiota of a T2DM mouse model with a long term vision of being able to target the gut microbiota to reduce the number of animals used in experiments. Male B6.V-Lep(ob)/J mice were characterized according to a number of characteristics related to T2DM, inflammation and gut microbiota. All findings were thereafter correlated to one another in a linear regression model. The total gut microbiota profile correlated to glycated haemoglobin, and high proportions of Prevotellaceae and Lachnospiraceae correlated to impaired or improved glucose intolerance, respectively. In addition, Akkermansia muciniphila disappeared with age as glucose intolerance worsened. A high proportion of regulatory T cells correlated to the gut microbiota and improved glucose tolerance. Furthermore, high levels of IL-10, IL-12 and TNF-α correlated to impaired glucose tolerance, blood glucose or glycated haemoglobin. The findings indicate that gut microbiota may contribute to variation in various disease read-outs in the B6.V-Lep(ob)/J model and considering them in both quality assurance and data evaluation for the B6.V-Lep(ob)/J model may have a reducing impact on the inter-individual variation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. QCM-4, a 5-HT₃ receptor antagonist ameliorates plasma HPA axis hyperactivity, leptin resistance and brain oxidative stress in depression and anxiety-like behavior in obese mice.

    Science.gov (United States)

    Kurhe, Yeshwant; Mahesh, Radhakrishnan; Devadoss, Thangaraj

    2015-01-02

    Several preclinical studies have revealed antidepressant and anxiolytic-like effect of 5-HT3 receptor antagonists. In our earlier study, we have reported the antidepressive-like effect of 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) in obese mice subjected to chronic stress. The present study deals with the biochemical mechanisms associated with depression co-morbid with obesity. Mice were fed with high fat diet (HFD) for 14 weeks, further subjected for treatment with QCM-4 (1 and 2mg/kg p.o.) and standard antidepressant escitalopram (ESC) (10mg/kg p.o.) for 28 days. Behavioral assays for depression such as sucrose preference test (SPT), forced swim test (FST) and for anxiety such as light and dark test (LDT) and hole board test (HBT) were performed in obese mice. Biochemical assessments including plasma leptin and corticosterone concentration followed by brain oxidative stress parameters malonaldehyde (MDA) and reduced glutathione (GSH) were performed. Results confirmed that QCM-4 exhibits antidepressive effect by increasing the sucrose consumption in SPT, reducing immobility time in FST and anxiolytic effect by increasing transitions and time in light chamber in LDT, increasing head dip and crossing score in HBT. Furthermore, QCM-4 attenuated the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity by reducing the plasma corticosterone, reversing altered plasma leptin, restoring the imbalance of brain MDA and GSH concentration. In conclusion, QCM-4 showed antidepressive and anxiolytic effect by reversing the behavioral alterations that were supported by biochemical estimations in obese mice. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Boar seminal immunosuppressive fraction attenuates the leptin concentration and restores the thymus mass during pregnancy in mice

    Czech Academy of Sciences Publication Activity Database

    Veselský, Leopold; Holáň, Vladimír; Dostál, Jaromír; Železná, Blanka

    2004-01-01

    Roč. 127, č. 5 (2004), s. 581-585 ISSN 1470-1626 R&D Projects: GA ČR GA303/01/0615; GA MZd NI6883 Institutional research plan: CEZ:AV0Z5052915 Keywords : pregnancy * leptin level * seminal immunosuppressor Subject RIV: EC - Immunology Impact factor: 2.181, year: 2004

  5. Brain Structure and Function Associated with Younger Adults in Growth Hormone Receptor-Deficient Humans.

    Science.gov (United States)

    Nashiro, Kaoru; Guevara-Aguirre, Jaime; Braskie, Meredith N; Hafzalla, George W; Velasco, Rico; Balasubramanian, Priya; Wei, Min; Thompson, Paul M; Mather, Mara; Nelson, Marvin D; Guevara, Alexandra; Teran, Enrique; Longo, Valter D

    2017-02-15

    Growth hormone receptor deficiency (GHRD) results in short stature, enhanced insulin sensitivity, and low circulating levels of insulin and insulin-like growth factor 1 (IGF-1). Previous studies in mice and humans suggested that GHRD has protective effects against age-related diseases, including cancer and diabetes. Whereas GHRD mice show improved age-dependent cognitive performance, the effect of GHRD on human cognition remains unknown. Using MRI, we compared brain structure, function, and connectivity between 13 people with GHRD and 12 unaffected relatives. We assessed differences in white matter microstructural integrity, hippocampal volume, subregional volumes, and cortical thickness and surface area of selected regions. We also evaluated brain activity at rest and during a hippocampal-dependent pattern separation task. The GHRD group had larger surface areas in several frontal and cingulate regions and showed trends toward larger dentate gyrus and CA1 regions of the hippocampus. They had lower mean diffusivity in the genu of the corpus callosum and the anterior thalamic tracts. The GHRD group showed enhanced cognitive performance and greater task-related activation in frontal, parietal, and hippocampal regions compared with controls. Furthermore, they had greater functional synchronicity of activity between the precuneus and the rest of the default mode network at rest. The results suggest that, compared with controls, GHRD subjects have brain structure and function that are more consistent with those observed in younger adults reported in previous studies. Further investigation may lead to improved understanding of underlying mechanisms and could contribute to the identification of treatments for age-related cognitive deficits. SIGNIFICANCE STATEMENT People and mice with growth hormone receptor deficiency (GHRD or Laron syndrome) are protected against age-related diseases including cancer and diabetes. However, in humans, it is unknown whether cognitive

  6. Sida rhomboidea. Roxb Leaf Extract Down-Regulates Expression of PPARγ2 and Leptin Genes in High Fat Diet Fed C57BL/6J Mice and Retards in Vitro 3T3L1 Pre-Adipocyte Differentiation

    Directory of Open Access Journals (Sweden)

    A. V. Ramachandran

    2011-07-01

    Full Text Available Sida rhomboidea. Roxb leaf extract (SRLE is being used by the populace of North-East India to alleviate symptoms of diabetes and obesity. We have previously reported its hypolipidemic and anti-diabetic properties. In this study, we report the effect of SRLE on (i in vivo modulation of genes controlling high fat diet (HFD induced obesity and (ii in vitro 3T3L1 pre-adipocyte differentiation and leptin release. Supplementation with SRLE significantly prevented HFD induced increment in bodyweight, plasma lipids and leptin, visceral adiposity and adipocyte hypertrophy. Also, SRLE supplementation reduced food intake, down regulated PPARγ2, SREBP1c, FAS and LEP expressions and up-regulated CPT-1 in epididymal adipose tissue compared to obese mice. In vitro adipogenesis of 3T3L1 pre-adipocytes was significantly retarded in the presence of SRLE extract. Also decreased triglyceride accumulation, leptin release and glyceraldehyde-3-Phosphate dehydrogenase activity along with higher glycerol release without significant alteration of viability of 3T3L1 pre-adipocytes, was recorded. Our findings suggest that prevention of HFD induced visceral adiposity is primarily by down regulation of PPARγ2 and leptin gene expression coupled with attenuation of food intake in C57BL/6J mice. SRLE induced prevention of pre-adipocytes differentiation, and leptin release further substantiated these findings and scientifically validates the potential application of SRLE as a therapeutic agent against obesity.

  7. CORRELATION BETWEEN GUT MICROBIOTA AND DEVELOPMENT OF GLUCOSE INTOLERANCE IN B6.V-Lepob/J LEPTIN DEFICIENT MICE

    DEFF Research Database (Denmark)

    Ellekilde, Merete; Hansen, Camilla Hartmann Friis; Nielsen, Dennis Sandris

    -Lepob/J leptin deficient mouse, a model of severe obesity and type 2 diabetes, was correlated with development of glucose intolerance. GM composition was analyzed by means of denaturing gradient gel electrophoresis (DGGE), a culture independent approach, separating PCR-derived DNA amplicons of bacterial 16S r......RNA. Disease development was monitored by weekly weight and blood glucose measurements supplemented with measurements of oral glucose tolerance, HbA1c%, plasma insulin and plasma cytokines. A significant correlation was demonstrated between GM composition and glucose intolerance. Also, a significant...... correlation was found between blood glucose, HbA1c% and glucose intolerance and the pro-inflammatory cytokine IL-12, supporting the correlation found between gut and disease, as IL-12 is secreted after microbial stimulation of immunological cells – e.g. In the gut. Further investigations concerning...

  8. Adipocyte iron regulates leptin and food intake.

    Science.gov (United States)

    Gao, Yan; Li, Zhonggang; Gabrielsen, J Scott; Simcox, Judith A; Lee, Soh-hyun; Jones, Deborah; Cooksey, Bob; Stoddard, Gregory; Cefalu, William T; McClain, Donald A

    2015-09-01

    Dietary iron supplementation is associated with increased appetite. Here, we investigated the effect of iron on the hormone leptin, which regulates food intake and energy homeostasis. Serum ferritin was negatively associated with serum leptin in a cohort of patients with metabolic syndrome. Moreover, the same inverse correlation was observed in mice fed a high-iron diet. Adipocyte-specific loss of the iron exporter ferroportin resulted in iron loading and decreased leptin, while decreased levels of hepcidin in a murine hereditary hemochromatosis (HH) model increased adipocyte ferroportin expression, decreased adipocyte iron, and increased leptin. Treatment of 3T3-L1 adipocytes with iron decreased leptin mRNA in a dose-dependent manner. We found that iron negatively regulates leptin transcription via cAMP-responsive element binding protein activation (CREB activation) and identified 2 potential CREB-binding sites in the mouse leptin promoter region. Mutation of both sites completely blocked the effect of iron on promoter activity. ChIP analysis revealed that binding of phosphorylated CREB is enriched at these two sites in iron-treated 3T3-L1 adipocytes compared with untreated cells. Consistent with the changes in leptin, dietary iron content was also directly related to food intake, independently of weight. These findings indicate that levels of dietary iron play an important role in regulation of appetite and metabolism through CREB-dependent modulation of leptin expression.

  9. Liver PPARα and UCP2 are involved in the regulation of obesity and lipid metabolism by swim training in genetically obese db/db mice

    International Nuclear Information System (INIS)

    Oh, Ki Sook; Kim, Mina; Lee, Jinmi; Kim, Min Jeong; Nam, Youn Shin; Ham, Jung Eun; Shin, Soon Shik; Lee, Chung Moo; Yoon, Michung

    2006-01-01

    Swim training for 6 weeks significantly decreased body weight gain, adipose tissue mass, and adipocyte size in both sexes of genetically obese db/db mice compared with their respective sedentary controls. Swim training also caused significant decreases in serum levels of free fatty acids, triglycerides, and total cholesterol in both sexes of obese mice. Concomitantly, hepatic mRNA levels of peroxisome proliferator-activated receptor α (PPARα) target enzymes responsible for mitochondrial and peroxisomal fatty acid β-oxidation were significantly increased by swim training. Moreover, mRNA levels of uncoupling protein 2 (UCP2) in liver were also markedly increased by swim training. In conclusion, these results suggest that swim training-induced transcriptional activation of hepatic PPARα target enzymes and UCP2 may effectively prevent body weight gain, adiposity, and lipid disorders caused by leptin receptor deficiency in both sexes of mice

  10. 20 years of leptin: leptin and reproduction: past milestones, present undertakings, and future endeavors.

    Science.gov (United States)

    Chehab, Farid F

    2014-10-01

    The association between leptin and reproduction originated with the leptin-mediated correction of sterility in ob/ob mice and initiation of reproductive function in normal female mice. The uncovering of a central leptin pathway regulating food intake prompted the dissection of neuroendocrine mechanisms involving leptin in the metabolic control of reproduction. The absence of leptin receptors on GnRH neurons incited a search for intermediary neurons situated between leptin-responsive and GnRH neurons. This review addresses the most significant findings that have furthered our understanding of recent progress in this new field. The role of leptin in puberty was impacted by the discovery of neurons that co-express kisspeptin, neurokinin B, and dynorphin and these could act as leptin intermediates. Furthermore, the identification of first-order leptin-responsive neurons in the premammilary ventral nucleus and other brain regions opens new avenues to explore their relationship to GnRH neurons. Central to these advances is the unveiling that agouti-related protein/neuropeptide Y neurons project onto GnRH and kisspeptin neurons, allowing for a crosstalk between food intake and reproduction. Finally, while puberty is a state of leptin sensitivity, mid-gestation represents a state of leptin resistance aimed at building energy stores to sustain pregnancy and lactation. The mechanisms underlying leptin resistance in pregnancy have lagged; however, the establishment of this natural state is significant. Reproduction and energy balance are tightly controlled and backed up by redundant mechanisms that are critical for the survival of our species. It will be the goal of the following decade to shed new light on these complex and essential pathways. © 2014 Society for Endocrinology.

  11. Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin induced migration of breast carcinoma cells

    Science.gov (United States)

    Knight, Brandi B.; Oprea-Ilies, Gabriela M.; Nagalingam, Arumugam; Yang, Lily; Cohen, Cynthia; Saxena, Neeraj K.; Sharma, Dipali

    2012-01-01

    Obese breast cancer patients exhibit a higher risk for larger tumor burden and increased metastasis. Molecular effects of obesity on carcinogenesis are mediated by autocrine and paracrine effects of adipocytokine leptin. Leptin participates in tumor progression and metastasis of human breast. We show that leptin induces clonogenicity and migration potential of breast cancer cells. We found that survivin expression is induced in response to leptin. In this study, we examine the role and leptin-mediated regulation of survivin. Leptin treatment leads to survivin upregulation, due in part to the activation of Notch1 and release of transcriptionally active Notch1-intracellular-domain (NICD). ChIP analysis show that NICD gets recruited to survivin promoter at CSL-binding-site in response to leptin treatment. Inhibition of Notch1 activity inhibits leptin-induced survivin upregulation. Leptin-induced transactivation of EGFR is involved in leptin-mediated Notch1 and survivin upregulation showing a novel upstream role of leptin-EGFR-Notch1 axis. We further show that leptin-induced migration of breast cancer cells requires survivin, as overexpression of survivin further increases, whereas silencing survivin abrogates leptin-induced migration. Using a pharmacological approach to inhibit survivin, we show that 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors (HRIs), lovastatin, can effectively inhibit leptin-induced survivin expression and migration. Importantly, leptin increased breast tumor growth in nude mice. These data show a novel role for survivin in leptin-induced migration and put forth pharmacological survivin inhibition as a potential novel therapeutic target. This conclusion is supported by in vivo data showing overexpression of leptin and survivin in epithelial cells of high grade ductal carcinoma in situ and high grade invasive carcinoma. PMID:21555376

  12. Remodeling of energy metabolism and absence of electrophysiological changes in hearts of obese hyperleptinemic mice. New insights into the pleiotropic role of leptin

    Directory of Open Access Journals (Sweden)

    Rocío eGuzmán-Ruiz

    2013-11-01

    Full Text Available Dietary treatment with high-fat diets (HFD triggers diabetes and hyperleptinemia, concomitantly with a partial state of leptin resistance that affects hepatic and adipose tissue but not the heart. In this context, characterized by widespread steatosis, cardiac lipid content remains unchanged. As previously reported, HFD-evoked hyperleptinemia could be a pivotal element contributing to increase fatty acid (FA metabolism in the heart and to to prevent cardiac steatosis. This metabolic adaptation might theoretically reduce energy efficiency in cardiomyocytes and lead to cardiac electrophysiological remodeling. Therefore the aim of the current study has been to investigate the impact of long-term HFD on cardiac metabolism and electrophysiological properties of the principal ionic currents responsible of the action potential duration in mouse cardiomyocytes. Male C57BL/6J mice were fed a control (10% kcal from fat or HFD (45% kcal from fat during 32 weeks. Quantification of enzymatic activities regulating mitochondrial uptake of pyruvate and FA showed an increase of both carnitine-palmitoyltransferase and citrate synthase activities together with a decrease of lactate dehydrogenase and pyruvate dehydrogenase activities. Increased expression of uncoupling protein-3, Mn- and Cu/Zn-superoxide dismutases and catalase were also detected. Total glutathione/oxidized glutathione ratios were unaffected by HFD. These data suggest that HFD triggers adaptive mechanisms aimed at i facilitating FA catabolism, and ii preventing oxidative stress. All these changes did not affect the duration of action potentials in cardiomyocytes and only slightly modified electrocardiographic parameters.

  13. Thyroid hormone and leptin in the testis

    Directory of Open Access Journals (Sweden)

    Cristiane Fonte Ramos

    2014-11-01

    Full Text Available Leptin is primarily expressed in white adipose tissue; however, it is expressed in the hypothalamus and reproductive tissues as well. Leptin acts by activating the leptin receptors (Ob-Rs. Additionally, the regulation of several neuroendocrine and reproductive functions, including the inhibition of glucocorticoids and enhancement of thyroxine and sex hormone concentrations in humans and mice are leptin functions. It has been suggested that thyroid hormones (TH could directly regulate leptin expression. Additionally, hypothyroidism compromises the intracellular integration of leptin signaling specifically in the arcuate nucleus. Two TH receptor isoforms are expressed in the testis, TRa and TRb, with TRa being the predominant one that is present in all stages of development. The effects of TH involve the proliferation and differentiation of Sertoli and Leydig cells during development, spermatogenesis and steroidogenesis. In this context, TH disorders are associated with sexual dysfunction. An endocrine and/or direct paracrine effect of leptin on the gonads inhibits testosterone production in Leydig cells. Further studies are necessary to clarify the effects of both hormones in the testis during hypothyroidism. The goal of this review is to highlight the current knowledge regarding leptin and TH in the testis.

  14. [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, small molecule synthetic peptide leptin mimetics, improve glycemic control in diet-induced obese (DIO) mice.

    Science.gov (United States)

    Wang, Anke; Anderson, Brian M; Novakovic, Zachary M; Grasso, Patricia

    2018-03-01

    We have previously shown that following oral delivery in dodecyl maltoside (DDM), [D-Leu-4]-OB3 and its myristic acid conjugate, MA-[D-Leu-4]-OB3, improved energy balance and glucose homeostasis in genetically obese/diabetic mouse models. More recently, we have provided immunohistochemical evidence indicating that these synthetic peptide leptin mimetics cross the blood-brain barrier and concentrate in the area of the arcuate nucleus of the hypothalamus in normal C57BL/6J and Swiss Webster mice, in genetically obese ob/ob mice, and in diet-induced obese (DIO) mice. In the present study, we describe the effects of oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on glycemic control in diet-induced (DIO) mice, a non-genetic rodent model of obesity and its associated insulin resistance, which more closely recapitulates common obesity and diabetes in humans. Male C57BL/6J and DIO mice, 17, 20, and 28 weeks of age, were maintained on a low-fat or high-fat diet and given vehicle (DDM) alone or [D-Leu-4]-OB3 or MA-[D-Leu-4]-OB3 in DDM by oral gavage for 12 or 14 days. Body weight gain, food and water intake, fasting blood glucose, oral glucose tolerance, and serum insulin levels were measured. Our data indicate that (1) [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 restore glucose tolerance in male DIO mice maintained on a high-fat diet to levels comparable to those of non-obese C57BL/6J wild-type mice of the same age and sex maintained on a low-fat diet; and (2) the influence of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on glycemic control appears to be independent of their effects on energy balance. These results suggest that [D-Leu-4]-OB3 and/or MA-[D-Leu-4]-OB3 may have application to the management of the majority of cases of common obesity in humans, a state characterized at least in part, by leptin resistance resulting from a defect in leptin transport across the blood-brain barrier. They further suggest that these small molecule synthetic peptide leptin mimetics, through their

  15. Hyperleptinemia is required for the development of leptin resistance.

    Directory of Open Access Journals (Sweden)

    Zachary A Knight

    2010-06-01

    Full Text Available Leptin regulates body weight by signaling to the brain the availability of energy stored as fat. This negative feedback loop becomes disrupted in most obese individuals, resulting in a state known as leptin resistance. The physiological causes of leptin resistance remain poorly understood. Here we test the hypothesis that hyperleptinemia is required for the development of leptin resistance in diet-induced obese mice. We show that mice whose plasma leptin has been clamped to lean levels develop obesity in response to a high-fat diet, and the magnitude of this obesity is indistinguishable from wild-type controls. Yet these obese animals with constant low levels of plasma leptin remain highly sensitive to exogenous leptin even after long-term exposure to a high fat diet. This shows that dietary fats alone are insufficient to block the response to leptin. The data also suggest that hyperleptinemia itself can contribute to leptin resistance by downregulating cellular response to leptin as has been shown for other hormones.

  16. Inactivation of SOCS3 in leptin receptor-expressing cells protects mice from diet-induced insulin resistance but does not prevent obesity a

    OpenAIRE

    Pedroso, João A.B.; Buonfiglio, Daniella C.; Cardinali, Lais I.; Furigo, Isadora C.; Ramos-Lobo, Angela M.; Tirapegui, Julio; Elias, Carol F.; Donato, Jose

    2014-01-01

    Therapies that improve leptin sensitivity have potential as an alternative treatment approach against obesity and related comorbidities. We investigated the effects of Socs3 gene ablation in different mouse models to understand the role of SOCS3 in the regulation of leptin sensitivity, diet-induced obesity (DIO) and glucose homeostasis. Neuronal deletion of SOCS3 partially prevented DIO and improved glucose homeostasis. Inactivation of SOCS3 only in LepR-expressing cells protected against lep...

  17. Leptin and psychiatry

    African Journals Online (AJOL)

    QuickSilver

    obese and normal body weight controls, and negatively corre- lated with weight loss due to food restriction. Reports of studies of leptin in patients with anorexia nervosa are limited. In starved female anorectics at very low body weights, leptin levels are reduced significantly.15,16 Leptin in-. Fig. 2. A schematic representation ...

  18. Hypothalamic leptin action is mediated by histone deacetylase 5

    DEFF Research Database (Denmark)

    Kabra, Dhiraj G; Pfuhlmann, Katrin; García-Cáceres, Cristina

    2016-01-01

    Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and...

  19. Effects of aqueous extract of Portulaca oleracea L. on oxidative stress and liver, spleen leptin, PARα and FAS mRNA expression in high-fat diet induced mice.

    Science.gov (United States)

    Chen, Bendong; Zhou, Haining; Zhao, Wenchao; Zhou, Wenyan; Yuan, Quan; Yang, Guangshun

    2012-08-01

    We reported that an aqueous extract of Portulaca oleracea L. inhibited high-fat-diet-induced oxidative injury in a dose-dependent manner. Male kunming mice (5-weeks-old, 24 g) were used in this experiment. After a 4-day adaptation period, animals were randomly divided into four groups (n = 10 in each group); Group 1: animals received normal powdered rodent diet; Group 2: animals received high fat diet; Groups 3 and 4: animals received high fat diet and were fed by gavage to mice once a day with aqueous extract at the doses of 100 and 200 mg/kg body weight, respectively. In mice fed with high-fat diet, blood and liver lipid peroxidation level was significantly increased, whereas antioxidant enzymes activities were markedly decreased compared to normal control mice. Administration of an aqueous extract of P. oleracea L. significantly dose-dependently reduced levels of blood and liver lipid peroxidation and increased the activities of blood and liver antioxidant enzymes activities in high fat mice. Moreover, administration of an aqueous extract of P. oleracea L. significantly dose-dependently increase liver Leptin/β-actin (B), and Liver PPARα/β-actin, decrease liver, spleen FAS mRNA, p-PERK and p-PERK/PERK protein expression levels. Taken together, these data demonstrate that aqueous extract of P. oleracea L. can markedly alleviate high fat diet-induced oxidative injury by enhancing blood and liver antioxidant enzyme activities, modulating Leptin/β-actin (B), and Liver PPARα/β-actin, decrease liver, spleen FAS mRNA, p-PERK and p-PERK/PERK protein expression levels in mice.

  20. Leptin im Knochenstoffwechsel

    Directory of Open Access Journals (Sweden)

    Vock L

    2003-01-01

    Full Text Available Leptin ist ein in Adipozyten exprimiertes Hormon mit vielfältigen Funktionen im gesamten Organismus. Verschiedene Studien legen eine positive Wirkung von Leptin auf den Knochenstoffwechsel nahe. In vitro führte die Inkubation von Knochenmarkstromazellen mit Leptin zu deren Differenzierung zu Osteoblasten und Mineralisation der Matrix. Bei ovarektomierten Ratten konnte durch Leptin der Knochenverlust vermindert werden. Überraschenderweise zeigten andere Studien eine zentrale inhibitorische Wirkung von Leptin auf Osteoblasten bei Nagern. Diese einander scheinbar widersprechenden Ergebnisse zeigen, daß die molekularen Mechanismen, mit welchen Leptin auf den Knochenstoffwechsel wirkt, noch nicht ausreichend verstanden werden. In klinischen Studien findet sich eine protektive Wirkung von Fettmasse und "body mass index" (BMI auf die Knochendichte (postmenopausaler Frauen überwiegend bestätigt. Damit im Einklang, konnten erhöhte Leptinspiegel gefunden werden. Ob Leptin nun direkt in den Knochenstoffwechsel eingreift oder bloß indirekt etwa über eine erhöhte mechanische Belastung, läßt sich aus klinischen Studien allein nicht beantworten. Hingegen dürfte Leptin im Knochenstoffwechsel von Männern keine oder nur eine untergeordnete Rolle spielen. Die Situation bei Kindern und Jugendlichen ist noch unklar, wobei eine positive Wirkung von Leptin in fetalem Knochen relativ sicher ist. Leptin könnte jedoch auch im Wachstum und der Knochenreifung bei Kindern und Jugendlichen eine Rolle spielen.

  1. In Uncontrolled Diabetes, Hyperglucagonemia and Ketosis Result From Deficient Leptin Action in the Parabrachial Nucleus.

    Science.gov (United States)

    Meek, Thomas H; Matsen, Miles E; Faber, Chelsea L; Samstag, Colby L; Damian, Vincent; Nguyen, Hong T; Scarlett, Jarrad M; Flak, Jonathan N; Myers, Martin G; Morton, Gregory J

    2018-04-01

    Growing evidence implicates neurons that project from the lateral parabrachial nucleus (LPBN) to the hypothalamic ventromedial nucleus (VMN) in a neurocircuit that drives counterregulatory responses to hypoglycemia, including increased glucagon secretion. Among LPBN neurons in this circuit is a subset that expresses cholecystokinin (LPBNCCK neurons) and is tonically inhibited by leptin. Because uncontrolled diabetes is associated with both leptin deficiency and hyperglucagonemia, and because intracerebroventricular (ICV) leptin administration reverses both hyperglycemia and hyperglucagonemia in this setting, we hypothesized that deficient leptin inhibition of LPBNCCK neurons drives activation of this LPBN→VMN circuit and thereby results in hyperglucagonemia. Here, we report that although bilateral microinjection of leptin into the LPBN does not ameliorate hyperglycemia in rats with streptozotocin-induced diabetes mellitus (STZ-DM), it does attenuate the associated hyperglucagonemia and ketosis. To determine if LPBN leptin signaling is required for the antidiabetic effect of ICV leptin in STZ-DM, we studied mice in which the leptin receptor was selectively deleted from LPBNCCK neurons. Our findings show that although leptin signaling in these neurons is not required for the potent antidiabetic effect of ICV leptin, it is required for leptin-mediated suppression of diabetic hyperglucagonemia. Taken together, these findings suggest that leptin-mediated effects in animals with uncontrolled diabetes occur through actions involving multiple brain areas, including the LPBN, where leptin acts specifically to inhibit glucagon secretion and associated ketosis.

  2. Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation.

    Science.gov (United States)

    Lourenço, Elaine V; Liu, Aijing; Matarese, Giuseppe; La Cava, Antonio

    2016-09-20

    Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptin-sufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.

  3. Hematopoietic androgen receptor deficiency promotes visceral fat deposition in male mice without impairing glucose homeostasis

    OpenAIRE

    Rubinow, K. B.; Wang, S.; den Hartigh, L. J.; Subramanian, S.; Morton, G. J.; Buaas, F. W.; Lamont, D.; Gray, N.; Braun, R. E.; Page, S. T.

    2015-01-01

    Androgen deficiency in men increases body fat, but the mechanisms by which testosterone suppresses fat deposition have not been elucidated fully. Adipose tissue macrophages express the androgen receptor (AR) and regulate adipose tissue remodeling. Thus, testosterone signaling in macrophages could alter the paracrine function of these cells and thereby contribute to the metabolic effects of androgens in men. A metabolic phenotyping study was performed to determine whether the loss of AR signal...

  4. Curcumin modulation of high fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice

    Science.gov (United States)

    Consuming curcumin may benefit health by modulating lipid metabolism and suppressing atherogenesis. Fatty acid binding proteins (FABP-4/aP2) and CD36 expression are key factors in lipid accumulation in macrophages and foam cell formation in atherogenesis. Our earlier observations suggest that curcum...

  5. CD1d deficiency inhibits the development of abdominal aortic aneurysms in LDL receptor deficient mice

    NARCIS (Netherlands)

    van Puijvelde, Gijs H. M.; Foks, Amanda C.; van Bochove, Rosemarie E.; Bot, Ilze; Habets, Kim L. L.; de Jager, Saskia C.; ter Borg, Mariëtte N. D.; van Osch, Puck; Boon, Louis; Vos, Mariska; de Waard, Vivian; Kuiper, Johan

    2018-01-01

    An abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta leading to serious complications and mostly to death. AAA development is associated with an accumulation of inflammatory cells in the aorta including NKT cells. An important factor in promoting the recruitment of these

  6. Dietary fat interacts with PCBs to induce changes in lipid metabolism in LDL receptor deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Hennig, B.; Reiterer, G.; Toborek, M.; Matveev, S.V.; Daugherty, A.; Smart, E. [Univ. of Kentucky, Lexington (United States); Robertson, L.W. [Univ. of Iowa, Iowa City (United States)

    2004-09-15

    From epidemiological studies, there is substantial evidence that cardiovascular diseases are linked to environmental pollution and that exposure to polycyclic and/or polyhalogenated aromatic hydrocarbons can lead to human cardiovascular toxicity. A major route of exposure to PCBs in humans is via oral ingestion of contaminated food products. Therefore, circulating environmental contaminants derived from diets, such as PCBs, are in intimate contact with the vascular endothelium. Endothelial activation and dysfunction is an important factor in the overall regulation of vascular lesion pathology. In addition to endothelial barrier dysfunction, another functional change in atherosclerosis is the activation of the endothelium that is manifested as an increase in the expression of specific cytokines and adhesion molecules. These cytokines and adhesion molecules are proposed to mediate the inflammatory aspects of the disease by regulating the vascular entry of leukocytes. Alterations in lipid profile and lipid metabolism as a result of exposure to PCBs may be important components of endothelial cell dysfunction. Little is known about the interaction of dietary fats and PCBs in the pathology of atherosclerosis. We have reported a significant disruption in endothelial barrier function when cells were exposed to linoleic acid. In the current study we aimed to demonstrate the PCB-fatty acid interaction in vivo and hypothesized that PCB toxicity can be modulated by the type of fat consumed.

  7. Leptin, obesity and cardiovascular disease.

    Science.gov (United States)

    Correia, Marcelo Lima de Gusmao; Haynes, William Geoffrey

    2004-03-01

    Obesity is a risk factor for cardiovascular diseases. Leptin levels are increased in obesity and leptin exhibits cardiovascular actions that may contribute to increased cardiovascular risk. We review the sympathetic, renal and vascular actions of leptin and their relevance to cardiovascular disease. Leptin possesses cardio-renal actions potentially contributing to obesity-related hypertension including generalized sympathoactivation. However, given that leptin resistance occurs in obesity, it has been difficult to link hyperleptinemia with hypertension. One possibility is that leptin resistance is confined to the metabolic effects of leptin, with preservation of its sympathoexcitatory actions. Other mechanisms may contribute to the pressor effects of leptin. For instance, angiotensin II induces leptin generation. Leptin also potentiates the pressor effect of insulin. Therefore, interactions between angiotensin II and insulin with leptin could have deleterious cardiovascular effects in obesity. Additionally, leptin appears to stimulate vascular inflammation, oxidative stress and hypertophy. These actions may contribute to the pathogenesis of hypertension, atherosclerosis, and left ventricular hypertrophy. The potential actions of leptin in the pathophysiology of cardiovascular complications of obesity are diverse, despite evidence of leptin resistance to its metabolic actions. However, most information about cardiovascular actions of leptin derives from in-vitro and animal studies. Future research in humans is widely awaited.

  8. Body Mass Influences Cortical Bone Mass Independent of Leptin Signaling

    OpenAIRE

    Iwaniec, U.T.; Dube, M.G.; Boghossian, S.; Song, H.; Helferich, W.G.; Turner, R.T.; Kalra, S.P.

    2008-01-01

    Obesity in humans is associated with increased bone mass. Leptin, a hormone produced by fat cells, functions as a sentinel of energy balance, and may mediate the putative positive effects of body mass on bone. We performed studies in male C57Bl/6 wild type (WT) and leptin-deficient ob/ob mice to determine whether body mass gain induced by high fat intake increases bone mass and, if so, whether this requires central leptin signaling. The relationship between body mass and bone mass and archite...

  9. Serotonin 5-HT2C receptor-independent expression of hypothalamic NOR1, a novel modulator of food intake and energy balance, in mice

    Energy Technology Data Exchange (ETDEWEB)

    Nonogaki, Katsunori, E-mail: knonogaki-tky@umin.ac.jp [Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine (Japan); Department of Lifestyle Medicine, Biomedical Engineering Center, Tohoku University (Japan); Kaji, Takao [Department of Lifestyle Medicine, Biomedical Engineering Center, Tohoku University (Japan); Ohba, Yukie; Sumii, Makiko [Center of Excellence, Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine (Japan); Wakameda, Mamoru; Tamari, Tomohiro [Charles River Laboratories Japan, Inc. (Japan)

    2009-08-21

    NOR1, Nur77 and Nurr1 are orphan nuclear receptors and members of the NR4A subfamily. Here, we report that the expression of hypothalamic NOR1 was remarkably decreased in mildly obese {beta}-endorphin-deficient mice and obese db/db mice with the leptin receptor mutation, compared with age-matched wild-type mice, whereas there were no genotypic differences in the expression of hypothalamic Nur77 or Nurr1 in these animals. The injection of NOR1 siRNA oligonucleotide into the third cerebral ventricle significantly suppressed food intake and body weight in mice. On the other hand, the decreases in hypothalamic NOR1 expression were not found in non-obese 5-HT2C receptor-deficient mice. Moreover, systemic administration of m-chlorophenylpiperazine (mCPP), a 5-HT2C/1B receptor agonist, had no effect on hypothalamic NOR1 expression, while suppressing food intake in {beta}-endorphin-deficient mice. These findings suggest that 5-HT2C receptor-independent proopiomelanocortin-derived peptides regulate the expression of hypothalamic NOR1, which is a novel modulator of feeding behavior and energy balance.

  10. Effects of low-intensity pulsed electromagnetic fields on bone microarchitecture, mechanical strength and bone turnover in type 2 diabetic db/db mice.

    Science.gov (United States)

    Li, Jianjun; Zeng, Zhaobin; Zhao, Yantao; Jing, Da; Tang, Chuhua; Ding, Yin; Feng, Xue

    2017-09-07

    Type 2 diabetic patients have impaired bone quality, leading to increased fracture risk. Substantial evidence demonstrates that pulsed electromagnetic fields (PEMF) could resist osteopenia/osteoporosis induced by estrogen deficiency and disuse. However, the effects of PEMF on osteopenia/osteoporosis associated with diabetes, especially for more prevalent type 2 diabetes, remain poorly understood. We herein investigated the skeletal effects and mechanisms of PEMF (15 Hz, 20 Gs) on leptin receptor-deficient db/db mice with typical type 2 diabetic symptoms. Our µCT results showed that 12-week PEMF exposure significantly improved both cancellous and cortical bone microarchitecture in db/db mice. Three-point bending and biomechanical indentation testing demonstrated that PEMF improved whole-bone structural properties and tissue-level material properties in db/db mice. PEMF significantly promoted bone formation in db/db mice evidenced by increased serum osteocalcin and bone mineral apposition rate, whereas PEMF exerted no observable alteration in bone resorption. Real-time PCR showed that PEMF upregulated tibial gene expression of osteoblastogenesis-related of canonical Wnt/β-catenin signaling but not osteoclastogenesis-related RANKL-RANK signaling in db/db mice. Our findings demonstrate that PEMF improved bone quantity and quality with obvious anabolic activities in db/db mice, and imply that PEMF might become a clinically applicable treatment modality for improving bone quality in type 2 diabetic patients.

  11. Serotonin 5-HT2C receptor-independent expression of hypothalamic NOR1, a novel modulator of food intake and energy balance, in mice

    International Nuclear Information System (INIS)

    Nonogaki, Katsunori; Kaji, Takao; Ohba, Yukie; Sumii, Makiko; Wakameda, Mamoru; Tamari, Tomohiro

    2009-01-01

    NOR1, Nur77 and Nurr1 are orphan nuclear receptors and members of the NR4A subfamily. Here, we report that the expression of hypothalamic NOR1 was remarkably decreased in mildly obese β-endorphin-deficient mice and obese db/db mice with the leptin receptor mutation, compared with age-matched wild-type mice, whereas there were no genotypic differences in the expression of hypothalamic Nur77 or Nurr1 in these animals. The injection of NOR1 siRNA oligonucleotide into the third cerebral ventricle significantly suppressed food intake and body weight in mice. On the other hand, the decreases in hypothalamic NOR1 expression were not found in non-obese 5-HT2C receptor-deficient mice. Moreover, systemic administration of m-chlorophenylpiperazine (mCPP), a 5-HT2C/1B receptor agonist, had no effect on hypothalamic NOR1 expression, while suppressing food intake in β-endorphin-deficient mice. These findings suggest that 5-HT2C receptor-independent proopiomelanocortin-derived peptides regulate the expression of hypothalamic NOR1, which is a novel modulator of feeding behavior and energy balance.

  12. Leptin differentially regulates chondrogenesis in mouse vertebral and tibial growth plates.

    Science.gov (United States)

    Yu, Bo; Jiang, Kaibiao; Chen, Bin; Wang, Hantao; Li, Xinfeng; Liu, Zude

    2017-05-31

    Leptin plays an important role in mediating chondrogenesis of limb growth plate. Previous studies suggest that bone structures and development of spine and limb are different. The expression of Ob-Rb, the gene that encodes leptin receptors, is vertebral and appendicular region-specific, suggesting the regulation of leptin on VGP and TGP chondrogenesis may be very different. The aim of the present study was to investigate the differential regulation of leptin on the chondrogenesis of vertebral growth plate (VGP) and tibial growth plate (TGP). We compared the VGP and TGP from wild type (C57BL/6) and leptin-deficient (ob/ob) mice. We then generated primary cultures of TGP and VGP chondrocytes. By treating the primary cells with different concentrations of leptin in vitro, we analyzed proliferation and apoptosis of the primary chondrocytes from TGP and VGP. We further measured expression of chondrogenic-related genes in these cells that had been incubated with different doses of leptin. Leptin-deficient mice of 8-week-old had shorter tibial and longer vertebral lengths than the wide type mice. Disturbed columnar structure was observed for TGP but not for VGP. In primary chondrocyte cultures, leptin inhibited VGP chondrocyte proliferation but promoted their apoptosis. Collagen IIA and aggrecan mRNA, and the protein levels of proliferation- and chondrogenesis-related markers, including PCNA, Sox9, and Smad4, were downregulated by leptin in a dose-dependent manner. In contrast, leptin stimulated the proliferation and chondrogenic differentiation of TGP chondrocytes at physiological levels (i.e., 10 and 50 ng/mL) but not at high levels (i.e., 100 and 1000 ng/mL). Leptin exerts a stimulatory effect on the proliferation and chondrogenic differentiation of the long bone growth plate but an inhibitory effect on the spine growth plate. The ongoing study will shed light on the regulatory mechanisms of leptin in bone development and metabolism.

  13. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice

    NARCIS (Netherlands)

    Everard, A.; Derrien, M.M.N.; Possemiers, S.; Vos, de W.M.; Delzenne, N.M.; Schrenzel, J.; Cani, P.D.

    2011-01-01

    OBJECTIVE To investigate deep and comprehensive analysis of gut microbial communities and biological parameters after prebiotic administration in obese and diabetic mice. RESEARCH DESIGN AND METHODS Genetic (ob/ob) or diet-induced obese and diabetic mice were chronically fed with prebiotic-enriched

  14. Leptin differentially regulate STAT3 activation in ob/ob mouse adipose mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    Zhou Zhou

    2012-12-01

    Full Text Available Abstract Background Leptin-deficient ob/ob mice exhibit adipocyte hypertrophy and hyperplasia as well as elevated adipose tissue and systemic inflammation. Multipotent stem cells isolated from adult adipose tissue can differentiate into adipocytes ex vivo and thereby contribute toward increased adipocyte cell numbers, obesity, and inflamm ation. Currently, information is lacking regarding regulation of adipose stem cell numbers as well as leptin-induced inflammation and its signaling pathway in ob/ob mice. Methods Using leptin deficient ob/ob mice, we investigated whether leptin injection into ob/ob mice increases adipose stem cell numbers and adipose tissue inflammatory marker MCP-1 mRNA and secretion levels. We also determined leptin mediated signaling pathways in the adipose stem cells. Results We report here that adipose stem cell number is significantly increased following leptin injection in ob/ob mice and with treatment of isolated stem cells with leptin in vitro. Leptin also up-regulated MCP-1 secretion in a dose- and time-dependent manner. We further showed that increased MCP-1 mRNA levels were due to increased phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3 Ser727 but not STAT3 Tyr705 phosphorylation, suggesting differential regulation of MCP-1 gene expression under basal and leptin-stimulated conditions in adipose stem cells. Conclusions Taken together, these studies demonstrate that leptin increases adipose stem cell number and differentially activates STAT3 protein resulting in up-regulation of MCP-1 gene expression. Further studies of mechanisms mediating adipose stem cell hyperplasia and leptin signaling in obesity are warranted and may help identify novel anti-obesity target strategies.

  15. Proinflammatory adipokine leptin mediates disinfection byproduct bromodichloromethane-induced early steatohepatitic injury in obesity

    Energy Technology Data Exchange (ETDEWEB)

    Das, Suvarthi [Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208 (United States); Kumar, Ashutosh [Free Radical Metabolism Group, Laboratory of Toxicology and Pharmacology, Research Triangle Park, NC 27709 (United States); Seth, Ratanesh Kumar [Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208 (United States); Tokar, Erik J. [Inorganic Toxicology Group, National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Kadiiska, Maria B. [Free Radical Metabolism Group, Laboratory of Toxicology and Pharmacology, Research Triangle Park, NC 27709 (United States); Waalkes, Michael P. [Inorganic Toxicology Group, National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Mason, Ronald P. [Free Radical Metabolism Group, Laboratory of Toxicology and Pharmacology, Research Triangle Park, NC 27709 (United States); Chatterjee, Saurabh, E-mail: schatt@mailbox.sc.edu [Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208 (United States)

    2013-06-15

    Today's developed world faces a major public health challenge in the rise in the obese population and the increased incidence in fatty liver disease. There is a strong association among diet induced obesity, fatty liver disease and development of nonalcoholic steatohepatitis but the environmental link to disease progression remains unclear. Here we demonstrate that in obesity, early steatohepatitic lesions induced by the water disinfection byproduct bromodichloromethane are mediated by increased oxidative stress and leptin which act in synchrony to potentiate disease progression. Low acute exposure to bromodichloromethane (BDCM), in diet-induced obesity produced oxidative stress as shown by increased lipid peroxidation, protein free radical and nitrotyrosine formation and elevated leptin levels. Exposed obese mice showed histopathological signs of early steatohepatitic injury and necrosis. Spontaneous knockout mice for leptin or systemic leptin receptor knockout mice had significantly decreased oxidative stress and TNF-α levels. Co-incubation of leptin and BDCM caused Kupffer cell activation as shown by increased MCP-1 release and NADPH oxidase membrane assembly, a phenomenon that was decreased in Kupffer cells isolated from leptin receptor knockout mice. In obese mice that were BDCM-exposed, livers showed a significant increase in Kupffer cell activation marker CD68 and, increased necrosis as assessed by levels of isocitrate dehydrogenase, events that were decreased in the absence of leptin or its receptor. In conclusion, our results show that exposure to the disinfection byproduct BDCM in diet-induced obesity augments steatohepatitic injury by potentiating the effects of leptin on oxidative stress, Kupffer cell activation and cell death in the liver. - Highlights: ► BDCM acute exposure sensitizes liver to increased free radical stress in obesity. ► BDCM-induced higher leptin contributes to early steatohepatitic lesions. ► Increased leptin mediates

  16. Deteriorated glucose metabolism with a high-protein, low-carbohydrate diet in db mice, an animal model of type 2 diabetes, might be caused by insufficient insulin secretion.

    Science.gov (United States)

    Arimura, Emi; Pulong, Wijang Pralampita; Marchianti, Ancah Caesarina Novi; Nakakuma, Miwa; Abe, Masaharu; Ushikai, Miharu; Horiuchi, Masahisa

    2017-02-01

    We previously showed the deleterious effects of increased dietary protein on renal manifestations and glucose metabolism in leptin receptor-deficient (db) mice. Here, we further examined its effects on glucose metabolism, including urinary C-peptide. We also orally administered mixtures corresponding to low- or high-protein diets to diabetic mice. In diet experiments, under pair-feeding (equivalent energy and fat) conditions using a metabolic cage, mice were fed diets with different protein content (L diet: 12 % protein, 71 % carbohydrate, 17 % fat; H diet: 24 % protein, 59 % carbohydrate, 17 % fat) for 15 days. In oral administration experiments, the respective mixtures (L mixture: 12 % proline, 71 % maltose or starch, 17 % linoleic acid; H mixture: 24 % proline, 59 % maltose or starch, 17 % linoleic acid) were supplied to mice. Biochemical parameters related to glucose metabolism were measured. The db-H diet mice showed significantly higher water intake, urinary volume, and glucose levels than db-L diet mice but similar levels of excreted urinary C-peptide. In contrast, control-H diet mice showed significantly higher C-peptide excretion than control-L diet mice. Both types of mice fed H diet excreted high levels of urinary albumin. When maltose mixtures were administered, db-L mixture mice showed significantly higher blood glucose after 30 min than db-H mixture mice. However, db mice administered starch-H mixture showed significantly higher blood glucose 120-300 min post-administration than db-L mixture mice, although both groups exhibited similar insulin levels. High-protein, low-carbohydrate diets deteriorated diabetic conditions and were associated with insufficient insulin secretion in db mice. Our findings may have implications for dietary management of diabetic symptoms in human patients.

  17. Pharmacokinetics (PK), Pharmacodynamics (PD) and Integrated PK/PD Modeling of a Novel Long Acting FGF21 Clinical Candidate PF-05231023 in Diet-Induced Obese and Leptin-Deficient Obese Mice

    Science.gov (United States)

    Bernardo, Barbara; Yan, Qingyun; Zhu, Yimin; Brenner, Martin B.; Vage, Chandra; Logan, Alison; Calle, Roberto; Talukdar, Saswata

    2015-01-01

    Pharmacological administration of fibroblast growth factor 21 (FGF21) improves metabolic profile in preclinical species and humans. FGF21 exerts its metabolic effects through formation of beta-klotho (KLB)/FGF receptor 1c FGFR1c complex and subsequent signaling. Data from various in vitro systems demonstrate the intact C- and N-terminus of FGF21 is required for binding with KLB, and interaction with FGFR1c, respectively. However the relative roles of the termini for in vivo pharmacological effects are unclear. Here we report PF-05231023, a long-acting FGF21 analogue which is unique in that the half-life and subcutaneous (SC) bioavailability of the intact C-terminus are significantly different from those of the intact N-terminus (2 vs. 22 hr for half-life and 4~7 vs. ~50% SC bioavailability). Therefore, this molecule serves as a valuable tool to evaluate the relative roles of intact C-terminus vs. N-terminus in in vivo pharmacology studies in preclinical species. We determined the effects of PF-05231023 administration on body weight (BW) loss and glucose reduction during an oral glucose tolerance test (OGTT) following SC and intravenous (IV) administration in diet-induced obese (DIO) and leptin-deficient obese (ob/ob) mice, respectively. Our data show that the intact N-terminus of FGF21 in PF-05231023 appears to be sufficient to drive glucose lowering during OGTT and sustain BW loss in DIOs. Further, PK/PD modeling suggests that while the intact FGF21 C-terminus is not strictly required for glucose lowering during OGTT in ob/ob mice or for BW reduction in DIO mice, the higher potency conferred by intact C-terminus contributes to a rapid initiation of pharmacodynamic effects immediately following dosing. These results provide additional insight into the strategy of developing stabilized versions of FGF21 analogs to harness the full spectrum of its metabolic benefits. PMID:25790234

  18. Correlation of the leptin

    DEFF Research Database (Denmark)

    Finucane, F; Luan, J; Wareham, N

    2009-01-01

    AIMS/HYPOTHESIS: Obesity is the dominant cause of insulin resistance. In adult humans it is characterised by a combination of adipocyte hypertrophy and, to a lesser extent, adipocyte hyperplasia. As hypertrophic adipocytes secrete more leptin and less adiponectin, the plasma leptin......:adiponectin ratio (LAR) has been proposed as a potentially useful measure of insulin resistance and vascular risk. We sought to assess the usefulness of the LAR as a measure of insulin resistance in non-diabetic white adults. METHODS: Leptin and adiponectin levels were measured in 2,097 non-diabetic individuals...... from the Ely and European Group for the Study of Insulin Resistance (EGIR) Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study cohorts. LAR was compared with fasting insulin and HOMA-derived insulin sensitivity (HOMA-S) in all individuals and with the insulin sensitivity index...

  19. An age-dependent interaction with leptin unmasks ghrelin's bone-protective effects

    Science.gov (United States)

    The mutual interplay between energy homeostasis and bone metabolism is an important emerging concept. Ghrelin and leptin antagonize each other in regulating energy balance, but the role of this interaction in bone metabolism is unknown. Using ghrelin receptor and leptin-deficient mice, we show that ...

  20. Phenotypic Dichotomy Following Developmental Exposure to Perfluorooctanic Acid (PFOA) Exposure in CD-1 Mice: Low Doses Induce Elevated Serum, Leptin, Insulin, and Overweight in Mid-Life.

    Science.gov (United States)

    The synthetic surfactant, perfluorooctanoic acid (PFOA) is a proven developmental toxicant in mice, causing prenatal pregnancy loss, increased neonatal mortality, delayed eye opening, and abnormal mammary gland growth in animals exposed during fetal life. PFOA is found in the ser...

  1. Leptin potentiates GABAergic synaptic transmission in the developing rodent hippocampus.

    Directory of Open Access Journals (Sweden)

    Damien eGuimond

    2014-08-01

    Full Text Available It is becoming increasingly clear that leptin is not only a hormone regulating energy homeostasis but also a neurotrophic factor impacting a number of brain regions, including the hippocampus. Although leptin promotes the development of GABAergic transmission in the hypothalamus, little is known about its action on the GABAergic system in the hippocampus. Here we show that leptin modulates GABAergic transmission onto developing CA3 pyramidal cells of newborn rats. Specifically, leptin induces a long-lasting potentiation (LLP-GABAA of miniature GABAA receptor-mediated postsynaptic current (GABAA-PSC frequency. Leptin also increases the amplitude of evoked GABAA-PSCs in a subset of neurons along with a decrease in the coefficient of variation and no change in the paired-pulse ratio, pointing to an increased recruitment of functional synapses. Adding pharmacological blockers to the recording pipette showed that the leptin-induced LLP-GABAA requires postsynaptic calcium released from internal stores, as well as postsynaptic MAPK/ERK kinases 1 and/or 2 (MEK1/2, phosphoinositide 3 kinase (PI3K and calcium-calmodulin kinase kinase (CaMKK. Finally, study of CA3 pyramidal cells in leptin-deficient ob/ob mice revealed a reduction in the basal frequency of miniature GABAA-PSCs compared to wild type littermates. In addition, presynaptic GAD65 immunostaining was reduced in the CA3 stratum pyramidale of mutant animals, both results converging to suggest a decreased number of functional GABAergic synapses in ob/ob mice. Overall, these results show that leptin potentiates and promotes the development of GABAergic synaptic transmission in the developing hippocampus likely via an increase in the number of functional synapses, and provide insights into the intracellular pathways mediating this effect. This study further extends the scope of leptin’s neurotrophic action to a key regulator of hippocampal development and function, namely GABAergic transmission.

  2. Monitoring leptin activity using the chicken leptin receptor.

    Science.gov (United States)

    Hen, Gideon; Yosefi, Sera; Ronin, Ana; Einat, Paz; Rosenblum, Charles I; Denver, Robert J; Friedman-Einat, Miriam

    2008-05-01

    We report on the construction of a leptin bioassay based on the activation of chicken leptin receptor in cultured cells. A human embryonic kidney (HEK)-293 cell line, stably transfected with the full-length cDNA of chicken leptin receptor together with a STAT3-responsive reporter gene specifically responded to recombinant human and Xenopus leptins. The observed higher sensitivity of chicken leptin receptor to the former is in agreement with the degree of sequence similarity among these species (about 60 and 38% identical amino acids between humans and chickens, and between humans and Xenopus respectively). The specific activation of signal transduction through the chicken leptin receptor, shown here for the first time, suggests that the transition of Gln269 (implicated in the Gln-to-Pro Zucker fatty mutation in rats) to Glu in chickens does not impair its activity. Analysis of leptin-like activity in human serum samples of obese and lean subjects coincided well with leptin levels determined by RIA. Serum samples of pre- and post partum cows showed a tight correlation with the degree of adiposity. However, specific activation of the chicken leptin receptor in this assay was not observed with serum samples from broiler or layer chickens (representing fat and lean phenotypes respectively) or with those from turkey. Similar leptin receptor activation profiles were observed with cells transfected with human leptin receptor. Further work is needed to determine whether the lack of leptin-like activity in the chicken serum samples is due to a lack of leptin in this species or simply to a serum level of leptin that is below the detection threshold.

  3. Circulating leptin and thyroid dysfunction

    DEFF Research Database (Denmark)

    Zimmermann-Belsing, Tina; Brabant, Georg; Holst, Jens Juul

    2003-01-01

    the fields of nutrition, metabolism and endocrinology. Leptin is accepted as an adipose signal, and even though the underlying mechanisms are not fully clarified, leptin, in addition to the thyroid hormones, is believed to be involved in regulation during the switch from the fed to the starved state...... relationship between leptin and thyroid hormones, there might also be a peripheral relationship although this effect is not clear. Both thyroid hormones and leptin might be involved in the adaptive thermogenesis through mitochondrial uncoupling proteins and heat production because both thyroxine...... hormone involvement in thermogenesis and regulation of uncoupling proteins. In this review, we have focused on leptin in relation to thyroid pathophysiology....

  4. Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation.

    Science.gov (United States)

    Angle, Brittany M; Do, Rylee Phuong; Ponzi, Davide; Stahlhut, Richard W; Drury, Bertram E; Nagel, Susan C; Welshons, Wade V; Besch-Williford, Cynthia L; Palanza, Paola; Parmigiani, Stefano; vom Saal, Frederick S; Taylor, Julia A

    2013-12-01

    Exposure to bisphenol A (BPA) is implicated in many aspects of metabolic disease in humans and experimental animals. We fed pregnant CD-1 mice BPA at doses ranging from 5 to 50,000μg/kg/day, spanning 10-fold below the reference dose to 10-fold above the currently predicted no adverse effect level (NOAEL). At BPA doses below the NOAEL that resulted in average unconjugated BPA between 2 and 200pg/ml in fetal serum (AUC0-24h), we observed significant effects in adult male offspring: an age-related change in food intake, an increase in body weight and liver weight, abdominal adipocyte mass, number and volume, and in serum leptin and insulin, but a decrease in serum adiponectin and in glucose tolerance. For most of these outcomes non-monotonic dose-response relationships were observed; the highest BPA dose did not produce a significant effect for any outcome. A 0.1-μg/kg/day dose of DES resulted in some but not all low-dose BPA outcomes. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Leptin: a cardiovascular perspective

    African Journals Online (AJOL)

    Review Article: Leptin: a cardiovascular perspective. 72. 2012 Volume 17 No 2. JEMDSA. Introduction. Within the realms of noncommunicable disease development in South Africa, obesity is a disease that causes concern. This especially holds true for type 2 diabetes and cardiovascular diseases. Disheartened.

  6. Effects of sex steroid hormones and menopause on serum leptin concentrations.

    Science.gov (United States)

    Di Carlo, C; Tommaselli, G A; Nappi, C

    2002-12-01

    Leptin is a protein secreted by adipocytes; its circulating levels are correlated to fat mass and it acts on the hypothalamic centers regulating body weight. Leptin may also play an important role in regulating reproductive function. Indeed, ob/ob mice, lacking leptin due to a genetic mutation, are obese and infertile; administration of recombinant leptin to these animals reduces body weight and restores fertility. A sexual dimorphism in serum leptin levels has also been observed, with higher concentrations in women. Studies in vitro seem to indicate that estrogens stimulate leptin secretion, while in vivo studies are extremely discordant. In humans, several studies showed increased, unmodified and decreased leptin levels after the menopause. Furthermore, hormonal replacement therapy (HRT) after the menopause was reported to result in unmodified, increased or decreased leptin levels. It is likely that the effects of postmenopausal hypoestrogenism on leptin levels are masked by the postmenopausal changes in body composition. Indeed, after menopause, there is an increase in body weight, body mass index (BMI) and fat mass with a centralization of fat distribution. Administration of HRT may stop these changes and even restore a premenopausal pattern, leading then to decreased leptin levels.

  7. Proteomics Analysis of Skeletal Muscle from Leptin-Deficient ob/ob Mice Reveals Adaptive Remodeling of Metabolic Characteristics and Fiber Type Composition

    DEFF Research Database (Denmark)

    Schönke, Milena; Björnholm, Marie; Chibalin, Alexander V

    2018-01-01

    Skeletal muscle insulin resistance, an early metabolic defect in the pathogenesis of type 2 diabetes (T2D), may be a cause or consequence of altered protein expression profiles. Proteomics technology offers enormous promise to investigate molecular mechanisms underlying pathologies, however...... mice in mere two fractions in a short time (8 h per sample). We identified more than 6000 proteins with 118 proteins differentially regulated in obesity. This included protein kinases, phosphatases, and secreted and fiber type associated proteins. Enzymes involved in lipid metabolism in skeletal muscle...... from ob/ob mice were increased, providing evidence against reduced fatty acid oxidation in lipid-induced insulin resistance. Mitochondrial and peroxisomal proteins, as well as components of pyruvate and lactate metabolism, were increased. Finally, the skeletal muscle proteome from ob/ob mice displayed...

  8. Functional evolution of leptin of Ochotona curzoniae in adaptive thermogenesis driven by cold environmental stress.

    Directory of Open Access Journals (Sweden)

    Jie Yang

    Full Text Available BACKGROUND: Environmental stress can accelerate the directional selection and evolutionary rate of specific stress-response proteins to bring about new or altered functions, enhancing an organism's fitness to challenging environments. Plateau pika (Ochotona curzoniae, an endemic and keystone species on Qinghai-Tibetan Plateau, is a high hypoxia and low temperature tolerant mammal with high resting metabolic rate and non-shivering thermogenesis to cope in this harsh plateau environment. Leptin is a key hormone related to how these animals regulate energy homeostasis. Previous molecular evolutionary analysis helped to generate the hypothesis that adaptive evolution of plateau pika leptin may be driven by cold stress. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis, recombinant pika leptin was first purified. The thermogenic characteristics of C57BL/6J mice injected with pika leptin under warm (23±1°C and cold (5±1°C acclimation is investigated. Expression levels of genes regulating adaptive thermogenesis in brown adipose tissue and the hypothalamus are compared between pika leptin and human leptin treatment, suggesting that pika leptin has adaptively and functionally evolved. Our results show that pika leptin regulates energy homeostasis via reduced food intake and increased energy expenditure under both warm and cold conditions. Compared with human leptin, pika leptin demonstrates a superior induced capacity for adaptive thermogenesis, which is reflected in a more enhanced β-oxidation, mitochondrial biogenesis and heat production. Moreover, leptin treatment combined with cold stimulation has a significant synergistic effect on adaptive thermogenesis, more so than is observed with a single cold exposure or single leptin treatment. CONCLUSIONS/SIGNIFICANCE: These findings support the hypothesis that cold stress has driven the functional evolution of plateau pika leptin as an ecological adaptation to the Qinghai-Tibetan Plateau.

  9. PPAR agonist-induced reduction of Mcp1 in atherosclerotic plaques of obese, insulin-resistant mice depends on adiponectin-induced Irak3 expression.

    Directory of Open Access Journals (Sweden)

    Maarten Hulsmans

    Full Text Available Synthetic peroxisome proliferator-activated receptor (PPAR agonists are used to treat dyslipidemia and insulin resistance. In this study, we examined molecular mechanisms that explain differential effects of a PPARα agonist (fenofibrate and a PPARγ agonist (rosiglitazone on macrophages during obesity-induced atherogenesis. Twelve-week-old mice with combined leptin and LDL-receptor deficiency (DKO were treated with fenofibrate, rosiglitazone or placebo for 12 weeks. Only rosiglitazone improved adipocyte function, restored insulin sensitivity, and inhibited atherosclerosis by decreasing lipid-loaded macrophages. In addition, it increased interleukin-1 receptor-associated kinase-3 (Irak3 and decreased monocyte chemoattractant protein-1 (Mcp1 expressions, indicative of a switch from M1 to M2 macrophages. The differences between fenofibrate and rosiglitazone were independent of Pparγ expression. In bone marrow-derived macrophages (BMDM, we identified the rosiglitazone-associated increase in adiponectin as cause of the increase in Irak3. Interestingly, the deletion of Irak3 in BMDM (IRAK3(-/- BMDM resulted in activation of the canonical NFκB signaling pathway and increased Mcp1 protein secretion. Rosiglitazone could not decrease the elevated Mcp1 secretion in IRAK3(-/- BMDM directly and fenofibrate even increased the secretion, possibly due to increased mitochondrial reactive oxygen species production. Furthermore, aortic extracts of high-fat insulin-resistant LDL-receptor deficient mice, with lower adiponectin and Irak3 and higher Mcp1, showed accelerated atherosclerosis. In aggregate, our results emphasize an interaction between PPAR agonist-mediated increase in adiponectin and macrophage-associated Irak3 in the protection against atherosclerosis by PPAR agonists.

  10. Effect of Green Tea Extract-Enriched Diets on Insulin and Leptin Levels, Oxidative Stress Parameters and Antioxidant Enzymes Activities in Obese Mice

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    Bártíková Hana

    2017-09-01

    Full Text Available Green tea and green tea extracts (GTE are often incorporated into diet intended to weight reduction, although the information about their efficacy in obese individuals is insufficient. The present study was designed to follow up the effect of defined and standardized GTE in mice with obesity induced by monosodium L-glutamate. Obese mice were fed with GTE-supplemented diet in three dosage regimens: 28-day and 3-day intake of 1 g GTE in 1 kg of diet and 28-day intake of 0.1 g GTE in 1 kg of diet. The information on body weight, food intake, oxidation stress parameters in blood and antioxidant enzymes activity in liver and small intestine was obtained. High doses of GTE decreased the specific activities of glutathione reductase and catalase and increased concentrations of malondialdehyde in blood. Specific activities of antioxidant enzymes in the liver and small intestine were not altered after GTE treatment except the decrease of NAD(PH:quinone oxidoreductase activity. Our results showed that GTE did not affect average body weight and did not markedly improve antioxidant status in glutamate-induced obese mice. Moreover, intake of high doses of GTE made antioxidant defense in obese animals even worse.

  11. Pharmacokinetics (PK, pharmacodynamics (PD and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF-05231023 in diet-induced obese and leptin-deficient obese mice.

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    Yan Weng

    Full Text Available Pharmacological administration of fibroblast growth factor 21 (FGF21 improves metabolic profile in preclinical species and humans. FGF21 exerts its metabolic effects through formation of beta-klotho (KLB/FGF receptor 1c FGFR1c complex and subsequent signaling. Data from various in vitro systems demonstrate the intact C- and N-terminus of FGF21 is required for binding with KLB, and interaction with FGFR1c, respectively. However the relative roles of the termini for in vivo pharmacological effects are unclear. Here we report PF-05231023, a long-acting FGF21 analogue which is unique in that the half-life and subcutaneous (s.c. bioavailability of the intact C-terminus are significantly different from those of the intact N-terminus (2 vs. 22 hr for half-life and 4~7 vs. ~50% SC bioavailability. Therefore, this molecule serves as a valuable tool to evaluate the relative roles of intact C-terminus vs. N-terminus in in vivo pharmacology studies in preclinical species. We determined the effects of PF-05231023 administration on body weight (BW loss and glucose reduction during an oral glucose tolerance test (OGTT following SC and intravenous (i.v. administration in diet-induced obese (DIO and leptin-deficient obese (ob/ob mice, respectively. Our data show that the intact N-terminus of FGF21 in PF-05231023 appears to be sufficient to drive glucose lowering during OGTT and sustain BW loss in DIOs. Further, PK/PD modeling suggests that while the intact FGF21 C-terminus is not strictly required for glucose lowering during OGTT in ob/ob mice or for BW reduction in DIO mice, the higher potency conferred by intact C-terminus contributes to a rapid initiation of pharmacodynamic effects immediately following dosing. These results provide additional insight into the strategy of developing stabilized versions of FGF21 analogs to harness the full spectrum of its metabolic benefits.

  12. Leptin-induced RORγt expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus1

    OpenAIRE

    Yu, Yiyun; Liu, Yaoyang; Shi, Fu-Dong; Zou, Hejian; Matarese, Giuseppe; Cava, Antonio La

    2013-01-01

    Th17 CD4+ cells promote inflammation and autoimmunity. Here we report that Th17 cell frequency is reduced in ob/ob mice that are genetically deficient in the adipokine leptin, and that the administration of leptin to ob/ob mice restored Th17 cell numbers to values comparable to those found in wild type animals. Leptin promoted Th17 responses in normal human CD4+ T cells and in mice, both in vitro and in vivo, by inducing RORγt transcription. Leptin also increased Th17 responses in (NZB × NZW)...

  13. Weight-loss changes PPAR expression, reduces atherosclerosis and improves cardiovascular function in obese insulin-resistant mice

    Energy Technology Data Exchange (ETDEWEB)

    Verreth, Wim; Verhamme, Peter; Pelat, Michael; Ganame, Javier; Bielicki, John K.; Mertens, Ann; Quarck, Rozenn; Benhabiles, Nora; Marguerie, Gerard; Mackness, Bharti; Mackness, Mike; Ninio, Ewa; Herregods, Marie-Christine; Balligand, Jean-Luc; Holvoet, Paul

    2003-09-01

    Weight-loss in obese insulin-resistant, but not in insulin-sensitive, persons reduces CHD risk. It is not known to what extent changes in the adipose gene expression profile are important for reducing CHD risk. We studied the effect of diet restriction-induced weight-loss on gene expression in adipose tissue, atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia and insulin-resistance are associated with hypertension, impaired left ventricle function and accelerated atherosclerosis in those mice. Diet restriction during 12 weeks caused a 45% weight-loss and changes in the gene expression in adipose tissue of PPARa and PPAR? and of key genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. These changes were associated with increased insulin-sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. Thus, induction of PPARa and PPAR? in adipose tissue is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight-loss. Our observations point to the critical role of PPARs in the pathogenesis of cardiovascular features of the metabolic syndrome.

  14. Leptin Downregulates LPS-Induced Lung Injury: Role of Corticosterone and Insulin

    Directory of Open Access Journals (Sweden)

    Maristella A. Landgraf

    2014-03-01

    Full Text Available Background/Aims: We investigated the effects of leptin in the development of lipopolysaccharide (LPS-induced acute lung inflammation (ALI in lean mice. Methods: Mice were administered leptin (1.0µg/g or leptin (1.0µg/g followed by LPS (1.5µg/g intranasally. Additionally, some animals were given LPS (1.5µg/g or saline intranasally alone, as a control. Tissue samples and fluids were collected six hours after instillation. Results: We demonstrated that leptin alone did not induce any injury. Local LPS exposure resulted in significant acute lung inflammation, characterized by a substantial increase in total cells, mainly neutrophils, in bronchoalveolar lavages (BAL. We also observed a significant lymphocyte influx into the lungs associated with enhanced lung expression of chemokines and cytokines (KC, RANTES, TNF-α, IFN-γ, GM-CSF and VEGF. LPS-induced ALI was characterized by the enhanced expression of ICAM-1 and iNOS in the lungs. Mice that received LPS showed an increase in insulin levels. Leptin, when administered prior to LPS instillation, abolished all of these effects. LPS induced an increase in corticosterone levels, and leptin potentiated this event. Conclusion: These data suggest that exogenous leptin may promote protection during sepsis, and downregulation of the insulin levels and upregulation of corticosterone may be important mechanisms in the amelioration of LPS-induced ALI.

  15. Dapagliflozin-lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice.

    Science.gov (United States)

    Åstrand, Annika; Wingren, Cecilia; Benjamin, Audra; Tregoning, John S; Garnett, James P; Groves, Helen; Gill, Simren; Orogo-Wenn, Maria; Lundqvist, Anders J; Walters, Dafydd; Smith, David M; Taylor, John D; Baker, Emma H; Baines, Deborah L

    2017-05-01

    Hyperglycaemia increases glucose concentrations in airway surface liquid and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti-diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice. The effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6J (wild type, WT) or leptin receptor-deficient (db/db) mice, treated orally with dapagliflozin prior to intranasal dosing with LPS or inoculation with P. aeruginosa. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid-filled lung technique. Fasting blood, airway glucose and lactate concentrations were elevated in the db/db mouse lung. LPS challenge increased inflammatory cells in bronchoalveolar lavage fluid from WT and db/db mice with and without dapagliflozin treatment. P. aeruginosa colony-forming units (CFU) were increased in db/db lungs. Pretreatment with dapagliflozin reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in db/db mice towards those seen in WT. Dapagliflozin had no adverse effects on the inflammatory response in the mouse or pulmonary glucose transport or fluid absorption in the rat lung. Pharmacological lowering of blood glucose with dapagliflozin effectively reduced P. aeruginosa infection in the lungs of diabetic mice and had no adverse pulmonary effects in the rat. Dapagliflozin has potential to reduce the use, or augment the effect, of antimicrobials in the prevention or treatment of pulmonary infection. © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

  16. Insulin and Leptin Signaling Interact in the Mouse Kiss1 Neuron during the Peripubertal Period.

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    Xiaoliang Qiu

    Full Text Available Reproduction requires adequate energy stores for parents and offspring to survive. Kiss1 neurons, which are essential for fertility, have the potential to serve as the central sensors of metabolic factors that signal to the reproductive axis the presence of stored calories. Paradoxically, obesity is often accompanied by infertility. Despite excess circulating levels of insulin and leptin, obese individuals exhibit resistance to both metabolic factors in many neuron types. Thus, resistance to insulin or leptin in Kiss1 neurons could lead to infertility. Single deletion of the receptors for either insulin or the adipokine leptin from Kiss1 neurons does not impair adult reproductive dysfunction. However, insulin and leptin signaling pathways may interact in such a way as to obscure their individual functions. We hypothesized that in the presence of genetic or obesity-induced concurrent insulin and leptin resistance, Kiss1 neurons would be unable to maintain reproductive function. We therefore induced a chronic hyperinsulinemic and hyperleptinemic state in mice lacking insulin receptors in Kiss1 neurons through high fat feeding and examined the impact on fertility. In an additional, genetic model, we ablated both leptin and insulin signaling in Kiss1 neurons (IR/LepRKiss mice. Counter to our hypothesis, we found that the addition of leptin insensitivity did not alter the reproductive phenotype of IRKiss mice. We also found that weight gain, body composition, glucose and insulin tolerance were normal in mice of both genders. Nonetheless, leptin and insulin receptor deletion altered pubertal timing as well as LH and FSH levels in mid-puberty in a reciprocal manner. Our results confirm that Kiss1 neurons do not directly mediate the critical role that insulin and leptin play in reproduction. However, during puberty kisspeptin neurons may experience a critical window of susceptibility to the influence of metabolic factors that can modify the onset of

  17. Circulating leptin and thyroid dysfunction

    DEFF Research Database (Denmark)

    Zimmermann-Belsing, Tina; Brabant, Georg; Holst, Jens Juul

    2003-01-01

    the fields of nutrition, metabolism and endocrinology. Leptin is accepted as an adipose signal, and even though the underlying mechanisms are not fully clarified, leptin, in addition to the thyroid hormones, is believed to be involved in regulation during the switch from the fed to the starved state....... It is not clear whether leptin and the melanocortin pathways interact with the thyroid axis under physiological conditions other than during starvation or in response to severe illness, both states in which the hypothalamo-pituitary-thyroid axis may be severely suppressed. In addition to the suggested central...... relationship between leptin and thyroid hormones, there might also be a peripheral relationship although this effect is not clear. Both thyroid hormones and leptin might be involved in the adaptive thermogenesis through mitochondrial uncoupling proteins and heat production because both thyroxine...

  18. IGF-1R and Leptin Expression Profile and the Effects of Metformin Treatment on Metabolic and Endocrine Parameters in PCOS Mice

    Directory of Open Access Journals (Sweden)

    Luis Eduardo Prado Correia

    2017-01-01

    Full Text Available We aim to assess the effects of metformin treatment on metabolic and endocrine parameters and genes expression related to the insulin-responsive pathway in polycystic ovary syndrome (PCOS. This study comprises twenty-eight obese mice divided into three metformin-treated groups for seven and twenty days and eight nonobese and nontreated ones. We found a significant decrease in glycemia after metformin treatment at days seven and twenty. However, we did not observe differences in body weight measurement. Histologically, after twenty days we observed follicular development with regression of androgenic effects. Levels of IGF-1R protein expression were low after twenty days of treatment, but LEP proteins showed an overexpression in the ovarian stroma. We assessed the IGF-1R and LEP mRNAs levels; data showed a significant overexpression of LEP after seven days of treatment, while the IGF-1R was downregulated. Metformin therapy seems to exert a beneficial effect on histological and anovulatory features, reducing follicular number and pyknosis formation, possibly involved in the reversion of androgenic stimulus. Expression of IGF-1 and LEPR indicates a relevant role in androgenic features reversion present in PCOS, hormonal equilibrium, body weight regulation, and glucose metabolism, therefore, under phenotype obesity and infertility regulation in this model.

  19. A new leptin-mediated mechanism for stimulating fatty acid oxidation: a pivotal role for sarcolemmal FAT/CD36.

    Science.gov (United States)

    Momken, Iman; Chabowski, Adrian; Dirkx, Ellen; Nabben, Miranda; Jain, Swati S; McFarlan, Jay T; Glatz, Jan F C; Luiken, Joost J F P; Bonen, Arend

    2017-01-01

    Leptin stimulates fatty acid oxidation in muscle and heart; but, the mechanism by which these tissues provide additional intracellular fatty acids for their oxidation remains unknown. We examined, in isolated muscle and cardiac myocytes, whether leptin, via AMP-activated protein kinase (AMPK) activation, stimulated fatty acid translocase (FAT/CD36)-mediated fatty acid uptake to enhance fatty acid oxidation. In both mouse skeletal muscle and rat cardiomyocytes, leptin increased fatty acid oxidation, an effect that was blocked when AMPK phosphorylation was inhibited by adenine 9-β-d-arabinofuranoside or Compound C. In wild-type mice, leptin induced the translocation of FAT/CD36 to the plasma membrane and increased fatty acid uptake into giant sarcolemmal vesicles and into cardiomyocytes. In muscles of FAT/CD36-KO mice, and in cardiomyocytes in which cell surface FAT/CD36 action was blocked by sulfo-N-succinimidyl oleate, the leptin-stimulated influx of fatty acids was inhibited; concomitantly, the normal leptin-stimulated increase in fatty acid oxidation was also prevented, despite the normal leptin-induced increase in AMPK phosphorylation. Conversely, in muscle of AMPK kinase-dead mice, leptin failed to induce the translocation of FAT/CD36, along with a failure to stimulate fatty acid uptake and oxidation. Similarly, when siRNA was used to reduce AMPK in HL-1 cardiomyocytes, leptin failed to induce the translocation of FAT/CD36. Our studies have revealed a novel mechanism of leptin-induced fatty acid oxidation in muscle tissue; namely, this process is dependent on the activation of AMPK to induce the translocation of FAT/CD36 to the plasma membrane, thereby stimulating fatty acid uptake. Without increasing this leptin-stimulated, FAT/CD36-dependent fatty acid uptake process, leptin-stimulated AMPK phosphorylation does not enhance fatty acid oxidation. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  20. Hypothalamic CART is a new anorectic peptide regulated by leptin.

    Science.gov (United States)

    Kristensen, P; Judge, M E; Thim, L; Ribel, U; Christjansen, K N; Wulff, B S; Clausen, J T; Jensen, P B; Madsen, O D; Vrang, N; Larsen, P J; Hastrup, S

    1998-05-07

    The mammalian hypothalamus strongly influences ingestive behaviour through several different signalling molecules and receptor systems. Here we show that CART (cocaine- and amphetamine-regulated transcript), a brain-located peptide, is a satiety factor and is closely associated with the actions of two important regulators of food intake, leptin and neuropeptide Y. Food-deprived animals show a pronounced decrease in expression of CART messenger RNA in the arcuate nucleus. In animal models of obesity with disrupted leptin signalling, CART mRNA is almost absent from the arcuate nucleus. Peripheral administration of leptin to obese mice stimulates CART mRNA expression. When injected intracerebroventricularly into rats, recombinant CART peptide inhibits both normal and starvation-induced feeding, and completely blocks the feeding response induced by neuropeptide Y. An antiserum against CART increases feeding in normal rats, indicating that CART may be an endogenous inhibitor of food intake in normal animals.

  1. Cutting edge: Leptin-induced RORγt expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus.

    Science.gov (United States)

    Yu, Yiyun; Liu, Yaoyang; Shi, Fu-Dong; Zou, Hejian; Matarese, Giuseppe; La Cava, Antonio

    2013-04-01

    Th17 CD4(+) cells promote inflammation and autoimmunity. In this study, we report that Th17 cell frequency is reduced in ob/ob mice (that are genetically deficient in the adipokine leptin) and that the administration of leptin to ob/ob mice restored Th17 cell numbers to values comparable to those found in wild-type animals. Leptin promoted Th17 responses in normal human CD4(+) T cells and in mice, both in vitro and in vivo, by inducing RORγt transcription. Leptin also increased Th17 responses in (NZB × NZW)F1 lupus-prone mice, whereas its neutralization in those autoimmune-prone mice inhibited Th17 responses. Because Th17 cells play an important role in the development and maintenance of inflammation and autoimmunity, these findings envision the possibility to modulate abnormal Th17 responses via leptin manipulation, and they reiterate the link between metabolism/nutrition and susceptibility to autoimmunity.

  2. Modeling the impact of growth and leptin deficits on the neuronal regulation of blood pressure.

    Science.gov (United States)

    Steinbrekera, Baiba; Roghair, Robert

    2016-11-01

    The risk of hypertension is increased by intrauterine growth restriction (IUGR) and preterm birth. In the search for modifiable etiologies for this life-threatening cardiovascular morbidity, a number of pathways have been investigated, including excessive glucocorticoid exposure, nutritional deficiency and aberration in sex hormone levels. As a neurotrophic hormone that is intimately involved in the cardiovascular regulation and whose levels are influenced by glucocorticoids, nutritional status and sex hormones, leptin has emerged as a putative etiologic and thus a therapeutic agent. As a product of maternal and late fetal adipocytes and the placenta, circulating leptin typically surges late in gestation and declines after delivery until the infant consumes sufficient leptin-containing breast milk or accrues sufficient leptin-secreting adipose tissue to reestablish the circulating levels. The leptin deficiency seen in IUGR infants is a multifactorial manifestation of placental insufficiency, exaggerated glucocorticoid exposure and fetal adipose deficit. The preterm infant suffers from the same cascade of events, including separation from the placenta, antenatal steroid exposure and persistently underdeveloped adipose depots. Preterm infants remain leptin deficient beyond term gestation, rendering them susceptible to neurodevelopmental impairment and subsequent cardiovascular dysregulation. This pathologic pathway is efficiently modeled by placing neonatal mice into atypically large litters, thereby recapitulating the perinatal growth restriction-adult hypertension phenotype. In this model, neonatal leptin supplementation restores the physiologic leptin surge, attenuates the leptin-triggered sympathetic activation in adulthood and prevents leptin- or stress-evoked hypertension. Further pathway interrogation and clinical translation are needed to fully test the therapeutic potential of perinatal leptin supplementation. © 2016 Society for Endocrinology.

  3. Leptin and TNF-alpha levels in patients with chronic obstructive pulmonary disease and their relationship to nutritional parameters.

    Science.gov (United States)

    Calikoglu, Mukadder; Sahin, Gulsah; Unlu, Ali; Ozturk, Candan; Tamer, Lülüfer; Ercan, Bahadir; Kanik, Arzu; Atik, Uğur

    2004-01-01

    Leptin is a protein mainly secreted by adipocytes, and the major function of leptin was its role in body weight regulation. In humans, there was a strong correlation between leptin and nutritional parameters, such as body mass index (BMI) and fat mass (FM). Administration of recombinant leptin to OB/OB mice, which have a genetic defect in leptin production, reduces food intake, increases energy expenditure, and decreases body weight. It is suggested that increased levels of circulating leptin levels may contribute to anorexia and weight loss in pathologic conditions including chronic obstructive pulmonary disease (COPD). Recent studies have provided evidence for a link between leptin and proinflammatory cytokines such as TNF-alpha. This study aimed to detect serum leptin and TNF-alpha levels in COPD patients without weight loss during stable disease and acute exacerbation, and to investigate relationships between leptin, TNF-alpha and nutritional parameters at different stages of the disease. 26 stable COPD patients, 16 COPD patients with acute exacerbation and 15 control subjects participated in this study. To eliminate the effects of sex differences, all patients and controls were male. BMI, percent ideal body weight, percent FM, sum of skinfold thickness and serum leptin and TNF-alpha levels were measured in all participants. Leptin and TNF-alpha levels were measured by ELISA. Serum leptin and TNF-alpha levels were significantly higher in the patients experiencing exacerbation than in the stable patients and controls. Although leptin levels were lower and TNF-alpha levels were higher in the stable patient group than in the controls, these differences were not statistically different. Leptin levels were significantly correlated with the nutritional parameters in both control and stable groups. However, in patients with acute exacerbation, a correlation between leptin and nutritional parameters was not found. There was no significant relationship between TNF

  4. Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain

    OpenAIRE

    Morabito, Michael V.; Ravussin, Yann; Mueller, Bridget R.; Skowronski, Alicja A.; Watanabe, Kazuhisa; Foo, Kylie S.; Lee, Samuel X.; Lehmann, Anders; Hjorth, Stephan; Zeltser, Lori M.; LeDuc, Charles A.; Leibel, Rudolph L.

    2017-01-01

    Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minu...

  5. Integral Role of PTP1B in Adiponectin-Mediated Inhibition of Oncogenic Actions of Leptin in Breast Carcinogenesis

    Directory of Open Access Journals (Sweden)

    LaTonia Taliaferro-Smith

    2013-01-01

    Full Text Available The molecular effects of obesity are mediated by alterations in the levels of adipocytokines. High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a “guardian angel adipocytokine” for its protective role against various obesity-related pathogenesis including breast cancer. In the present study, investigating the role of adiponectin as a potential inhibitor of leptin, we show that adiponectin treatment inhibits leptin-induced clonogenicity and anchorage-independent growth. Leptin-stimulated migration and invasion of breast cancer cells is also effectively inhibited by adiponectin. Analyses of the underlying molecular mechanisms reveal that adiponectin suppresses activation of two canonical signaling molecules of leptin signaling axis: extracellular signal-regulated kinase (ERK and Akt. Pretreatment of breast cancer cells with adiponectin protects against leptin-induced activation of ERK and Akt. Adiponectin increases expression and activity of the physiological inhibitor of leptin signaling, protein tyrosine phosphatase 1B (PTP1B, which is found to be integral to leptin-antagonist function of adiponectin. Inhibition of PTP1B blocks adiponectin-mediated inhibition of leptin-induced breast cancer growth. Our in vivo studies show that adenovirus-mediated adiponectin treatment substantially reduces leptin-induced mammary tumorigenesis in nude mice. Exploring therapeutic strategies, we demonstrate that treatment of breast cancer cells with rosiglitazone results in increased adiponectin expression and inhibition of migration and invasion. Rosiglitazone treatment also inhibits leptin-induced growth of breast cancer cells. Taken together, these data show that adiponectin treatment can inhibit the oncogenic actions of leptin through blocking its downstream signaling molecules and raising adiponectin levels could be a rational therapeutic strategy for breast

  6. Integral role of PTP1B in adiponectin-mediated inhibition of oncogenic actions of leptin in breast carcinogenesis.

    Science.gov (United States)

    Taliaferro-Smith, LaTonia; Nagalingam, Arumugam; Knight, Brandi Brandon; Oberlick, Elaine; Saxena, Neeraj K; Sharma, Dipali

    2013-01-01

    The molecular effects of obesity are mediated by alterations in the levels of adipocytokines. High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a "guardian angel adipocytokine" for its protective role against various obesity-related pathogenesis including breast cancer. In the present study, investigating the role of adiponectin as a potential inhibitor of leptin, we show that adiponectin treatment inhibits leptin-induced clonogenicity and anchorage-independent growth. Leptin-stimulated migration and invasion of breast cancer cells is also effectively inhibited by adiponectin. Analyses of the underlying molecular mechanisms reveal that adiponectin suppresses activation of two canonical signaling molecules of leptin signaling axis: extracellular signal-regulated kinase (ERK) and Akt. Pretreatment of breast cancer cells with adiponectin protects against leptin-induced activation of ERK and Akt. Adiponectin increases expression and activity of the physiological inhibitor of leptin signaling, protein tyrosine phosphatase 1B (PTP1B), which is found to be integral to leptin-antagonist function of adiponectin. Inhibition of PTP1B blocks adiponectin-mediated inhibition of leptin-induced breast cancer growth. Our in vivo studies show that adenovirus-mediated adiponectin treatment substantially reduces leptin-induced mammary tumorigenesis in nude mice. Exploring therapeutic strategies, we demonstrate that treatment of breast cancer cells with rosiglitazone results in increased adiponectin expression and inhibition of migration and invasion. Rosiglitazone treatment also inhibits leptin-induced growth of breast cancer cells. Taken together, these data show that adiponectin treatment can inhibit the oncogenic actions of leptin through blocking its downstream signaling molecules and raising adiponectin levels could be a rational therapeutic strategy for breast carcinoma in obese patients

  7. Leptin and bone mineral density

    DEFF Research Database (Denmark)

    Morberg, Cathrine M.; Tetens, Inge; Black, Eva

    2003-01-01

    .001). An inverse relation between BMD adjusted for body weight and serum leptin emerged in both the control group (r = -0.186; P multiple linear regression, fat mass, lean body mass, and occupational physical activity were positively associated...

  8. Sip-jeon-dea-bo-tang, a traditional herbal medicine, ameliorates cisplatin-induced anorexia via the activation of JAK1/STAT3-mediated leptin and IL-6 production in the fat tissue of mice.

    Science.gov (United States)

    Woo, Sang-Mi; Choi, Youn Kyung; Kim, Ah-Jeong; Yun, Yee Jin; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong Gyu

    2016-04-01

    Despite its therapeutic advantages, chemotherapy can also cause adverse effects, including anorexia and loss of appetite. Although numerous patients with cancer have been reported to suffer from anorexia during or following chemotherapy, treatment options for anorexia remain to be determined. In Asian countries, traditional medicines are widely used to treat problems with appetite; sip-jeon-dea-bo-tang (SJDBT) is one of those medicines used for the treatment of anorexia. The present study demonstrated that SJDBT ameliorated cisplatin-induced anorexia. In a mouse model of chemotherapy-induced anorexia, oral administration of SJDBT prevented the cisplatin-induced reduction of food intake, inhibiting weight loss. The results of multiplex assays showed that SJDBT only altered the levels of interleukin (IL)-6 and leptin in the serum and fat tissue. In addition, SJDBT maintained the serum leptin level and increased the serum IL-6 level, whereas cisplatin reduced the levels of both serum leptin and IL‑6. Furthermore, SJDBT was revealed to increase the levels of leptin and IL-6 in the fat tissue by activating the JAK1/STAT3 signaling pathway. In conclusion, the present results revealed that SJDBT ameliorated cisplatin-induced anorexia, suggesting its usefulness in the prevention of anorexia during chemotherapy.

  9. Leptin increases prostate cancer aggressiveness.

    Science.gov (United States)

    López Fontana, Constanza M; Maselli, María E; Pérez Elizalde, Rafael F; Di Milta Mónaco, Nicolás A; Uvilla Recupero, Ana L; López Laur, José D

    2011-12-01

    Recent studies indicate that adipose tissue and adipocytokines might affect the development of prostate cancer (PCa). Leptin would have a stimulating effect on prostate cancer cells by inducing promotion and progression, whereas adiponectin would have a protective effect. The aim of this study was to determine the relation between body composition, leptin, and adiponectin levels with the prevalence and aggressiveness of PCa in men of Mendoza, Argentina. Seventy volunteers between 50 and 80 years (35 healthy men as control group and 35 with PCa) were selected. The PCa group was subclassified according to the Gleason Score (GS). Digital rectal examination, transrectal ultrasound, and prostatic biopsy were performed; PSA, testosterone, leptin, and adiponectin levels were determined; and a nutritional interview including anthropometric measurements and a food frequency questionnaire was carried out. Statistical analysis was performed by Student t test, ANOVA I, and Bonferroni (p Body mass index and percentage of body fat mass were not statistically different between PCa and control groups. However, body fat mass was higher in subjects with more aggressive tumors (p = 0.032). No differences were observed regarding leptin levels between the groups. Nevertheless, leptin levels were higher in subjects with high GS (p consumption and nutrient intake did not differ in the studied groups. In conclusion, body composition and leptin are related to the PCa aggressiveness but not with its prevalence.

  10. Leptin receptor expressing neurons express phosphodiesterase-3B (PDE3B) and leptin induces STAT3 activation in PDE3B neurons in the mouse hypothalamus.

    Science.gov (United States)

    Sahu, Maitrayee; Sahu, Abhiram

    2015-11-01

    Leptin signaling in the hypothalamus is critical for normal food intake and body weight regulation. Cumulative evidence suggests that besides the signal transducer and activator of transcription-3 (STAT3) pathway, several non-STAT3 pathways including the phosphodiesterase-3B (PDE3B) pathway mediate leptin signaling in the hypothalamus. We have shown that PDE3B is localized in various hypothalamic sites implicated in the regulation of energy homeostasis and that the anorectic and body weight reducing effects of leptin are mediated by the activation of PDE3B. It is still unknown if PDE3B is expressed in the long form of the leptin-receptor (ObRb)-expressing neurons in the hypothalamus and whether leptin induces STAT3 activation in PDE3B-expressing neurons. In this study, we examined co-localization of PDE3B with ObRb neurons in various hypothalamic nuclei in ObRb-GFP mice that were treated with leptin (5mg/kg, ip) for 2h. Results showed that most of the ObRb neurons in the arcuate nucleus (ARC, 93%), ventromedial nucleus (VMN, 94%), dorsomedial nucleus (DMN, 95%), ventral premammillary nucleus (PMv, 97%) and lateral hypothalamus (LH, 97%) co-expressed PDE3B. We next examined co-localization of p-STAT3 and PDE3B in the hypothalamus in C57BL6 mice that were treated with leptin (5mg/kg, ip) for 1h. The results showed that almost all p-STAT3 positive neurons in different hypothalamic nuclei including ARC, VMN, DMN, LH and PMv areas expressed PDE3B. These results suggest the possibility for a direct role for the PDE3B pathway in mediating leptin action in the hypothalamus. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. C5a receptor deficiency alters energy utilization and fat storage.

    Directory of Open Access Journals (Sweden)

    Christian Roy

    Full Text Available To investigate the impact of whole body C5a receptor (C5aR deficiency on energy metabolism and fat storage.Male wildtype (WT and C5aR knockout (C5aRKO mice were fed a low fat (CHOW or a high fat high sucrose diet-induced obesity (DIO diet for 14 weeks. Body weight and food intake were measured weekly. Indirect calorimetry, dietary fatload clearance, insulin and glucose tolerance tests were also evaluated. Liver, muscle and adipose tissue mRNA gene expression were measured by RT-PCR.At week one and 12, C5aRKO mice on DIO had increased oxygen consumption. After 12 weeks, although food intake was comparable, C5aRKO mice had lower body weight (-7% CHOW, -12% DIO as well as smaller gonadal (-38% CHOW, -36% DIO and inguinal (-29% CHOW, -30% DIO fat pads than their WT counterparts. Conversely, in WT mice, C5aR was upregulated in DIO vs CHOW diets in gonadal adipose tissue, muscle and liver, while C5L2 mRNA expression was lower in C5aRKO on both diet. Furthermore, blood analysis showed lower plasma triglyceride and non-esterified fatty acid levels in both C5aRKO groups, with faster postprandial triglyceride clearance after a fatload. Additionally, C5aRKO mice showed lower CD36 expression in gonadal and muscle on both diets, while DGAT1 expression was higher in gonadal (CHOW and liver (CHOW and DIO and PPARγ was increased in muscle and liver.These observations point towards a role (either direct or indirect for C5aR in energy expenditure and fat storage, suggesting a dual role for C5aR in metabolism as well as in immunity.

  12. Leptin Is Produced by Parathyroid Glands and Stimulates Parathyroid Hormone Secretion.

    Science.gov (United States)

    Hoang, Don; Broer, Niclas; Sosa, Julie A; Abitbol, Nathalie; Yao, Xiaopan; Li, Fangyong; Rivera-Molina, Felix; Toomre, Derek K; Roman, Sanziana A; Sue, Gloria; Kim, Samuel; Li, Alexander Y; Callender, Glenda G; Simpson, Christine; Narayan, Deepak

    2017-12-01

    We asked if leptin and its cognate receptor were present in normal and diseased parathyroid glands, and if so, whether they had any functional effects on parathyroid hormone (PTH) secretion in parathyroid neoplasms. The parathyroid glands acting through PTH play a critical role in the regulation of serum calcium. Based on leptin's recently discovered role in bone metabolism, we hypothesized these glands were the sites of a functional interaction between these 2 hormones. From July 2010 to July 2011, 96 patients were enrolled in a prospective study of leptin and hyperparathyroidism, all of whom were enrolled based on their diagnosis of hyperparathyroidism, and their candidacy for surgical intervention provided informed consent. Immediately after parathyroidectomy, 100 to 300 mg of adenomatous or hyperplastic diseased parathyroid tissue was prepared and processed according to requirements of the following: in situ hybridization, immunohistochemistry, immunofluorescence by conventional and spinning disc confocal microscopy, electron microscopy, parathyroid culture, whole organ explant, and animal model assays. Leptin, leptin receptor (long isoform), and PTH mRNA transcripts and protein were detected in an overlapping fashion in parathyroid chief cells in adenoma and hyperplastic glands, and also in normal parathyroid by in situ hybridization, qRT-PCR, and immunohistochemistry. Confocal microscopy confirmed active exogenous leptin uptake in cultured parathyroid cells. PTH secretion in explants increased in response to leptin and decreased with leptin receptor signaling inhibition by AG490, a JAK2/STAT3 inhibitor. Ob/ob mice injected with mouse leptin exhibited increased PTH levels from baseline. Taken together, these data suggest that leptin is a functionally active product of the parathyroid glands and stimulates PTH release.

  13. Leptin levels in infertile males

    International Nuclear Information System (INIS)

    Jahan, S.; Bibi, R.; Ahmed, S.

    2011-01-01

    Objective: To determine the leptin levels in the serum of normal, sub fertile and infertile men. Study Design: Analytical study. Place and Duration of Study: Department of Animal Sciences Quaid-e-Azam University, Islamabad, National Institute of Health (NIH), Islamabad and Dr. Salma and Kafeel Medical Centre, Islamabad, from April to December 2009. Methodology: Serum leptin levels hormonal concentrations (LH, FSH and testosterone) were determined by EIA in 154 males including 24 (15.58%) fertile, 19 (12.34%) polyzoospermic (PZs), 26 (16.88%) teratozoospermic (TZs), 27 (17.53%) astheno-teratozoospermic (ATZs), 18 (11.69%) oligozoospermic (OZs), 18 (11.69%) oligo-astheno-teratozoospermic (OATZs), 11 (7.14%) obstructive azoospermic (OBST-AZOOs) and 11 (7.14%) non-obstructive azoospermic (NON-OBST-AZOOs). BMI was also determined, divided into groups of greater than 24. Hormonal concentrations were compared by ANOVA and correlation was performed by using Graph pad prism version 5. Results: Significantly high levels of leptin concentrations were found in fertile (p 24 compared to fertile and infertile male patients with BMI 24. Leptin showed a significant positive correlation with LH (p < 0.01) and FSH (p < 0.002) and a significant negative correlation with testosterone (p < 0.001). Conclusion: Abnormal leptin level was significantly associated with fertility problems in males. Providing a link between leptin and reproduction factors contributing in control of testosterone and gonadotropins secretion in many aspects depending on fertility status in male subjects. BMI appears to have significant association with serum leptin levels. (author)

  14. Leptin as local inflammatory marker in COPD.

    Science.gov (United States)

    Broekhuizen, R; Vernooy, J H J; Schols, A M W J; Dentener, M A; Wouters, E F M

    2005-01-01

    Chronic inflammation of the lung is a characteristic finding in chronic obstructive pulmonary disease (COPD). Leptin is a pleiotropic cytokine thought to play a role in host response to inflammation. As recent studies have shown that leptin receptors are present in the lung, this study aimed to determine if leptin is detectable in induced sputum of COPD patients and if there is a relationship between leptin and other inflammatory markers in sputum. Sputum was induced in 14 male patients with moderate COPD (FEV1: 56 (15) % pred.). Leptin, total tumour necrosis factor (TNF)-alpha, and C-reactive protein (CRP) were analyzed in induced sputum supernatant by ELISA. Leptin was also determined in EDTA plasma. Leptin was detectable in induced sputum of 10 COPD patients. A significant relationship was found between sputum leptin and CRP (r = 0.943, P leptin and sputum leptin were inversely correlated (r = -0.643, P leptin is detectable in induced sputum of patients with moderate COPD and is related to other inflammatory markers. The observed correlations between leptin and inflammatory markers in sputum may indicate that leptin is involved in the local inflammatory response in COPD.

  15. 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

    2016-09-01

    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.

  16. Genetics Home Reference: congenital leptin deficiency

    Science.gov (United States)

    ... Description Congenital leptin deficiency is a condition that causes severe obesity beginning in the first few months of life. ... are unknown. Congenital leptin deficiency is a rare cause of obesity. Researchers are studying the factors involved in more ...

  17. Serum leptin and insulin tests in obesity

    International Nuclear Information System (INIS)

    Yang Yin; Jiang Xiaojin; Leng Xiumei

    2001-01-01

    Objective: To study the clinical significance and the relations of leptin and insulin on obesity group. Methods: Leptin and insulin were tested with radioimmunoassay (RIA) in pre-obesity group and obesity group respectively. Results: Serum leptin and insulin levels were significantly elevated in obesity group compare with the controls (P<0.01). Conclusion: Changing with insulin, the elevation of leptin in obesity group has been identified as an important agent of diabetes mellitus (DM)

  18. Testosterone interacts with the feedback mechanisms engaged by Tyr985 of the leptin receptor and diet-induced obesity.

    Science.gov (United States)

    Johnson, Joshua A; Calo, Sal; Nair, Lekshmi; IglayReger, Heidi B; Greenwald-Yarnell, Megan; Skorupski, Josh; Myers, Martin G; Bodary, Peter F

    2012-11-01

    Inhibitory signaling through Tyr985 of the leptin receptor contributes to the attenuation of anorectic leptin action in obese animals. Leptin receptor (LEPR-B) Tyr985Leu homozygote mutant mice (termed l/l) were previously generated to study Tyr985's contributions to inhibition of LEPR-B signaling; young female l/l mice display a lean, leptin-sensitive phenotype, while young male l/l are not significantly different from wild-type. We report here that testosterone (but not estrogen) determines the sex-specificity of the l/l phenotype. This provides additional insight into the cellular mechanism by which gonadal hormones determine central sensitivity to leptin, and may help elucidate the long-noted sex differences in leptin sensitivity. Additionally, we observed that Tyr985 signaling protects against a diet-dependent switch that exacerbates obesity with high fat feeding, such that the enhanced leptin sensitivity of l/l mice on a normal diet leads to increased adiposity in the face of chronic high-fat diet. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Studies on leptin utilizing to obesity

    International Nuclear Information System (INIS)

    Zhao Minghui

    2001-01-01

    Leptin is a hormone synthesized and secreted by lipid cells. It is a product encoded and expressed by the obese gene. Administration of recombinant leptin decreases food intake, increases energy expenditure and promotes weight loss. Most studies indicate that leptin is a main regulating factor of catabolism and anabolism of adipose tissue. The circulating leptin level is a sensitive index which indicates the confusion of the rate of lipid metabolism such as hyperlipemia, lipo-liver and so on. The human leptin radioimmunoassay has been developed to quantitate human leptin in plasma or serum, and to further investigate the relationship between serum leptin concentration and body fat, gender, age, sexual hormones, endocrine of insulin, etc. Especially, serum leptin concentrations are correlated with body-mass-index (BMI), suggesting that most obese persons are resistant to leptin; Those who are relatively deficient of leptin may become the good candidates of leptin treatment in the future. The discovery and application of leptin make the study of obesity, non-insulin dependent diabetes and other correlation diseases enter a new stage

  20. Genistein Precipitated Hypothyroidism, Altered Leptin and C ...

    African Journals Online (AJOL)

    Genistein Precipitated Hypothyroidism, Altered Leptin and C-Reactive Protein Synthesis in Pregnant Rats. ... Thyroid hormone, C-reactive protein (CRP) and leptin assay was carried using the blood samples. Leptin was also assayed in the placenta and amniotic fluid supernatant. Oral exposure of pregnant rats to genistein ...

  1. Leptin, adiponectin and pulmonary diseases.

    Science.gov (United States)

    Ali Assad, Nour; Sood, Akshay

    2012-10-01

    Adipose tissue produces leptin and adiponectin - energy-regulating adipokines that may also play a role in inflammatory pulmonary conditions, as suggested by some murine studies. Leptin and adiponectin and their respective receptors are expressed in the human lung. The association between systemic or airway leptin and asthma in humans is currently controversial, particularly among adults. The majority of the evidence among children however suggests that systemic leptin may be associated with greater asthma prevalence and severity, particularly among prepubertal boys and peripubertal/postpubertal girls. Systemic and airway leptin concentrations may also be disproportionately higher in chronic obstructive pulmonary disease (COPD) patients, particularly among women, and reflect greater airway inflammation and disease severity. Quite like leptin, the association between systemic and airway adiponectin and asthma in humans is also controversial. Some but not all studies, demonstrate that serum adiponectin concentrations are protective against asthma among premenopausal women and peripubertal girls. On the other hand, serum adiponectin concentrations are inversely associated with asthma severity among boys but positively associated among men. Further, systemic and airway adiponectin concentrations are higher in COPD patients than controls, as demonstrated by case-control studies of men. Systemic adiponectin is also positively associated with lung function in healthy adults but inversely associated with lung function in subjects with COPD. It is therefore possible that pro-inflammatory effects of adiponectin dominate under certain physiologic conditions and anti-inflammatory effects under others. The adipokine-lung disease literature has critical gaps that include a lack of adequately powered longitudinal or weight-intervention studies; inadequate adjustment for confounding effect of obesity; and unclear understanding of potential sex interactions. It is also uncertain

  2. Human skeletal muscle releases leptin in vivo

    DEFF Research Database (Denmark)

    Wolsk, Emil; Grøndahl, Thomas Sahl; Pedersen, Bente Klarlund

    2012-01-01

    Leptin is considered an adipokine, however, cultured myocytes have also been found to release leptin. Therefore, as proof-of-concept we investigated if human skeletal muscle synthesized leptin by measuring leptin in skeletal muscle biopsies. Following this, we quantified human skeletal muscle...... was unaltered. During saline infusion the adipose tissue release averaged 0.8 ± 0.3 ng min(-1) 100g tissue(-1) whereas skeletal muscle release was 0.5 ± 0.1 ng min(-1) 100g tissue(-1). In young healthy humans, skeletal muscle contribution to whole body leptin production could be substantial given the greater...

  3. Weight-dependent changes of immune system in adipose tissue: Importance of leptin

    International Nuclear Information System (INIS)

    Caspar-Bauguil, S.; Cousin, B.; Andre, M.; Nibbelink, M.; Galinier, A.; Periquet, B.; Casteilla, L.; Penicaud, L.

    2006-01-01

    Ancestral lymphoid cells reside in adipose tissues, and their numbers are highly altered in obesity. Leptin, production of which is correlated to fat mass, is strongly involved in the relationships between adipose tissues and immune system. We investigated in epididymal (EPI) and inguinal (ING) fat pads to determine whether 1) lymphocyte phenotypes were correlated to the tissue weight and 2) leptin was involved in such relationships. Immunohistological analyses revealed a tight relationship between the T and NK lymphocytes of the stromal vascular fraction and adipocytes. We identified a significant negative and positive correlation between EPI weight and the percentage of NK and total T cells respectively by cytofluorometric analyses. The NK and ancestral γδ T cell contents were directly dependent of leptin since they increased significantly in high-fat (HF) diet mice but not in leptin-deficient (ob/ob) mice as compared to control. By contrast, the αβ T cell content seemed independent of leptin because their percentages increased significantly with the EPI weight whatever the type of mice (control, HF, ob/ob). The present study suggests that adipose tissues present, according to their localization, different immunological mechanisms that might be involved in the regulation of adipose cells functions and proliferations

  4. Relevance of Serum Leptin and Leptin-Receptor Concentrations in Critically Ill Patients

    Directory of Open Access Journals (Sweden)

    Alexander Koch

    2010-01-01

    Full Text Available The adipocyte-derived cytokine leptin was implicated to link inflammation and metabolic alterations. We investigated the potential role of leptin components in critically ill patients, because systemic inflammation, insulin resistance, and hyperglycemia are common features of critical illness. Upon admission to Medical Intensive Care Unit (ICU, free leptin and soluble leptin-receptor serum concentrations were determined in 137 critically ill patients (95 with sepsis, 42 without sepsis and 26 healthy controls. Serum leptin or leptin-receptor did not differ between patients or controls and were independent of sepsis. However, serum leptin was closely associated with obesity and diabetes and clearly correlated with markers of metabolism and liver function. Leptin-receptor was an unfavourable prognostic indicator, associated with mortality during three years follow-up. Our study indicates a functional role of leptin in the pathogenesis of severe illness and emphasizes the impact of complex metabolic alterations on the clinical outcome of critically ill patients.

  5. Goldfish Leptin-AI and Leptin-AII: Function and Central Mechanism in Feeding Control

    Directory of Open Access Journals (Sweden)

    Ai-Fen Yan

    2016-05-01

    Full Text Available In mammals, leptin is a peripheral satiety factor that inhibits feeding by regulating a variety of appetite-related hormones in the brain. However, most of the previous studies examining leptin in fish feeding were performed with mammalian leptins, which share very low sequence homologies with fish leptins. To elucidate the function and mechanism of endogenous fish leptins in feeding regulation, recombinant goldfish leptin-AI and leptin-AII were expressed in methylotrophic yeast and purified by immobilized metal ion affinity chromatography (IMAC. By intraperitoneal (IP injection, both leptin-AI and leptin-AII were shown to inhibit the feeding behavior and to reduce the food consumption of goldfish in 2 h. In addition, co-treatment of leptin-AI or leptin-AII could block the feeding behavior and reduce the food consumption induced by neuropeptide Y (NPY injection. High levels of leptin receptor (lepR mRNA were detected in the hypothalamus, telencephalon, optic tectum and cerebellum of the goldfish brain. The appetite inhibitory effects of leptins were mediated by downregulating the mRNA levels of orexigenic NPY, agouti-related peptide (AgRP and orexin and upregulating the mRNA levels of anorexigenic cocaine-amphetamine-regulated transcript (CART, cholecystokinin (CCK, melanin-concentrating hormone (MCH and proopiomelanocortin (POMC in different areas of the goldfish brain. Our study, as a whole, provides new insights into the functions and mechanisms of leptins in appetite control in a fish model.

  6. Increased atherosclerosis in mice with increased vascular biglycan content.

    Science.gov (United States)

    Thompson, Joel C; Tang, Tao; Wilson, Patricia G; Yoder, Meghan H; Tannock, Lisa R

    2014-07-01

    The response to retention hypothesis of atherogenesis proposes that atherosclerosis is initiated via the retention of atherogenic lipoproteins by vascular proteoglycans. Co-localization studies suggest that of all the vascular proteoglycans, biglycan is the one most closely co-localized with LDL. The goal of this study was to determine if over-expression of biglycan in hyperlipidemic mice would increase atherosclerosis development. Transgenic mice were developed by expressing biglycan under control of the smooth muscle actin promoter, and were crossed to the LDL receptor deficient (C57BL/6 background) atherosclerotic mouse model. Biglycan transgenic and non-transgenic control mice were fed an atherogenic Western diet for 4-12 weeks. LDL receptor deficient mice overexpressing biglycan under control of the smooth muscle alpha actin promoter had increased atherosclerosis development that correlated with vascular biglycan content. Increased vascular biglycan content predisposes to increased lipid retention and increased atherosclerosis development. Published by Elsevier Ireland Ltd.

  7. A novel method to generate T-cell receptor-deficient chimeric antigen receptor T cells.

    Science.gov (United States)

    Kamiya, Takahiro; Wong, Desmond; Png, Yi Tian; Campana, Dario

    2018-03-13

    Practical methods are needed to increase the applicability and efficacy of chimeric antigen receptor (CAR) T-cell therapies. Using donor-derived CAR-T cells is attractive, but expression of endogenous T-cell receptors (TCRs) carries the risk for graft-versus-host-disease (GVHD). To remove surface TCRαβ, we combined an antibody-derived single-chain variable fragment specific for CD3ε with 21 different amino acid sequences predicted to retain it intracellularly. After transduction in T cells, several of these protein expression blockers (PEBLs) colocalized intracellularly with CD3ε, blocking surface CD3 and TCRαβ expression. In 25 experiments, median TCRαβ expression in T lymphocytes was reduced from 95.7% to 25.0%; CD3/TCRαβ cell depletion yielded virtually pure TCRαβ-negative T cells. Anti-CD3ε PEBLs abrogated TCRαβ-mediated signaling, without affecting immunophenotype or proliferation. In anti-CD3ε PEBL-T cells, expression of an anti-CD19-41BB-CD3ζ CAR induced cytokine secretion, long-term proliferation, and CD19 + leukemia cell killing, at rates meeting or exceeding those of CAR-T cells with normal CD3/TCRαβ expression. In immunodeficient mice, anti-CD3ε PEBL-T cells had markedly reduced GVHD potential; when transduced with anti-CD19 CAR, these T cells killed engrafted leukemic cells. PEBL blockade of surface CD3/TCRαβ expression is an effective tool to prepare allogeneic CAR-T cells. Combined PEBL and CAR expression can be achieved in a single-step procedure, is easily adaptable to current cell manufacturing protocols, and can be used to target other T-cell molecules to further enhance CAR-T-cell therapies. © 2018 by The American Society of Hematology.

  8. LEPTIN AND OBESITY – NEUROENDOCRINE , METABOLIC AND ATHEROGENIC EFFECTS OF LEPTIN

    Directory of Open Access Journals (Sweden)

    Mišo Šabovič

    2003-01-01

    Full Text Available Background. Leptin is an adipocyte-derived hormone that was recently discovered. Leptin and leptin resistance play an important role in the pathogenesis of obesity. Leptin acts by binding to specific receptors in the hypothalamus to alter the expression of several neuropeptides that regulate food intake and energy expenditure. As commonly found, obese persons have leptin resistance and consequently attenuated effects of leptin. Mechanism underlying leptin resistance has not been explained yet: it might be the result of a receptor or post receptor defect, impaired transport of leptin through cerebrovascular barrier or inactivation of leptin by binding proteins. Phase I and II clinical trials proved that recombinant leptin administration to humans is safe. First results of the current phase III clinical trials demonstrated that leptin is moderately effective in the treatment of obesity.Conclusions. Beside anti-obesity effect, leptin can have important metabolic and neuroendocrine effects. It is involved in glucose metabolism and insulin secretion, pathogenesis of polymetabolic syndrome, diabetes and arterial hypertension. In addition it affects some processes of atherothrombosis. It interacts with and significantly influences hypothalamic-pituitaryadrenal, thyroid, sexual glands and growth hormone axes. Explaining the mechanism of leptin resistance could be important for understanding the pathogenesis of obesity and associated pathologic states as polymetabolic syndrom, diabetes, arterial hipertension and atherothrombosis.

  9. Gene Expression of Leptin and Long Leptin Receptor Isoform in Endometriosis: A Case-Control Study

    Directory of Open Access Journals (Sweden)

    Andrea Prestes Nácul

    2013-01-01

    Full Text Available In this study, leptin/BMI ratio in serum and peritoneal fluid and gene expression of leptin and long form leptin receptor (OB-RL were assessed in eutopic and ectopic endometria of women with endometriosis and controls. Increased serum leptin/BMI ratio was found in endometriosis patients. Leptin and OB-RL gene expression was significantly higher in ectopic versus eutopic endometrium of patients and controls. A positive, significant correlation was observed between leptin and OB-RL transcripts in ectopic endometria and also in eutopic endometria in endometriosis and control groups. A negative and significant correlation was found between OB-RL mRNA expression and peritoneal fluid leptin/BMI ratio only in endometriosis. These data suggest that, through a modulatory interaction with its active receptor, leptin might play a role in the development of endometrial implants.

  10. Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats

    Science.gov (United States)

    Borges, Beatriz de Carvalho; Rorato, Rodrigo C.; Uchoa, Ernane Torres; Marangon, Paula B.; Elias, Carol F.; Antunes-Rodrigues, Jose

    2014-01-01

    Leptin resistance is induced by the feedback inhibitors tyrosine phosphatase-1B (PTP1B) and decreased Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) signaling. To investigate the participation of PTP1B and SHP-2 in LPS-induced leptin resistance, we injected repeated (6-LPS) intraperitoneal LPS doses (100 μg/kg ip) for comparison with a single (1-LPS) treatment and evaluated the expression of SHP-2, PTP1B, p-ERK1/2, and p-STAT3 in the hypothalamus of male Wistar rats. The single LPS treatment increased the expression of p-STAT3 and PTP1B but not SHP-2. The repeated LPS treatment reduced SHP-2, increased PTP1B, and did not change p-STAT3. We observed that the PTP1B expression induced by the endotoxin was highly colocalized with leptin receptor cells in the hypothalamus of LepRb-IRES-Cre-tdTomato reporter mice. The single, but not the repeated, LPS treatment decreased the food intake and body weight. Leptin had no stimulatory effect on the hypophagia, body weight loss, or pSTAT3 expression in 6-LPS rats, indicating leptin unresponsiveness. Notably, the PTP1B inhibitor (3.0 nmol/rat in 5 μl icv) restored the LPS-induced hypophagia in 6-LPS rats and restored the ability of leptin to reduce food intake and body weight as well as to phosphorylate STAT3 in the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus. The present data suggest that an increased PTP1B expression in the hypothalamus underlies the development of leptin resistance during repeated exposure to LPS. Our findings contribute to understanding the mechanisms involved in leptin resistance during low-grade inflammation as seen in obesity. PMID:25352433

  11. Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats.

    Science.gov (United States)

    Borges, Beatriz de Carvalho; Rorato, Rodrigo C; Uchoa, Ernane Torres; Marangon, Paula B; Elias, Carol F; Antunes-Rodrigues, Jose; Elias, Lucila L K

    2015-01-01

    Leptin resistance is induced by the feedback inhibitors tyrosine phosphatase-1B (PTP1B) and decreased Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) signaling. To investigate the participation of PTP1B and SHP-2 in LPS-induced leptin resistance, we injected repeated (6-LPS) intraperitoneal LPS doses (100 μg/kg ip) for comparison with a single (1-LPS) treatment and evaluated the expression of SHP-2, PTP1B, p-ERK1/2, and p-STAT3 in the hypothalamus of male Wistar rats. The single LPS treatment increased the expression of p-STAT3 and PTP1B but not SHP-2. The repeated LPS treatment reduced SHP-2, increased PTP1B, and did not change p-STAT3. We observed that the PTP1B expression induced by the endotoxin was highly colocalized with leptin receptor cells in the hypothalamus of LepRb-IRES-Cre-tdTomato reporter mice. The single, but not the repeated, LPS treatment decreased the food intake and body weight. Leptin had no stimulatory effect on the hypophagia, body weight loss, or pSTAT3 expression in 6-LPS rats, indicating leptin unresponsiveness. Notably, the PTP1B inhibitor (3.0 nmol/rat in 5 μl icv) restored the LPS-induced hypophagia in 6-LPS rats and restored the ability of leptin to reduce food intake and body weight as well as to phosphorylate STAT3 in the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus. The present data suggest that an increased PTP1B expression in the hypothalamus underlies the development of leptin resistance during repeated exposure to LPS. Our findings contribute to understanding the mechanisms involved in leptin resistance during low-grade inflammation as seen in obesity. Copyright © 2015 the American Physiological Society.

  12. Interleukin-21 receptor deficiency increases the initial toll-like receptor 2 response but protects against joint pathology by reducing Th1 and Th17 cells during streptococcal cell wall arthritis.

    Science.gov (United States)

    Marijnissen, Renoud J; Roeleveld, Debbie M; Young, Deborah; Nickerson-Nutter, Cheryl; Abdollahi-Roodsaz, Shahla; Garcia de Aquino, Sabrina; van de Loo, Fons A J; van Spriel, Annemiek B; Boots, Annemieke M H; van den Berg, Wim B; Koenders, Marije I

    2014-04-01

    The cytokine interleukin-21 (IL-21) can have both proinflammatory and immunosuppressive effects. The purpose of this study was to investigate the potential dual role of IL-21 in experimental arthritis in relation to Th17 cells. Antigen-induced arthritis (AIA) and chronic streptococcal cell wall (SCW) arthritis were induced in IL-21 receptor-deficient (IL-21R(-/-) ) and wild-type mice. Knee joints, synovial tissue, and serum were analyzed for arthritis pathology and inflammatory markers. During AIA and chronic SCW arthritis, IL-21R deficiency protected against severe inflammation and joint destruction. This was accompanied by suppressed serum IgG1 levels and antigen-specific T cell responses. Levels of IL-17 were reduced during AIA, and synovial lymphocytes isolated during SCW arthritis for flow cytometry demonstrated that mainly IL-17+ interferon-γ (IFNγ)-positive T cells were reduced in IL-21R(-/-) mice. However, during the acute phases of SCW arthritis, significantly higher joint swelling scores were observed, consistent with enhanced tumor necrosis factor and IL-6 expression. Interestingly, IL-21R(-/-) mice were significantly less capable of up-regulating suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 messenger RNA. IL-21 stimulation also affected the Toll-like receptor 2 (TLR-2)/caspase recruitment domain 15 response to SCW fragments in vitro, indicating that impaired SOCS regulation in the absence of IL-21 signaling might contribute to the increased local activation during SCW arthritis. In contrast to the proinflammatory role of IL-21 in adaptive immunity, which drives IL-17+IFN+ cells and joint pathology during chronic experimental arthritis, IL-21 also has an important immunosuppressive role, presumably by inhibiting TLR signaling via SOCS-1 and SOCS-3. If this dual role of IL-21 in various immune processes is present in human disease, it could make IL-21 a difficult therapeutic target in rheumatoid arthritis. Copyright © 2014 by the American

  13. 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...

  14. Mother and Infant Body Mass Index, Breast Milk Leptin and Their Serum Leptin Values

    Directory of Open Access Journals (Sweden)

    Francesco Savino

    2016-06-01

    Full Text Available Purpose: This study investigates correlations between mother and infant Body Mass Index (BMI, their serum leptin values and breast milk leptin concentration in early infancy. Subjects and Methods: We determined serum leptin values in 58 healthy infants and leptin values in their mothers’ breast milk, using radioimmunoassay (RIA. Infant and maternal anthropometrics were measured. Results: Median leptin concentration was 3.9 ng/mL (interquartile range (IQR: 2.75 in infant serum, 4.27 ng/mL (IQR: 5.62 in maternal serum and 0.89 ng/mL (IQR: 1.32 in breast milk. Median maternal BMI and weight were 24 kg/m2 (IQR: 4.41 and 64 kg (IQR: 15. Median infant BMI was 15.80 kg/cm2 (IQR: 4.02, while average weight was 5.130 kg (IQR: 1.627. Infants serum leptin values positively correlated with infants’ BMI (p = 0.001; r = 0.213 and breast milk leptin (p = 0.03; r = 0.285. Maternal serum leptin values positively correlated with maternal BMI (p = 0.000, r = 0.449 and breast milk leptin ones (p = 0.026; r = 0.322. Conclusion: Breast milk leptin and maternal BMI could influence infant serum leptin values. Further studies are needed to better elucidate the role of genetics and environment on infant leptin production and risk of obesity later in life.

  15. Novel mechanism by which probucol lowers low density lipoprotein levels demonstrated in the LDL receptor-deficient rabbit

    International Nuclear Information System (INIS)

    Naruszewicz, M.; Carew, T.E.; Pittman, R.C.; Witztum, J.L.; Steinberg, D.

    1984-01-01

    Treatment of low density lipoprotein (LDL) receptor-deficient rabbits (WHHL rabbits) with probucol (1% w/w in a chow diet) lowered their LDL-cholesterol levels by 36%, consonant with the reported effectiveness of the drug in patients deficient in the LDL receptor. Initial studies of LDL fractional catabolic rate (FCR) using 125 I-labeled LDL prepared from the serum of untreated WHHL rabbits showed no difference between probucol-treated WHHL rabbits and untreated WHHL rabbits. When, however, 125 I-labeled LDL was prepared from donor WHHL rabbits under treatment with probucol and injected back into them, the FCR was found to be increased by about 50% above that measured simultaneously using 131 I-labeled LDL prepared from untreated WHHL donors. The labeled LDL from probucol-treated donors was also metabolized more rapidly than that from untreated donors when injected into untreated WHHL rabbits or into untreated wild-type New Zealand White rabbits. Finally, it was shown that rabbit skin fibroblasts in culture degraded labeled LDL prepared from probucol-treated WHHL rabbits more rapidly than that prepared from untreated WHHL donors. This was true both for normal rabbit fibroblasts and also for WHHL skin fibroblasts, although the absolute degradation rates in the latter were, of course, much lower for both forms of LDL. The data indicate that a major mechanism by which probucol lowers LDL levels relates not to changes in the cellular mechanisms for LDL uptake or to changes in LDL production but rather to intrinsic changes in the structure and metabolism of the plasma LDL of the probucol-treated animal

  16. Leptin Reduces Pathology and Improves Memory in a Transgenic Mouse Model of Alzheimer’s Disease

    Science.gov (United States)

    Greco, Steven J.; Bryan, Kathryn J.; Sarkar, Sraboni; Zhu, Xiongwei; Smith, Mark A.; Ashford, J. Wesson; Johnston, Jane M.; Tezapsidis, Nikolaos; Casadesus, Gemma

    2010-01-01

    We have previously reported anti-amyloidogenic effects of leptin using in vitro and in vivo models and, more recently, demonstrated the ability of leptin to reduce tau phosphorylation in neuronal cells. The present study examined the efficacy of leptin in ameliorating the Alzheimer’s disease (AD)-like pathology in 6-month old CRND8 transgenic mice (TgCRND8) following 8 weeks of treatment. Leptin-treated transgenic mice showed significantly reduced levels of amyloid-β (Aβ)1-40 in both brain extracts (52% reduction, p=0.047) and serum (55% reduction, p=0.049), as detected by ELISA, and significant reduction in amyloid burden (47% reduction, p=0.041) in the hippocampus, as detected by immunocytochemistry. The decrease in the levels of Aβ in the brain correlated with a decrease in the levels of C99 C-terminal fragments of the amyloid-β protein precursor, consistent with a role for β-secretase in mediating the effect of leptin. In addition, leptin-treated TgCRND8 mice had significantly lower levels of phosphorylated tau, as detected by AT8 and anti-tau-Ser396 antibodies. Importantly, after 4 or 8 weeks of treatment, there was no significant increase in the levels of C-reactive protein, tumor necrosis factor-α, and cortisol in the plasma of leptin-treated TgCRND8 animals compared to saline-treated controls, indicating no inflammatory reaction. These biochemical and pathological changes were correlated with behavioral improvements, as early as after 4 weeks of treatment, as recorded by a novel object recognition test and particularly the contextual and cued fear conditioning test after 8 weeks of treatment. Leptin-treated TgCRND8 animals significantly outperformed saline-treated littermates in these behavioral tests. These findings solidly demonstrate the potential for leptin as a disease modifying therapeutic in transgenic animals of AD, driving optimism for its safety and efficacy in humans. PMID:20308782

  17. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism.

    Science.gov (United States)

    Park, Hyeong-Kyu; Ahima, Rexford S

    2015-01-01

    Leptin is secreted by adipose tissue and regulates energy homeostasis, neuroendocrine function, metabolism, immune function and other systems through its effects on the central nervous system and peripheral tissues. Leptin administration has been shown to restore metabolic and neuroendocrine abnormalities in individuals with leptin-deficient states, including hypothalamic amenorrhea and lipoatrophy. In contrast, obese individuals are resistant to leptin. Recombinant leptin is beneficial in patients with congenital leptin deficiency or generalized lipodystrophy. However, further research on molecular mediators of leptin resistance is needed for the development of targeted leptin sensitizing therapies for obesity and related metabolic diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8 + T cells aid progression of environment-linked nonalcoholic steatohepatitis

    International Nuclear Information System (INIS)

    Seth, Ratanesh Kumar; Das, Suvarthi; Kumar, Ashutosh; Chanda, Anindya; Kadiiska, Maria B.; Michelotti, Gregory; Manautou, Jose; Diehl, Anna Mae; Chatterjee, Saurabh

    2014-01-01

    Environmental toxins induce a novel CYP2E1/leptin signaling axis in liver. This in turn activates a poorly characterized innate immune response that contributes to nonalcoholic steatohepatitis (NASH) progression. To identify the relevant subsets of T-lymphocytes in CYP2E1-dependent, environment-linked NASH, we utilized a model of diet induced obese (DIO) mice that are chronically exposed to bromodichloromethane. Mice deficient in CYP2E1, leptin (ob/ob mice), or both T and B cells (Pfp/Rag2 double knockout (KO) mice) were used to delineate the role of each of these factors in metabolic oxidative stress-induced T cell activation. Results revealed that elevated levels of lipid peroxidation, tyrosyl radical formation, mitochondrial tyrosine nitration and hepatic leptin as a consequence of metabolic oxidative stress caused increased levels of hepatic CD57, a marker of peripheral blood lymphocytes including NKT cells. CD8 + CD57 + cytotoxic T cells but not CD4 + CD57 + cells were significantly decreased in mice lacking CYP2E1 and leptin. There was a significant increase in the levels of T cell cytokines IL-2, IL-1β, and IFN-γ in bromodichloromethane exposed DIO mice but not in mice that lacked CYP2E1, leptin or T and B cells. Apoptosis as evidenced by TUNEL assay and levels of cleaved caspase-3 was significantly lower in leptin and Pfp/Rag2 KO mice and highly correlated with protection from NASH. The results described above suggest that higher levels of oxidative stress-induced leptin mediated CD8 + CD57 + T cells play an important role in the development of NASH. It also provides a novel insight of immune dysregulation and may be a key biomarker in NASH. - Highlights: • Metabolic oxidative stress caused increased levels of hepatic CD57 expression. • CD8+ CD57+ cytotoxic T cells were decreased in mice lacking CYP2E1 and leptin. • There was a significant increase in T cell cytokines in toxin-treated mice. • Apoptosis was significantly lower in leptin and Pfp

  19. CYP2E1-dependent and leptin-mediated hepatic CD57 expression on CD8 + T cells aid progression of environment-linked nonalcoholic steatohepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Seth, Ratanesh Kumar; Das, Suvarthi [Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208 (United States); Kumar, Ashutosh [Free Radical Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Chanda, Anindya [Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208 (United States); Kadiiska, Maria B. [Free Radical Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Michelotti, Gregory [Division of Gastroenterology, Duke University, Durham, NC 27707 (United States); Manautou, Jose [Dept. of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092 (United States); Diehl, Anna Mae [Division of Gastroenterology, Duke University, Durham, NC 27707 (United States); Chatterjee, Saurabh, E-mail: schatt@mailbox.sc.edu [Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208 (United States)

    2014-01-01

    Environmental toxins induce a novel CYP2E1/leptin signaling axis in liver. This in turn activates a poorly characterized innate immune response that contributes to nonalcoholic steatohepatitis (NASH) progression. To identify the relevant subsets of T-lymphocytes in CYP2E1-dependent, environment-linked NASH, we utilized a model of diet induced obese (DIO) mice that are chronically exposed to bromodichloromethane. Mice deficient in CYP2E1, leptin (ob/ob mice), or both T and B cells (Pfp/Rag2 double knockout (KO) mice) were used to delineate the role of each of these factors in metabolic oxidative stress-induced T cell activation. Results revealed that elevated levels of lipid peroxidation, tyrosyl radical formation, mitochondrial tyrosine nitration and hepatic leptin as a consequence of metabolic oxidative stress caused increased levels of hepatic CD57, a marker of peripheral blood lymphocytes including NKT cells. CD8 + CD57 + cytotoxic T cells but not CD4 + CD57 + cells were significantly decreased in mice lacking CYP2E1 and leptin. There was a significant increase in the levels of T cell cytokines IL-2, IL-1β, and IFN-γ in bromodichloromethane exposed DIO mice but not in mice that lacked CYP2E1, leptin or T and B cells. Apoptosis as evidenced by TUNEL assay and levels of cleaved caspase-3 was significantly lower in leptin and Pfp/Rag2 KO mice and highly correlated with protection from NASH. The results described above suggest that higher levels of oxidative stress-induced leptin mediated CD8 + CD57 + T cells play an important role in the development of NASH. It also provides a novel insight of immune dysregulation and may be a key biomarker in NASH. - Highlights: • Metabolic oxidative stress caused increased levels of hepatic CD57 expression. • CD8+ CD57+ cytotoxic T cells were decreased in mice lacking CYP2E1 and leptin. • There was a significant increase in T cell cytokines in toxin-treated mice. • Apoptosis was significantly lower in leptin and Pfp

  20. Effect Of Leptin Status On Neuroendocrine- Reproductive ...

    African Journals Online (AJOL)

    The brain of each rat was harvested and processed into whole homogenate, and was used for some biochemicals assays (i.e isolation and purification of RNA, reverse transcription polymerase chain reaction (PCR), and leptin assay). The results showed that insulin increased the secretion of leptin, which in turn, reduced ...

  1. The Effects of Leptin on Breastfeeding Behaviour

    Directory of Open Access Journals (Sweden)

    Anna M. Cannon

    2015-09-01

    Full Text Available Breastfed infants have a reduced risk of becoming overweight and/or obese later in life. This protective effect has been partly attributed to leptin present in breastmilk. This study investigated 24-h variations of skim milk leptin and its relationship with breastmilk macronutrients and infant breastfeeding patterns. Exclusive breastfeeding mothers of term singletons (n = 19; age 10 ± 5 weeks collected pre- and post-feed breastmilk samples for every breastfeed over a 24-h period and test-weighed their infants to determine milk intake at every breastfeed over a 24-h period. Samples (n = 454 were analysed for leptin, protein, lactose and fat content. Skim milk leptin concentration did not change with feeding (p = 0.184. However, larger feed volumes (>105 g were associated with a decrease in post-feed leptin levels (p = 0.009. There was no relationship between the change in leptin levels and change in protein (p = 0.313 or lactose levels (p = 0.587 between pre- and post-feed milk, but there was a trend for a positive association with changes in milk fat content (p = 0.056. Leptin concentration significantly increased at night (p < 0.001 indicating a possible 24-h pattern. Leptin dose (ng was not associated with the time between feeds (p = 0.232. Further research should include analysis of whole breastmilk and other breastmilk fractions to extend these findings.

  2. Leptin: A cardiovascular perspective | Schutte | Journal of ...

    African Journals Online (AJOL)

    The development of obesity, as well as resultant type 2 diabetes, hypertension and cardiovascular disease, is causing concern in South Africa. Following the discovery of leptin in 1994, hopes were raised that the manipulation of the leptin axis might yield successful therapy for obesity. Although hope still remains, the role of ...

  3. Hypoxia preconditioned mesenchymal stem cells prevent cardiac fibroblast activation and collagen production via leptin.

    Directory of Open Access Journals (Sweden)

    Panpan Chen

    Full Text Available Activation of cardiac fibroblasts into myofibroblasts constitutes a key step in cardiac remodeling after myocardial infarction (MI, due to interstitial fibrosis. Mesenchymal stem cells (MSCs have been shown to improve post-MI remodeling an effect that is enhanced by hypoxia preconditioning (HPC. Leptin has been shown to promote cardiac fibrosis. The expression of leptin is significantly increased in MSCs after HPC but it is unknown whether leptin contributes to MSC therapy or the fibrosis process. The objective of this study was to determine whether leptin secreted from MSCs modulates cardiac fibrosis.Cardiac fibroblast (CF activation was induced by hypoxia (0.5% O2. The effects of MSCs on fibroblast activation were analyzed by co-culturing MSCs with CFs, and detecting the expression of α-SMA, SM22α, and collagen IαI in CFs by western blot, immunofluorescence and Sirius red staining. In vivo MSCs antifibrotic effects on left ventricular remodeling were investigated using an acute MI model involving permanent ligation of the left anterior descending coronary artery.Co-cultured MSCs decreased fibroblast activation and HPC enhanced the effects. Leptin deficit MSCs from Ob/Ob mice did not decrease fibroblast activation. Consistent with this, H-MSCs significantly inhibited cardiac fibrosis after MI and mediated decreased expression of TGF-β/Smad2 and MRTF-A in CFs. These effects were again absent in leptin-deficient MSCs.Our data demonstrate that activation of cardiac fibroblast was inhibited by MSCs in a manner that was leptin-dependent. The mechanism may involve blocking TGF-β/Smad2 and MRTF-A signal pathways.

  4. Muscarinic M3 receptors on structural cells regulate cigarette smoke-induced neutrophilic airway inflammation in mice

    NARCIS (Netherlands)

    Kistemaker, Loes E.M.; van Os, Ronald P.; Dethmers-Ausema, Albertina; Bos, I. Sophie T.; Hylkema, Machteld N.; van den Berge, Maarten; Hiemstra, Pieter S; Wess, Jürgen; Meurs, Herman; Kerstjens, Huib A.M.; Gosens, Reinoud

    2015-01-01

    Anticholinergics, blocking the muscarinic M-3 receptor, are effective bronchodilators for patients with chronic obstructive pulmonary disease. Recent evidence from M-3 receptor-deficient mice (M3R-/-) indicates that M-3 receptors also regulate neutrophilic inflammation in response to cigarette smoke

  5. Polymorphism in leptin receptor gene was associated with obesity in ...

    African Journals Online (AJOL)

    Pramudji Hastuti

    2016-01-11

    Jan 11, 2016 ... Abstract Background: Leptin is a hormone that regulates homeostasis energy through the cen- tral–peripheral mechanism as well as regulates hunger and satiety. Leptin receptor is important in leptin signal transduction that is located mainly in the hypothalamus. The mutation in leptin receptor (LEPR) gene ...

  6. Polymorphism in leptin receptor gene was associated with obesity in ...

    African Journals Online (AJOL)

    Background: Leptin is a hormone that regulates homeostasis energy through the central– peripheral mechanism as well as regulates hunger and satiety. Leptin receptor is important in leptin signal transduction that is located mainly in the hypothalamus. The mutation in leptin receptor (LEPR) gene causes splicing ...

  7. [Role of leptin in human reproduction (anorexia, bulimia)].

    Science.gov (United States)

    Pilka, L; Rumpík, D; Pilka, R

    2012-12-01

    Leptin may act as the critical link between adipose tissue and the reproductive system, indicating whether adequate energy reserves are presenting for normal reproductive functions. Future interventional studies involving leptin administration are excepted to further clarify this role of leptin and may provide new therapeutic options for the reproductive dysfunctions associated with states of relative leptin deficiency or resistance.

  8. Leptin: A proliferative factor for breast cancer?

    International Nuclear Information System (INIS)

    Caldefie-Chezet, F.; Damez, M.; Latour, M. de; Konska, G.; Mishellani, F.; Fusillier, C.; Guerry, M.; Penault-Llorca, F.; Guillot, J.; Vasson, M.-P.

    2005-01-01

    Mammary adipose tissue is an important source of paracrine mitogens and anti-mitogens, including insulin-like growth factor, transforming growth factors, and cytokines (especially, TNFα and IL-1β). Nevertheless, it is also an important source of the adipocytokine, leptin. Recently, leptin was reported to stimulate the proliferation of various cell types (pancreatic β cells, prostate, colorectal, lung, etc.) as a new growth factor. It was also shown to stimulate the proliferation of breast cancer cell lines. In this study, we conducted an immunohistochemical analysis of leptin expression in normal tissue and benign and malignant ductal breast cell, representing the different states of the invasion process. We determined for the first time that leptin is expressed both by ductal breast tumors and by benign lesions as atypical hyperplasia. This suggests that leptin may be taken up or synthesized by all modified ductal breast cells, and may prove a proliferative factor. Moreover, leptin is unexpressed by normal tissue in the healthy breast but is exhibited by the normal tissue in near vicinity of the malignant ductal breast lesions. We also postulated that leptin may be a prognostic or diagnostic factor for ductal breast cancer. These putative hypotheses require further study

  9. Leptin to adiponectin ratio in preeclampsia.

    Science.gov (United States)

    Khosrowbeygi, A; Ahmadvand, H

    2013-04-01

    The aim of the present study was to assess leptin/adiponectin ratio in preeclamptic patients compared with normal pregnant women. A cross-sectional study was designed. The study population consisted of 30 preeclamptic patients and 30 healthy pregnant women. Serum levels of total leptin and adiponectin were assessed using commercially available enzyme-linked immunosorbent assay methods. The one-way ANOVA and Student's t tests and Pearson's correlation analysis were used for statistical calculations. Levels of leptin and adiponectin were also adjusted for BMI. A p-value preeclamsia and imbalance between the adipocytokines could be involved in the pathogenesis of preeclampsia.

  10. Increased leptin/leptin receptor pathway affects systemic and airway inflammation in COPD former smokers.

    Science.gov (United States)

    Bruno, Andreina; Alessi, Marinella; Soresi, Simona; Bonanno, Anna; Riccobono, Loredana; Montalbano, Angela Marina; Albano, Giusy Daniela; Gjomarkaj, Mark; Profita, Mirella

    2011-01-01

    Leptin, a hormone produced mainly by adipose tissue, regulates food intake and energy expenditure. It is involved in inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and its deficiency is associated with increased susceptibility to the infection. The leptin receptor is expressed in the lung and in the neutrophils. We measured the levels of leptin, tumor necrosis factor alpha (TNF-α) and soluble form of intercellular adhesion molecule-1 (sICAM-1) in sputum and plasma from 27 smoker and former smoker patients with stable COPD using ELISA methods. Further we analyzed leptin and its receptor expression in sputum cells from 16 COPD patients using immunocytochemistry. In plasma of COPD patients, leptin was inversely correlated with TNF-α and positively correlated with the patient weight, whereas the levels of sICAM-1 were positively correlated with TNF-α. In sputum of COPD patients leptin levels were correlated with forced expiratory volume in 1 second/forced vitality capacity. Additionally, increased levels of sputum leptin and TNF-α were observed in COPD former smokers rather than smokers. Further the expression of leptin receptor in sputum neutrophils was significantly higher in COPD former smokers than in smokers, and the expression of leptin and its receptor was positively correlated in neutrophils of COPD former smokers. Our findings suggest a role of leptin in the local and systemic inflammation of COPD and, taking into account the involvement of neutrophils in this inflammatory disease, describe a novel aspect of the leptin/leptin receptor pathway in the regulation of host defense after smoking cessation.

  11. Leptin as well as Free Leptin Receptor Is Associated with Polycystic Ovary Syndrome in Young Women

    Directory of Open Access Journals (Sweden)

    Nasser M. Rizk

    2015-01-01

    Full Text Available Background and Aim. Leptin has two forms in the circulation: free and bound forms. The soluble leptin receptor (sOB-R circulates in the blood and can bind to leptin. The aim of this study is to assess the concentrations of the leptin and the sOB-R in PCOS and its relation to adiposity, insulin resistance, and androgens. Methods. A cross-sectional study included 78 female students aged 17–25 years. Fasting serum leptin and sOB-R concentrations were measured. The anthropometric variables and the hormonal profile such as insulin, female and male sex hormones, and prolactin were assessed. Results. In PCOS, leptin level (ng/ml and free leptin index (FLI increased significantly while sOB-R (ng/ml significantly decreased compared to control subjects. In age-matched subjects, obese PCOS had increased leptin level in ng/ml (median level with interquartile levels of 45.67 (41.98–48.04 and decreased sOB-R in ng/ml 11.47 (7.59–16.44 compared to lean PCOS 16.97 (10.60–45.55 for leptin and 16.62 (11.61–17.96 for sOB-R with p values 0.013 and 0.042, respectively. However, body mass index (BMI is significantly correlated with leptin and s-OBR, while no significant correlations with parameters of insulin resistance were detected. Conclusion. PCOS is associated with hyperleptinemia and increased free leptin index. Decreased sOB-R could be a compensatory mechanism for the defective action of leptin.

  12. Phocid seal leptin: tertiary structure and hydrophobic receptor binding site preservation during distinct leptin gene evolution.

    Directory of Open Access Journals (Sweden)

    John A Hammond

    Full Text Available The cytokine hormone leptin is a key signalling molecule in many pathways that control physiological functions. Although leptin demonstrates structural conservation in mammals, there is evidence of positive selection in primates, lagomorphs and chiropterans. We previously reported that the leptin genes of the grey and harbour seals (phocids have significantly diverged from other mammals. Therefore we further investigated the diversification of leptin in phocids, other marine mammals and terrestrial taxa by sequencing the leptin genes of representative species. Phylogenetic reconstruction revealed that leptin diversification was pronounced within the phocid seals with a high dN/dS ratio of 2.8, indicating positive selection. We found significant evidence of positive selection along the branch leading to the phocids, within the phocid clade, but not over the dataset as a whole. Structural predictions indicate that the individual residues under selection are away from the leptin receptor (LEPR binding site. Predictions of the surface electrostatic potential indicate that phocid seal leptin is notably different to other mammalian leptins, including the otariids. Cloning the grey seal leptin binding domain of LEPR confirmed that this was structurally conserved. These data, viewed in toto, support a hypothesis that phocid leptin divergence is unlikely to have arisen by random mutation. Based upon these phylogenetic and structural assessments, and considering the comparative physiology and varying life histories among species, we postulate that the unique phocid diving behaviour has produced this selection pressure. The Phocidae includes some of the deepest diving species, yet have the least modified lung structure to cope with pressure and volume changes experienced at depth. Therefore, greater surfactant production is required to facilitate rapid lung re-inflation upon surfacing, while maintaining patent airways. We suggest that this additional

  13. A bovine papillomavirus-1 based vector restores the function of the low-density lipoprotein receptor in the receptor-deficient CHO-ldlA7 cell line

    Directory of Open Access Journals (Sweden)

    Ustav Mart

    2002-04-01

    Full Text Available Abstract Background The rationale of using bovine papillomavirus-1 (BPV-1 derived vectors in gene therapy protocols lies in their episomal maintenance at intermediate to high copy number, and stable, high-level expression of the gene products. We constructed the BPV-1 based vector harbouring the human low-density lipoprotein receptor (LDLR gene cDNA and tested its ability to restore the function of the LDLR in the receptor-deficient cell line CHO-ldlA7. Results The introduced vector p3.7LDL produced functionally active LDL receptors in the receptor-deficient cell line CHO-ldlA7 during the 32-week period of observation as determined by the internalisation assay with the labelled LDL particles. Conclusion Bovine papillomavirus type-1 (BPV-1-derived vectors could be suitable for gene therapy due to their episomal maintenance at intermediate to high copy number and stable, high-level expression of the gene products. The constructed BPV-1 based vector p3.7LDL produced functionally active LDL receptors in the LDLR-deficient cell line CHO-ldlA7 during the 32-week period of observation. In vivo experiments should reveal, whether 1–5% transfection efficiency obtained in the current work is sufficient to bring about detectable and clinically significant lowering of the amount of circulating LDL cholesterol particles.

  14. Presynaptic Regulation of Leptin in a Defined Lateral Hypothalamus-Ventral Tegmental Area Neurocircuitry Depends on Energy State.

    Science.gov (United States)

    Liu, Jing-Jing; Bello, Nicholas T; Pang, Zhiping P

    2017-12-06

    Synaptic transmission controls brain activity and behaviors, including food intake. Leptin, an adipocyte-derived hormone, acts on neurons located in the lateral hypothalamic area (LHA) to maintain energy homeostasis and regulate food intake behavior. The specific synaptic mechanisms, cell types, and neural projections mediating this effect remain unclear. In male mice, using pathway-specific retrograde tracing, whole-cell patch-clamp recordings and post hoc cell type identification, we found that leptin reduces excitatory synaptic strength onto both melanin-concentrating hormone- and orexin-expressing neurons projecting from the LHA to the ventral tegmental area (VTA), which may affect dopamine signaling and motivation for feeding. A presynaptic mechanism mediated by distinct intracellular signaling mechanisms may account for this regulation by leptin. The regulatory effects of leptin depend on intact leptin receptor signaling. Interestingly, the synaptic regulatory function of leptin in the LHA-to-VTA neuronal pathway is highly sensitive to energy states: both energy deficiency (acute fasting) and excessive energy storage (high-fat diet-induced obesity) blunt the effect of leptin. These data revealed that leptin may regulate synaptic transmission in the LHA-to-VTA neurocircuitry in an inverted "U-shape" fashion dependent on plasma glucose levels and related to metabolic states. SIGNIFICANCE STATEMENT The lateral hypothalamic area (LHA) to ventral tegmental area (VTA) projection is an important neural pathway involved in balancing whole-body energy states and reward. We found that the excitatory synaptic inputs to both orexin- and melanin-concentrating hormone expressing LHA neurons projecting to the VTA were suppressed by leptin, a peptide hormone derived from adipocytes that signals peripheral energy status to the brain. Interestingly, energy states seem to affect how leptin regulates synaptic transmission since both the depletion of energy induced by acute food

  15. Plasma leptin concentrations in newborns of diabetic and nondiabetic mothers.

    Science.gov (United States)

    Gross, G A; Solenberger, T; Philpott, T; Holcomb, W L; Landt, M

    1998-04-01

    Leptin plays an important role in regulating body composition through modulation of appetite and energy expenditure. We hypothesized that leptin levels in umbilical cord blood correlate with newborn body weight and habitus. We also hypothesized that infants of diabetic mothers would demonstrate altered leptin metabolism. Venous blood was sampled at birth from the umbilical cords of 105 infants (74 infants of nondiabetic mothers, and 31 infants of diabetic mothers). Thirty-nine mothers had plasma leptin concentrations measured. Analysis was done using Student's t-test, Pearson's correlation, and Spearman's correlation. Univariate/multivariate regression was used for analysis of factors associated with leptin concentration in umbilical cord plasma. Maternal and newborn characteristics were correlated with log leptin levels in umbilical venous plasma. Leptin concentration in umbilical cord plasma correlated best with birth weight for newborns of both nondiabetic and diabetic mothers (p relationship between umbilical cord leptin level and newborn birth weight, as well as maternal DM, but not with gestational age. Similarly, there was no significant correlation with maternal plasma leptin concentration. The strong correlation of leptin concentration in umbilical cord plasma with newborn birth weight, and the lack of significant correlation with maternal leptin plasma levels, suggest that normal fetal leptin metabolism reflects fetal size and/or body habitus independent of maternal leptin metabolism. On the other hand, the higher umbilical plasma levels in infants of diabetic mothers may reflect an influence of altered fetal insulin homeostasis on fetal leptin metabolism, and suggests that maternal diabetes may influence fetal leptin metabolism.

  16. Leptin Regulation of Mammary Cell Growth

    National Research Council Canada - National Science Library

    Pighetti, Gina

    2000-01-01

    .... The studies of this proposal were designed to test the hypothesis that the interaction of leptin with its receptor regulates normal and pathologic mammary epithelial cell proliferation and/or differentiation...

  17. Benefits of leptin therapy in HIV patients

    Directory of Open Access Journals (Sweden)

    Uma Sinha

    2012-01-01

    Full Text Available Leptin therapy in human recombinant form has recently been used in HIV-associated lipodystrophy syndrome on experimental basis in some small short-term clinical trials. It has shown its beneficial effects only in hypoleptinemic HIV-infected patients by causing definite improvement in their insulin sensitivity, glucose tolerance, lipid status, and truncal obesity. Leptin prevents lipotoxicity and activates insulin signaling pathways through several postulated mechanisms. Central leptin insufficiency with peripheral hyperleptinemia has come out to be a significant contributor to the development of obesity and metabolic syndrome. In this article, we will review the basis of leptin therapy in HIV patients, with its promises. However, further larger clinical trials are needed to prove its long-term efficacy in the control of metabolic complications related to HIV therapy.

  18. Leptin and cancer: Pathogenesis and modulation

    Directory of Open Access Journals (Sweden)

    Deep Dutta

    2012-01-01

    Full Text Available Leptin, a product of Ob gene from adipocytes regulates appetite, energy expenditure and body mass composition by decreasing orexigenic and increasing anorexigenic neuropeptide release from hypothalamus. Research over the past few years have suggested leptin/leptin receptor dysregulation to have a role in the development of a large variety of malignancies like breast ca, thyroid ca, endometrial ca and gastrointestinal malignancies, predominantly through JAK/STAT pathway which modulates PI3K/AKT3 signaling, ERK1/2 signaling, expression of antiapoptotic proteins (like XIAP, systemic inflammation (TNF-α, IL6, angiogenic factors (VEGF and hypoxia inducible factor-1a (HIF-1a expression. In this review, the current understanding of leptin′s role in carcinogenesis has been elaborated. Also a few agents modulating leptin signaling to inhibit cancer cell growth has been described.

  19. Pivotal role of leptin in insulin effects

    Directory of Open Access Journals (Sweden)

    R.B. Ceddia

    1998-06-01

    Full Text Available The OB protein, also known as leptin, is secreted by adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks regulating ingestive behavior and energy balance. The two forms of leptin receptors (long and short forms have been identified in various peripheral tissues, a fact that makes them possible target sites for a direct action of leptin. It has been shown that the OB protein interferes with insulin secretion from pancreatic islets, reduces insulin-stimulated glucose transport in adipocytes, and increases glucose transport, glycogen synthesis and fatty acid oxidation in skeletal muscle. Under normoglycemic and normoinsulinemic conditions, leptin seems to shift the flux of metabolites from adipose tissue to skeletal muscle. This may function as a peripheral mechanism that helps control body weight and prevents obesity. Data that substantiate this hypothesis are presented in this review.

  20. The importance of leptin in animal science

    Directory of Open Access Journals (Sweden)

    Mirela Ahmadi

    2016-05-01

    Full Text Available There are two different neurons that control the energetic homeostasis in animals: appetite-stimulating and appetite-suppressing neurons. Leptin is a peptide hormone (also known as “satiety hormone”, released by adipose cells, being an anorexigenic compound which inhibit the hunger. Leptin function in animal organism is opposite by the action of ghrelin – a peptide hormone acting as an orexigenic compound that activate the hunger sensation. The quantity of leptin produced in organism is correlated by the size and the number of adipocytes, and of course by the lipid tissue mass. The action of leptin is in accordance with the neuropeptide Y that signaling the brain to increase the appetite and make the animal to eat. When the animals lose weight, the mass of adipose tissue is diminished, that has as consequence a decrease the leptin concentration in the blood. Blood leptin is correlated also with other characteristics, such as: fasting for a short term, stress, physical activity, sleep duration (prehibernation and hibernation, insulin concentration, obesity and diabetes.

  1. 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...

  2. The SH2B gene is associated with serum leptin and body fat in normal female twins

    NARCIS (Netherlands)

    Jamshidi, Yalda; Snieder, Harold; Ge, Dongliang; Spector, Tim D.; O'Dell, Sandra D.

    Src-homology-2 (SH2)-B, a Janus tyrosine kinase 2-interacting protein, has been identified recently as a key regulator of leptin and insulin sensitivity, glucose homeostasis, and body weight in mice. The aim of this study was to determine whether single-nucleotide polymorphisms (SNPs) in the human

  3. Elevated circulating leptin levels in arterial hypertension: relationship to arteriovenous overflow and extraction of leptin

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik; Holst, J J; Møller, Søren

    2000-01-01

    concentrations in such patients could be caused by altered rates of production or disposal, or both, the aim of the present study was to identify regions of leptin overflow into the bloodstream and of leptin extraction. Patients with arterial hypertension (n=12) and normotensive controls (n=20) were studied...

  4. Sheep oocyte expresses leptin and functional leptin receptor mRNA

    Directory of Open Access Journals (Sweden)

    Seyyed Jalil Taheri

    2016-09-01

    Conclusions: The result of present study reveals that leptin and its functional receptor (Ob-Rb mRNA are expressed in sheep oocyte and further studies should investigate the role(s of leptin on sheep oocyte physiology and embryo development.

  5. Hypoxic Living and Exercise Training Alter Adipose Tissue Leptin/Leptin Receptor in Rats

    Directory of Open Access Journals (Sweden)

    Yingli Lu

    2016-11-01

    Full Text Available Background: Hypobaric hypoxia results in weight loss in obese individuals, and exercise training is advocated for the treatment of obesity and its related metabolic dysfunctions. The purpose of this study was to investigate the effects of hypoxic living and exercise training on obesity and adipose tissue leptin/leptin receptor in dietary-induced obese rats. Methods: One hundred and thirty high-fat diet fed Sprague-Dawley rats were assigned into one of the following groups (n=10 each: control, sedentary hypoxic living for 1 to 4 weeks (SH1, SH2, SH3, and SH4, living and exercise training in normoxic conditions for 1 to 4 weeks (TN1, TN2, TN3, and TN4, and living and exercise training in hypoxic conditions for 1 to 4 weeks (TN1, TN2, TN3, and TN4. Epididymal adipose tissue expression levels of leptin and leptin receptor were determined. Results: Compared to hypoxic living and living and exercise training in normoxic conditions, living and exercise training in hypoxic conditions for 3-4 weeks resulted in lower Lee index (P<0.05 to P<0.01, and higher expression of leptin and leptin receptor (P<0.05 to P<0.01 in adipose tissue. Conclusion: In a rodent model of altitude training, living and exercise training in hypoxic conditions resulted in greater alterations in obesity and adipose tissue leptin/leptin receptor than hypoxic living alone and living and exercise training in normoxic conditions.

  6. Elevated circulating leptin levels in arterial hypertension: relationship to arteriovenous overflow and extraction of leptin

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik; Holst, J J; Møller, Søren

    2000-01-01

    Leptin, a peptide hormone produced mainly in fat cells, appears to be important for the regulation of metabolism, insulin secretion/sensitivity and body weight. Recently, elevated plasma leptin levels have been reported in patients with arterial hypertension. Because a change in circulating lepti...

  7. Elevated circulating leptin levels in arterial hypertension: relationship to arteriovenous overflow and extraction of leptin

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Holst, J J; Moller, S

    2000-01-01

    during catheterization with elective blood sampling from different vascular beds (artery, and renal, hepatic, iliac and cubital veins). Plasma leptin was determined by a radioimmunoassay. Patients with hypertension had significantly elevated levels of circulating leptin (12.8 ng/l, compared with 4.1 ng....../l in the controls; Pblood pressure (r=0.38-0.62, P...

  8. Leptin promoter variant G2548A is associated with serum leptin and ...

    Indian Academy of Sciences (India)

    Leptin is a protein hormone synthesized by adipocytes and is involved in the regulation of food intake and energy expenditure. We hypothesized that any change in the promoter sequence can affect the expression of the gene and hence leptin protein levels in the serum. The aim of the current study was to investigate the ...

  9. Role of leptin in reverse epidemiology in chronic kidney disease

    DEFF Research Database (Denmark)

    Scholze, Alexandra; Tepel, Martin

    2007-01-01

    , indicating leptin resistance. In healthy subjects increased leptin concentration constitutes a biomarker for increased cardiovascular risk. On the other hand, a recent prospective long-term study in patients with chronic kidney disease stage 5 on hemodialysis therapy showed that reduced serum leptin......Leptin is mainly produced by adipocytes and metabolized in the kidney. Leptin is taken up into the central nervous system by a saturable transport system, and controls appetite in rodents and in healthy subjects. Leptin acts on peripheral tissue and increases the inflammatory response...

  10. 5-HT2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress

    Directory of Open Access Journals (Sweden)

    Minal Jaggar

    2017-12-01

    Full Text Available Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin2A (5-HT2A receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC and hippocampus in 5-HT2A receptor knockout (5-HT2A−/− and wild-type mice of both sexes. While 5-HT2A−/− male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stress-evoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-HT2A−/− female mice with a hyperlipidemic baseline phenotype. 5-HT2A−/− male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes (Crh, Crhr1, Nr3c1, and Nr3c2, trophic factors (Bdnf, Igf1 and immediate early genes (IEGs (Arc, Fos, Fosb, Egr1-4 in the PFC and hippocampus were altered in 5-HT2A−/− mice both under baseline and CUS conditions. Our results support a role for the 5-HT2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT2A receptor to stress-evoked changes is sexually dimorphic. Keywords: 5-HT2A−/− mice, Prefrontal cortex, Hippocampus, Gene expression, Sexual dimorphism, Despair

  11. Leptin, adiponectin, leptin to adiponectin ratio and insulin resistance in depressive women.

    Science.gov (United States)

    Zeman, Miroslav; Jirak, Roman; Jachymova, Marie; Vecka, Marek; Tvrzicka, Eva; Zak, Ales

    2009-01-01

    Depressive disorder (DD) is associated with an increased risk of type 2 diabetes mellitus (DM2) and cardiovascular disease (CVD). It was suggested, that metabolic syndrome (MetS), cluster of metabolic and hormonal changes, such as insulin resistence (IR), abdominal obesity, dyslipidemia, arterial hypertension and elevated fasting glycaemia, could stand behind the connection. Recent findings have shown, that adipocytokines leptin and adiponectin might play a role in both depression and MetS. The aim of this pilot study was to observe the plasma concentrations of leptin, adiponectin, leptin-to-adiponectin ratio and indices of IR in women with depressive disorder. The plasma leptin, adiponectin, parameters of lipid and glucose homeostasis and indices of IR were investigated in a group of 38 women with DD. The results were compared with those of 38 healthy women of the control group, matched for age. Depressive women differed significantly from the controls in higher concentrations of plasma leptin (p DM2 or CVD.

  12. Automated pipeline to analyze non-contact infrared images of the paraventricular nucleus specific leptin receptor knock-out mouse model

    Science.gov (United States)

    Diaz Martinez, Myriam; Ghamari-Langroudi, Masoud; Gifford, Aliya; Cone, Roger; Welch, E. B.

    2015-03-01

    Evidence of leptin resistance is indicated by elevated leptin levels together with other hallmarks of obesity such as a defect in energy homeostasis.1 As obesity is an increasing epidemic in the US, the investigation of mechanisms by which leptin resistance has a pathophysiological impact on energy is an intensive field of research.2 However, the manner in which leptin resistance contributes to the dysregulation of energy, specifically thermoregulation,3 is not known. The aim of this study was to investigate whether the leptin receptor expressed in paraventricular nucleus (PVN) neurons plays a role in thermoregulation at different temperatures. Non-contact infrared (NCIR) thermometry was employed to measure surface body temperature (SBT) of nonanesthetized mice with a specific deletion of the leptin receptor in the PVN after exposure to room (25 °C) and cold (4 °C) temperature. Dorsal side infrared images of wild type (LepRwtwt/sim1-Cre), heterozygous (LepRfloxwt/sim1-Cre) and knock-out (LepRfloxflox/sim1-Cre) mice were collected. Images were input to an automated post-processing pipeline developed in MATLAB to calculate average and maximum SBTs. Linear regression was used to evaluate the relationship between sex, cold exposure and leptin genotype with SBT measurements. Findings indicate that average SBT has a negative relationship to the LepRfloxflox/sim1-Cre genotype, the female sex and cold exposure. However, max SBT is affected by the LepRfloxflox/sim1-Cre genotype and the female sex. In conclusion this data suggests that leptin within the PVN may have a neuroendocrine role in thermoregulation and that NCIR thermometry combined with an automated imaging-processing pipeline is a promising approach to determine SBT in non-anesthetized mice.

  13. Role of leptin in farm animals: a review.

    Science.gov (United States)

    Mácajová, M; Lamosová, D; Zeman, M

    2004-05-01

    The discovery of hormone leptin has led to better understanding of the energy balance control. In addition to its effects on food intake and energy expenditure, leptin has now been implicated as a mediator of diverse physiological functions. Recently, leptin has been cloned in several domestic species. The sequence similarity suggests a common function or mechanism of this peptide hormone across species. Leptin receptors are expressed in most of tissues, which is consistent with the multiplicity of leptin functions. The main goal of this review was to summarize knowledge about effect of leptin on physiology of farm animals. Experiments point to a stimulatory action of leptin on growth hormone (GH) secretion, normal growth and development of the brain. Surprisingly, leptin is synthesized at a high rate in placenta and may function as a growth factor for fetus, signalling the nutritional status from the mother to her offspring. Maturation of reproductive system can be stimulated by leptin administration. Morphological and hormonal changes, consistent with a major role of leptin in the reproductive system, have also been described, including the stimulation of the release of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin. Leptin has a substantial effect on food intake and feeding behaviour in animals. Administration of leptin reduces food intake. Its level decrease within hours after initiation of fasting. Leptin also serves as a mediator of the adaptation to fasting, and this role may be the primary function for which was the molecule evolved.

  14. Leptin signaling is required for adaptive changes in food intake, but not energy expenditure, in response to different thermal conditions.

    Science.gov (United States)

    Kaiyala, Karl J; Ogimoto, Kayoko; Nelson, Jarrell T; Schwartz, Michael W; Morton, Gregory J

    2015-01-01

    Survival of free-living animals depends on the ability to maintain core body temperature in the face of rapid and dramatic changes in their thermal environment. If food intake is not adjusted to meet the changing energy demands associated with changes of ambient temperature, a serious challenge to body energy stores can occur. To more fully understand the coupling of thermoregulation to energy homeostasis in normal animals and to investigate the role of the adipose hormone leptin to this process, comprehensive measures of energy homeostasis and core temperature were obtained in leptin-deficient ob/ob mice and their wild-type (WT) littermate controls when housed under cool (14°C), usual (22°C) or ∼ thermoneutral (30°C) conditions. Our findings extend previous evidence that WT mice robustly defend normothermia in response to either a lowering (14°C) or an increase (30°C) of ambient temperature without changes in body weight or body composition. In contrast, leptin-deficient, ob/ob mice fail to defend normothermia at ambient temperatures lower than thermoneutrality and exhibit marked losses of both body fat and lean mass when exposed to cooler environments (14°C). Our findings further demonstrate a strong inverse relationship between ambient temperature and energy expenditure in WT mice, a relationship that is preserved in ob/ob mice. However, thermal conductance analysis indicates defective heat retention in ob/ob mice, irrespective of temperature. While a negative relationship between ambient temperature and energy intake also exists in WT mice, this relationship is disrupted in ob/ob mice. Thus, to meet the thermoregulatory demands of different ambient temperatures, leptin signaling is required for adaptive changes in both energy intake and thermal conductance. A better understanding of the mechanisms coupling thermoregulation to energy homeostasis may lead to the development of new approaches for the treatment of obesity.

  15. Increased leptin/leptin receptor pathway affects systemic and airway inflammation in COPD former smokers

    Directory of Open Access Journals (Sweden)

    Bruno A

    2011-05-01

    Full Text Available Andreina Bruno1, Marinella Alessi2, Simona Soresi2, Anna Bonanno1, Loredana Riccobono1, Angela Marina Montalbano1, Giusy Daniela Albano1, Mark Gjomarkaj1, Mirella Profita11Institute of Biomedicine and Molecular Immunology, Italian National Research Council, Palermo, Italy; 2Dipartimento Biomedico di Biomedicina Interna e Specialistica, University Palermo, ItalyBackground: Leptin, a hormone produced mainly by adipose tissue, regulates food intake and energy expenditure. It is involved in inflammatory diseases such as chronic obstructive pulmonary disease (COPD and its deficiency is associated with increased susceptibility to the infection. The leptin receptor is expressed in the lung and in the neutrophils.Methods: We measured the levels of leptin, tumor necrosis factor alpha (TNF-a and soluble form of intercellular adhesion molecule-1 (sICAM-1 in sputum and plasma from 27 smoker and former smoker patients with stable COPD using ELISA methods. Further we analyzed leptin and its receptor expression in sputum cells from 16 COPD patients using immunocytochemistry.Results: In plasma of COPD patients, leptin was inversely correlated with TNF-a and positively correlated with the patient weight, whereas the levels of sICAM-1 were positively correlated with TNF-a. In sputum of COPD patients leptin levels were correlated with forced expiratory volume in 1 second/forced vitality capacity. Additionally, increased levels of sputum leptin and TNF-a were observed in COPD former smokers rather than smokers. Further the expression of leptin receptor in sputum neutrophils was significantly higher in COPD former smokers than in smokers, and the expression of leptin and its receptor was positively correlated in neutrophils of COPD former smokers.Conclusion: Our findings suggest a role of leptin in the local and systemic inflammation of COPD and, taking into account the involvement of neutrophils in this inflammatory disease, describe a novel aspect of the leptin/leptin

  16. Discovery of the elusive leptin in birds: identification of several 'missing links' in the evolution of leptin and its receptor.

    Directory of Open Access Journals (Sweden)

    Jeremy W Prokop

    Full Text Available Leptin is a pleiotropic protein best known for regulation of appetite and fat storage in mammals. While many leptin orthologs have been identified among vertebrates, an authentic leptin in birds has remained elusive and controversial. Here we identify leptin sequence from the Peregrine falcon, Falco peregrinus (pfleptin, and identify sequences from two other birds (mallard and zebra finch, and 'missing' vertebrates (elephant shark, alligator, Indian python, Chinese soft-shelled turtle, and coelacanth. The pattern of genes surrounding leptin (snd1, rbm28 is syntenic between the falcon and mammalian genomes. Phylogenetic analysis of all known leptin protein sequences improves our understanding of leptin's evolution. Structural modeling of leptin orthologs highlights a highly conserved hydrophobic core in the four-helix cytokine packing domain. A docked model of leptin with the leptin receptor for Peregrine falcon reveals several conserved amino acids important for the interaction and possible coevolution of leptin with its receptor. We also show for the first time, an authentic avian leptin sequence that activates the JAK-STAT signaling pathway. These newly identified sequences, structures, and tools for avian leptin and its receptor will allow elucidation of the function of these proteins in feral and domestic birds.

  17. The role of leptin in the respiratory system: an overview

    Directory of Open Access Journals (Sweden)

    Gourgoulianis Konstantinos I

    2010-10-01

    Full Text Available Abstract Since its cloning in 1994, leptin has emerged in the literature as a pleiotropic hormone whose actions extend from immune system homeostasis to reproduction and angiogenesis. Recent investigations have identified the lung as a leptin responsive and producing organ, while extensive research has been published concerning the role of leptin in the respiratory system. Animal studies have provided evidence indicating that leptin is a stimulant of ventilation, whereas researchers have proposed an important role for leptin in lung maturation and development. Studies further suggest a significant impact of leptin on specific respiratory diseases, including obstructive sleep apnoea-hypopnoea syndrome, asthma, COPD and lung cancer. However, as new investigations are under way, the picture is becoming more complex. The scope of this review is to decode the existing data concerning the actions of leptin in the lung and provide a detailed description of leptin's involvement in the most common disorders of the respiratory system.

  18. The role of leptin in the respiratory system: an overview.

    Science.gov (United States)

    Malli, Foteini; Papaioannou, Andriana I; Gourgoulianis, Konstantinos I; Daniil, Zoe

    2010-10-31

    Since its cloning in 1994, leptin has emerged in the literature as a pleiotropic hormone whose actions extend from immune system homeostasis to reproduction and angiogenesis. Recent investigations have identified the lung as a leptin responsive and producing organ, while extensive research has been published concerning the role of leptin in the respiratory system. Animal studies have provided evidence indicating that leptin is a stimulant of ventilation, whereas researchers have proposed an important role for leptin in lung maturation and development. Studies further suggest a significant impact of leptin on specific respiratory diseases, including obstructive sleep apnoea-hypopnoea syndrome, asthma, COPD and lung cancer. However, as new investigations are under way, the picture is becoming more complex. The scope of this review is to decode the existing data concerning the actions of leptin in the lung and provide a detailed description of leptin's involvement in the most common disorders of the respiratory system.

  19. Role of leptin during childhood growth and development.

    Science.gov (United States)

    Roemmich, J N; Rogol, A D

    1999-12-01

    Leptin, the product of the ob/ob gene in rodents, regulates energy balance and fertility. Two genetic models, the ob/ob mouse (deletion of leptin protein) and the db/db mouse (deletion of leptin receptor) have markedly augmented research in obesity. Human obesity is more closely linked to leptin resistance than to the absence of leptin. Serum leptin concentrations reflect the size of the subcutaneous fat depot better than total fat mass or abdominal visceral fat. At the initiation of puberty there is a divergence in circulating leptin concentrations between boys and girls. In boys, leptin concentrations increase and then markedly decrease to prepubertal concentration levels. In girls there are only increasing concentrations. The authors believe these patterns are relevant to the markedly different alterations in the regional distribution of body fat that occurs in boys and girls at puberty.

  20. The impact of leptin on perinatal development and psychopathology.

    Science.gov (United States)

    Valleau, Jeanette C; Sullivan, Elinor L

    2014-11-01

    Leptin has long been associated with metabolism as it is a critical regulator of both food intake and energy expenditure, but recently, leptin dysregulation has been proposed as a mechanism of psychopathology. This review discusses the evidence supporting a role for leptin in mental health disorders and describes potential mechanisms that may underlie this association. Leptin plays a critical role in pregnancy and in fetal growth and development. Leptin's role and profile during development is examined in available human studies, and the validity of applying studies conducted in animal models to the human population are discussed. Rodents experience a postnatal leptin surge, which does not occur in humans or larger animal models. This suggests that further research using large mammal models, which have a leptin profile across pregnancy and development similar to humans, are of high importance. Maternal obesity and hyperleptinemia correlate with increased leptin levels in the umbilical cord, placenta, and fetus. Leptin levels are thought to impact fetal brain development; likely by activating proinflammatory cytokines that are known to impact many of the neurotransmitter systems that regulate behavior. Leptin is likely involved in behavioral regulation as leptin receptors are widely distributed in the brain, and leptin influences cortisol release, the mesoaccumbens dopamine pathway, serotonin synthesis, and hippocampal synaptic plasticity. In humans, both high and low levels of leptin are reported to be associated with psychopathology. This inconsistency is likely due to differences in the metabolic state of the study populations. Leptin resistance, which occurs in the obese state, may explain how both high and low levels of leptin are associated with psychopathology, as well as the comorbidity of obesity with numerous mental illnesses. Leptin resistance is likely to influence disorders such as depression and anxiety where high leptin levels have been correlated

  1. The role of leptin in the respiratory system: an overview

    OpenAIRE

    Malli, Foteini; Papaioannou, Andriana I; Gourgoulianis, Konstantinos I; Daniil, Zoe

    2010-01-01

    Abstract Since its cloning in 1994, leptin has emerged in the literature as a pleiotropic hormone whose actions extend from immune system homeostasis to reproduction and angiogenesis. Recent investigations have identified the lung as a leptin responsive and producing organ, while extensive research has been published concerning the role of leptin in the respiratory system. Animal studies have provided evidence indicating that leptin is a stimulant of ventilation, whereas researchers have prop...

  2. Leptin responses to bovine interferon- α and insulin in cattle

    African Journals Online (AJOL)

    Leptin is a protein synthesized and secreted mainly by adipose tissue. Peripheral administration of different inflammatory cytokines increases both leptin protein and mRNA expression in rodents. We previously showed that injection of lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF-α) did not affect leptin ...

  3. Correlation between maternal and cord blood leptin and fetal growth

    African Journals Online (AJOL)

    SERVER

    2007-09-05

    Sep 5, 2007 ... IL -2 and growth hormone. The long form of the leptin receptor functions similarly to cytokine ... regulation of leptin synthesis and the risk for obesity in the offspring. In species such as the human and sheep, ..... Hormonal regulation of leptin levels in the fetus and neonate might be different from the endocrine ...

  4. Influence of age on leptin induced skeletal muscle signaling

    DEFF Research Database (Denmark)

    Guadalupe Grau, Amelia; Larsen, Steen; Guerra, Borja

    2014-01-01

    Age associated fat mass accumulation could be due to dysregulation of leptin signaling in skeletal muscle. Thus, we investigated total protein expression and phosphorylation levels of the long isoform of the leptin receptor (OB-Rb), and leptin signaling through Janus Kinase 2 (JAK2)/signal...... skeletal muscle of different age....

  5. Plumbagin Inhibits Leptin-Induced Proliferation of Hepatic Stellate ...

    African Journals Online (AJOL)

    Purpose: To investigate the protective effects of plumbagin against liver fibrosis and explore the influence of plumbagin on the proliferation of hepatic stellate cells (HSCs). Methods: HSC-LX2 cells were divided into blank/control group, 100 ng/ml leptin group, 100 ng/ml leptin + 2 μmol/L plumbagin group, 100 ng/ml leptin + ...

  6. Gender differences in leptin levels and physiology: a role for leptin in human reproduction.

    Science.gov (United States)

    Wauters, M; Van Gaal, L

    1999-01-01

    Leptin, an adipocyte-derived hormone known to play an important role in body-weight regulation, has been shown to be expressed differentially in men and women. These observations are potentially important for the understanding of differences between men and women in regulation of food intake, weight gain, and body fat distribution. Leptin is also involved in female fertility, especially in pubertal development. It may well be the triggering signal for the onset of puberty in girls. Although the exact mechanisms and interactions with sex steroids are not yet fully established, it is clear that leptin plays a role as an endocrine mediator in sexual development and reproduction.

  7. Role of leptin in female reproduction.

    Science.gov (United States)

    Pérez-Pérez, Antonio; Sánchez-Jiménez, Flora; Maymó, Julieta; Dueñas, José L; Varone, Cecilia; Sánchez-Margalet, Víctor

    2015-01-01

    Reproductive function is dependent on energy resources. The role of weight, body composition, fat distribution and the effect of diet have been largely investigated in experimental female animals as well as in women. Any alteration in diet and/or weight may induce abnormalities in timing of sexual maturation and fertility. However, the cellular mechanisms involved in the fine coordination of energy balance and reproduction are largely unknown. The brain and hypothalamic structures receive endocrine and/or metabolic signals providing information on the nutritional status and the degree of fat stores. Adipose tissue acts both as a store of energy and as an active endocrine organ, secreting a large number of biologically important molecules termed adipokines. Adipokines have been shown to be involved in regulation of the reproductive functions. The first adipokine described was leptin. Extensive research over the last 10 years has shown that leptin is not only an adipose tissue-derived messenger of the amount of energy stores to the brain, but also a crucial hormone/cytokine for a number of diverse physiological processes, such as inflammation, angiogenesis, hematopoiesis, immune function, and most importantly, reproduction. Leptin plays an integral role in the normal physiology of the reproductive system with complex interactions at all levels of the hypothalamic-pituitary gonadal (HPG) axis. In addition, leptin is also produced by placenta, where it plays an important autocrine function. Observational studies have demonstrated that states of leptin excess, deficiency, or resistance can be associated with abnormal reproductive function. This review focuses on the leptin action in female reproduction.

  8. Leptin Level in Women with Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Alexander V. Dreval, PhD, ScD

    2013-06-01

    Full Text Available A detailed study of the dynamics of leptin in the various types of disturbances in carbohydrate metabolism could reveal its role in the pathogenesis of Type 2 Diabetes Mellitus (T2DM. The aim of this study was to investigate the Fasting Leptin Level (FLL and effect of acute hyperinsulinemia during the Intravenous Glucose Tolerance Test (IVGTT on the leptin levels in women with Insulin Resistance Syndrome (IRS. Materials and Methods: In total, 59 obese women (54.0 [48.5-60.0] yrs; BMI – 33.2 [29.0-37.2] kg/m² with IRS (12 – obesity (NGT, 18 - ITG and 30 - T2DM were observed. The IVGTT test was done only in women with impaired glucose tolerance (IGT and T2DM. The leptin level was investigated during fasting conditions and again 120 min post glucose loading. Then the Hepatic glucose production Index (H-index was calculated using the IVGTT data. Results: The FLL in women with normal glucose tolerance (NGT was almost two times greater than in women with IGT and T2DM. A negative relationship was found to exist between FLL and HbA1c in T2DM (r=0.3, p8%. The leptin level significantly decreased at 120 min of IVGTT in both the IGT and T2DM groups (p<0.05. Conclusion: The FLL depended upon the degree of glucose metabolism impairment; postprandial leptin response to the glucose load was lower in the IGT group than in the T2DM subjects.

  9. Expression and immunohistochemical localization of leptin in human periapical granulomas

    Science.gov (United States)

    Martín-González, Jénifer; Carmona-Fernández, Antonio; Pérez-Pérez, Antonio; Sánchez-Jiménez, Flora; Sánchez-Margalet, Víctor

    2015-01-01

    Background Leptin, initially described as an adipocyte-derived hormone to regulate weight control, is expressed in normal and inflamed human dental pulp, being up-regulated during pulp experimental inflammation. Leptin receptor (LER) has been identified in human periapical granulomas. The aim of this study was to analyze and characterize the expression of leptin in human periapical granulomas. Material and Methods Fifteen periapical inflammatory lesions were obtained from extracted human teeth and teeth which underwent periapical surgery. After their morphological categorization as periapical granulomas and gradation of the inflammatory infiltrate, they were examined by immunohistochemistry using human leptin policlonal antibodies. Leptin mRNA expression was also determined by quantitative real-time PCR (qRT-PCR) and the amount of leptin protein was analyzed by immunoblot. Results All periapical lesions exhibited the characteristic of chronic granulomatous inflammatory process with inflammatory infiltrate grade III. Leptin+ cells were detected in 13 periapical granulomas (86.6%). The median number of Leptin+ cells in periapical granulomas was 1.70 (0.00-7.4). Amongst the inflammatory cells in the periapical granulomas, only macrophages were reactive to leptin antibodies. Western blot analysis revealed the presence in all samples of a protein with apparent molecular weight of approximately 16 kDa, corresponding to the estimated molecular weights of leptin. The expression of leptin mRNA was confirmed by qRT-PCR analysis and the size of the amplified fragment (296 bp for leptin and 194 bp for cyclophilin) was assessed by agarose gel electrophoresis. Conclusions For the first time, it has been demonstrated that human periapical granuloma expresses the adipokine leptin. Key words: Apical granuloma, dental pulp, endodontics, leptin, leptin receptor, immune system, immunohistochemistry, periapical inflammatory response. PMID:25662559

  10. Lateral hypothalamic serotonin is not stimulated during central leptin hypophagia.

    Science.gov (United States)

    Telles, Mônica Marques; da Silva, Thaís Girão; Watanabe, Regina Lúcia Harumi; de Andrade, Iracema Senna; Estadella, Debora; Nascimento, Cláudia Maria Oller; Oyama, Lila Missae; Ribeiro, Eliane Beraldi

    2013-06-10

    Whether leptin targets the hypothalamic serotonergic system to inhibit food intake is not established. We examined the effect of a short-term i.c.v. leptin treatment on serotonin microdialysate levels in rat lateral hypothalamus. Adipose tissue gene expression was also evaluated. Male rats received four daily injections of leptin (5 μg) or vehicle (with pair-feeding to leptin-induced intake) and a fifth injection during collection of LH microdialysates. We found that serotonin and 5-HIAA levels were not affected by the leptin pre-treatment, as basal levels were similar between the leptin and the pair-fed group. These levels remained unaltered after the acute leptin injection. For gene expression studies, rats were pre-treated with five daily injections of either leptin (5 μg) or vehicle (with either pair-feeding or ad libitum intake). mRNA levels of resistin, adiponectin, lipoprotein lipase, and PPAR-gamma were unaltered by either leptin or pair-feeding. Leptin gene expression was significantly reduced by leptin but not by pair-feeding, in both the retroperitoneal (-74%) and the epididymal (-99%) depots while no differences were observed in the subcutaneous depot. The observations confirmed the absence of an acute stimulatory effect of central leptin on serotonin release in the lateral hypothalamus and showed that the pre-treatment with leptin failed to modify this pattern. This indicates that components of the serotonergic system are probably not directly affected by leptin. Additionally, the central effect of leptin was able to downregulate its own adipose tissue gene expression in a depot-specific manner while other adipokine genes were not affected. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Duplicated leptin receptors in two species of eel bring new insights into the evolution of the leptin system in vertebrates.

    Directory of Open Access Journals (Sweden)

    Marina Morini

    Full Text Available Since its discovery in mammals as a key-hormone in reproduction and metabolism, leptin has been identified in an increasing number of tetrapods and teleosts. Tetrapods possess only one leptin gene, while most teleosts possess two leptin genes, as a result of the teleost third whole genome duplication event (3R. Leptin acts through a specific receptor (LEPR. In the European and Japanese eels, we identified two leptin genes, and for the first time in vertebrates, two LEPR genes. Synteny analyses indicated that eel LEPRa and LEPRb result from teleost 3R. LEPRb seems to have been lost in the teleost lineage shortly after the elopomorph divergence. Quantitative PCRs revealed a wide distribution of leptins and LEPRs in the European eel, including tissues involved in metabolism and reproduction. Noticeably, leptin1 was expressed in fat tissue, while leptin2 in the liver, reflecting subfunctionalization. Four-month fasting had no impact on the expression of leptins and LEPRs in control European eels. This might be related to the remarkable adaptation of silver eel metabolism to long-term fasting throughout the reproductive oceanic migration. In contrast, sexual maturation induced differential increases in the expression of leptins and LEPRs in the BPG-liver axis. Leptin2 was strikingly upregulated in the liver, the central organ of the reproductive metabolic challenge in teleosts. LEPRs were differentially regulated during sexual maturation, which may have contributed to the conservation of the duplicated LEPRs in this species. This suggests an ancient and positive role of the leptin system in the vertebrate reproductive function. This study brings new insights on the evolutionary history of the leptin system in vertebrates. Among extant vertebrates, the eel represents a unique case of duplicated leptins and leptin receptors as a result of 3R.

  12. Behavioral, hormonal and central serotonin modulating effects of injected leptin.

    Science.gov (United States)

    Haleem, Darakhshan J; Haque, Zeba; Inam, Qurrat-ul-Aen; Ikram, Huma; Haleem, Muhammad Abdul

    2015-12-01

    Leptin is viewed as an important target for developing novel therapeutics for obesity, depression/anxiety and cognitive dysfunctions. The present study therefore concerns behavioral, hormonal and central serotonin modulating effects of systemically injected leptin. Pharmacological doses (100 and 500 μg/kg) of leptin injected systemically decreased 24h cumulative food intake and body weight in freely feeding rats and improved acquisition and retention of memory in Morris water maze test. Potential anxiety reducing, hormonal and serotonin modulating effects of the peptide hormone were determined in a separate experiment. Animals injected with 100 or 500 μg/kg leptin were tested for anxiety in an elevated plus maze test 1h later. A significant increase in the number of entries and time passed in open arm of the elevated plus maze in leptin injected animals suggested pronounced anxiety reducing effect. Moreover, circulating levels of leptin correlated significantly with anxiety reducing effects of the peptide hormone. Serum serotonin increased and ghrelin decreased in leptin injected animals and correlated, positively and negatively respectively, with circulating leptin. Corticosterone increased at low dose and levels were normal at higher dose. Serotonin metabolism in the hypothalamus and hippocampus decreased only at higher dose of leptin. The results support a role of leptin in the treatment of obesity, anxiety and cognitive dysfunctions. It is suggested that hormonal and serotonin modulating effects of leptin can alter treatment efficacy in particularly comorbid conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Relationship Between the Serum Leptin and Children with Malnutrition

    International Nuclear Information System (INIS)

    Xu Jixun

    2010-01-01

    To investigate the relationship between the serum leptin and the children with malnutrition, the serum leptin levels in 50 malnourished children and 50 normal children were determined by RIA. The results showed that the serum leptin levels in children with malnutrition were significantly lower than that in control group (P<0.05). The serum leptin levels in children with malnutrition were positively correlated with body mass index values (r= 0.650, P<0.05), and positively correlated with serum albumin values (r= 0.740,P<0.05). The serum leptin levels in female children were higher than that in men children. The leptin may involve in the regulation of the body nutritional status of children. The serum leptin level may be correlated with the degree of child malnutrition and may be used as a laboratory indicator for the diagnosis of child malnutrition. (authors)

  14. Milk Leptin Surge and Biological Rhythms of Leptin and Other Regulatory Proteins in Breastmilk.

    Science.gov (United States)

    Nozhenko, Yuriy; Asnani-Kishnani, Madhu; Rodríguez, Ana M; Palou, Andreu

    2015-01-01

    A significant number of chronic diseases are linked to perinatal nutrition, and prevention may be associated to naturally occurring components of breast milk. One key hormone in breast milk is leptin, related with the protection from obesity in the adulthood, thus knowing its changes through the day or lactation is crucial. We aimed to investigate the daily rhythms in the milk levels of leptin, together with other two related hormones, ghrelin and adiponectin, during lactation (days 5, 10 and 15) in rat dams, and the relation with morphometric parameters (dams and pups). Summarizing the main results, the existence of biological rhythms, but not daily and maybe circasemidian, was confirmed for the three hormones at the earliest period of lactation. The correlations performed generally showed a possible dependence of milk hormone levels on plasma levels at the early phase of lactation, while with the progression of lactation this dependence may fade and the hormone levels are suggested to be more dependent on mammary gland production/maturation. There was also a correlation between milk leptin and adiponectin levels, especially in the first half of lactation, suggesting a possible parallel regulation. Interestingly, we describe a milk leptin surge around the mid of lactation (at day 10) which may be related with pup's growth (males and females) and with the well-known (in the literature) plasma leptin surge in pups. All this knowledge may be crucial for future applications in the development of formula milk and in relation with the role of leptin surge during lactation.

  15. Hindbrain leptin receptor stimulation enhances the anorexic response to cholecystokinin.

    Science.gov (United States)

    Williams, Diana L; Baskin, Denis G; Schwartz, Michael W

    2009-11-01

    Leptin is thought to reduce food intake, in part, by increasing sensitivity to satiation signals, including CCK. Leptin action in both forebrain and hindbrain reduces food intake, and forebrain leptin action augments both the anorexic and neuronal activation responses to CCK. Here, we asked whether leptin signaling in hindbrain also enhances these responses to CCK. We found that food intake was strongly inhibited at 30 min after a combination of 4th-intracerebroventricular (4th-icv) leptin injection and intraperitoneal CCK administration, whereas neither hormone affected intake during this period when given alone. Leptin injections targeted directly at the dorsal vagal complex (DVC) similarly enhanced the anorexic response to intraperitoneal CCK. Intra-DVC leptin injection also robustly increased the number of neurons positive for phospho-STAT3 staining in the area surrounding the site of injection, confirming local leptin receptor activation. Conversely, the anorexic response to 4th-icv leptin was completely blocked by IP devazepide, a CCKA-R antagonist, suggesting that hindbrain leptin reduces intake via a mechanism requiring endogenous CCK signaling. We then asked whether hindbrain leptin treatment enhances the dorsomedial hindbrain, hypothalamus, or amygdala c-Fos responses to IP CCK. We found that, in contrast to the effects of forebrain leptin administration, 4th-icv leptin injection had no effect on CCK-induced c-Fos in any structures examined. We conclude that leptin signaling in either forebrain or hindbrain areas can enhance the response to satiation signals and that multiple distinct neural circuits likely contribute to this interaction.

  16. Dietary components in the development of leptin resistance.

    Science.gov (United States)

    Vasselli, Joseph R; Scarpace, Philip J; Harris, Ruth B S; Banks, William A

    2013-03-01

    Classically, leptin resistance has been associated with increased body fat and circulating leptin levels, and the condition is believed to contribute to the onset and/or maintenance of obesity. Although a great deal is known about the central nervous system mechanisms mediating leptin resistance, considerably less is known about the role of diet in establishing and maintaining this altered hormonal state. An exciting new finding has recently been published demonstrating the existence of leptin resistance in normal-weight rats with lean leptin levels by feeding them a high-concentration-fructose diet. This finding has opened the possibility that specific macronutrients may be capable of inducing leptin resistance, independently of the amount of body fat or circulating leptin present in the treated animals. This review describes several lines of research that have recently emerged indicating that specific types of dietary sugars and fats are capable of inducing leptin resistance in experimental rodent models. The results further show that diet-induced leptin resistance is capable of increasing energy intake and elevating body weight gain under appropriate dietary challenges. It appears that biological mechanisms on multiple levels may underlie the dietary induction of leptin resistance, including alterations in the leptin blood-to-brain transport system, in peripheral glucose metabolism, and in central leptin receptor signaling pathways. What is clear from the findings reviewed here is that diet-induced leptin resistance can occur in the absence of elevated circulating leptin levels and body weight, rendering it a potential cause and/or predisposing factor to excess body weight gain and obesity.

  17. Dietary Components in the Development of Leptin Resistance123

    Science.gov (United States)

    Vasselli, Joseph R.; Scarpace, Philip J.; Harris, Ruth B. S.; Banks, William A.

    2013-01-01

    Classically, leptin resistance has been associated with increased body fat and circulating leptin levels, and the condition is believed to contribute to the onset and/or maintenance of obesity. Although a great deal is known about the central nervous system mechanisms mediating leptin resistance, considerably less is known about the role of diet in establishing and maintaining this altered hormonal state. An exciting new finding has recently been published demonstrating the existence of leptin resistance in normal-weight rats with lean leptin levels by feeding them a high-concentration-fructose diet. This finding has opened the possibility that specific macronutrients may be capable of inducing leptin resistance, independently of the amount of body fat or circulating leptin present in the treated animals. This review describes several lines of research that have recently emerged indicating that specific types of dietary sugars and fats are capable of inducing leptin resistance in experimental rodent models. The results further show that diet-induced leptin resistance is capable of increasing energy intake and elevating body weight gain under appropriate dietary challenges. It appears that biological mechanisms on multiple levels may underlie the dietary induction of leptin resistance, including alterations in the leptin blood-to-brain transport system, in peripheral glucose metabolism, and in central leptin receptor signaling pathways. What is clear from the findings reviewed here is that diet-induced leptin resistance can occur in the absence of elevated circulating leptin levels and body weight, rendering it a potential cause and/or predisposing factor to excess body weight gain and obesity. PMID:23493533

  18. Differential Expression of Claudin Family Proteins in Mouse Ovarian Serous Papillary Epithelial Adenoma in Aging FSH Receptor-Deficient Mutants

    Directory of Open Access Journals (Sweden)

    Jayaprakash Aravindakshan

    2006-12-01

    Full Text Available Ovarian cancer is a deadly disease with long latency. To understand the consequences of loss of folliclestimulating hormone receptor (FSH-R signaling and to explore why the atrophic and anovulatory ovaries of follitropin receptor knockout (FORKO mice develop different types of ovarian tumors, including serous papillary epithelial adenoma later in life, we used mRNA expression profiling to gain a comprehensive view of misregulated genes. Using real-time quantitative reverse transcription-polymerase chain reaction, protein analysis, and cellular localization, we show, for the first time, in vivo evidence that, in the absence of FSH-R signaling, claudin-3, claudin-4, and claudin-11 are selectively upregulated, whereas claudin-1 decreases in ovarian surface epithelium and tumors in comparison to wild type. In vitro experiments using a mouse ovarian surface epithelial cell line derived from wild-type females reveal direct hormonal influence on claudin proteins. Although recent studies suggest that cell junction proteins are differentially expressed in ovarian tumors in women, the etiology of such changes remains unclear. Our results suggest an altered hormonal environment resulting from FSH-R loss as a cause of early changes in tight junction proteins that predispose the ovary to late-onset tumors that occur with aging. More importantly, this study identifies claudin-11 overexpression in mouse ovarian serous cystadenoma.

  19. Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity.

    Science.gov (United States)

    Nice, Timothy J; Osborne, Lisa C; Tomov, Vesselin T; Artis, David; Wherry, E John; Virgin, Herbert W

    2016-06-01

    In order for a virus to persist, there must be a balance between viral replication and immune clearance. It is commonly believed that adaptive immunity drives clearance of viral infections and, thus, dysfunction or viral evasion of adaptive immunity is required for a virus to persist. Type I interferons (IFNs) play pleiotropic roles in the antiviral response, including through innate control of viral replication. Murine norovirus (MNoV) replicates in dendritic cells (DCs) and type I IFN signaling in DCs is important for early control of MNoV replication. We show here that the non-persistent MNoV strain CW3 persists systemically when CD11c positive DCs are unable to respond to type I IFN. Persistence in this setting is associated with increased early viral titers, maintenance of DC numbers, increased expression of DC activation markers and an increase in CD8 T cell and antibody responses. Furthermore, CD8 T cell function is maintained during the persistent phase of infection and adaptive immune cells from persistently infected mice are functional when transferred to Rag1-/- recipients. Finally, increased early replication and persistence are also observed in mixed bone marrow chimeras where only half of the CD11c positive DCs are unable to respond to type I IFN. These findings demonstrate that increased early viral replication due to a cell-intrinsic innate immune deficiency is sufficient for persistence and a functional adaptive immune response is not sufficient for viral clearance.

  20. Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity.

    Directory of Open Access Journals (Sweden)

    Timothy J Nice

    2016-06-01

    Full Text Available In order for a virus to persist, there must be a balance between viral replication and immune clearance. It is commonly believed that adaptive immunity drives clearance of viral infections and, thus, dysfunction or viral evasion of adaptive immunity is required for a virus to persist. Type I interferons (IFNs play pleiotropic roles in the antiviral response, including through innate control of viral replication. Murine norovirus (MNoV replicates in dendritic cells (DCs and type I IFN signaling in DCs is important for early control of MNoV replication. We show here that the non-persistent MNoV strain CW3 persists systemically when CD11c positive DCs are unable to respond to type I IFN. Persistence in this setting is associated with increased early viral titers, maintenance of DC numbers, increased expression of DC activation markers and an increase in CD8 T cell and antibody responses. Furthermore, CD8 T cell function is maintained during the persistent phase of infection and adaptive immune cells from persistently infected mice are functional when transferred to Rag1-/- recipients. Finally, increased early replication and persistence are also observed in mixed bone marrow chimeras where only half of the CD11c positive DCs are unable to respond to type I IFN. These findings demonstrate that increased early viral replication due to a cell-intrinsic innate immune deficiency is sufficient for persistence and a functional adaptive immune response is not sufficient for viral clearance.

  1. Kinetics of leptin binding to the Q223R leptin receptor.

    Directory of Open Access Journals (Sweden)

    Hans Verkerke

    Full Text Available Studies in human populations and mouse models of disease have linked the common leptin receptor Q223R mutation to obesity, multiple forms of cancer, adverse drug reactions, and susceptibility to enteric and respiratory infections. Contradictory results cast doubt on the phenotypic consequences of this variant. We set out to determine whether the Q223R substitution affects leptin binding kinetics using surface plasmon resonance (SPR, a technique that allows sensitive real-time monitoring of protein-protein interactions. We measured the binding and dissociation rate constants for leptin to the extracellular domain of WT and Q223R murine leptin receptors expressed as Fc-fusion proteins and found that the mutant receptor does not significantly differ in kinetics of leptin binding from the WT leptin receptor. (WT: ka 1.76×106±0.193×106 M-1 s-1, kd 1.21×10-4±0.707×10-4 s-1, KD 6.47×10-11±3.30×10-11 M; Q223R: ka 1.75×106±0.0245×106 M-1 s-1, kd 1.47×10-4±0.0505×10-4 s-1, KD 8.43×10-11±0.407×10-11 M. Our results support earlier findings that differences in affinity and kinetics of leptin binding are unlikely to explain mechanistically the phenotypes that have been linked to this common genetic variant. Future studies will seek to elucidate the mechanism by which this mutation influences susceptibility to metabolic, infectious, and malignant pathologies.

  2. Identifikasi Leptin pada Kesembuhan Luka Tikus yang Diberi Pakan Lemak Tinggi dan Aplikasi Zinc Topikal (LEPTIN IDENTIFICATION ON WOUND HEALING OF RAT GIVEN HIGH FAT DIET AND TOPICAL ZINC APPLICATION

    Directory of Open Access Journals (Sweden)

    Devita Anggraeni

    2013-07-01

    Full Text Available Leptin is a hormone produced by adipocytes and play an important role in wound healing. The objectiveof this research was to study the role of leptin in wound healing in mice experimentally given high fat dietsand its correlation to zinc. Thirty two male Sprague Dawley rats at three months of age were used in thisstudy. Rats were randomly allotted into four groups (A,B,C and D of 8. Rats in group A and B were fednormal diet, while rats in group C and D were fed high fat diet. After two months of treatment, skin incisionsurgery was performed at the back side of the rat. Incision wound was closed with single interruptedsuture. The wound of rats in group A and C were treated with vaseline, while in the group B and D weretreated with zinc 10%. One day after surgery, blood sample were collected frpm four rats from each groupand analysed for leptin (Rat leptin ELISA Int, Genway Biotech Inc. Wounded skin from all animals werealso taken for histopathological examination (Haematoxylin and Eosin. Three days after the surgery, thesame analysis were done for the remaining rats. Leptin level was analyzed statistically using ANOVA forfactorial experiment, while histopathologic analysis was done descriptively. The results showed that theleptin level was significantly affected by time (P<0.05, as leptin level in blood at three days after surgerywas significantly lower than the level at one day after surgery. Meanwhile, histopathological examinationshowed that the percentage of epidermal closure in animals in group A,B,C,and D were 75%, 100%, 25%and 75%, respectivelly. Therefore, it was concluded that topical application of zinc might have significanteffect on the wound healing of the rats fed normal diets as well as these that given a high fat diet.

  3. Influence of the metabolic syndrome on leptin and leptin receptor in breast cancer.

    Science.gov (United States)

    Carroll, Paul A; Healy, Laura; Lysaght, Joanne; Boyle, Terry; Reynolds, John V; Kennedy, M John; Pidgeon, Graham; Connolly, Elizabeth M

    2011-08-01

    Obesity and its associated metabolic syndrome (MetS) are recognized risk factors for breast cancer. The molecular basis for this association remains largely unknown. Adipokines, in particular leptin and adiponectin, are thought to form part of the mechanism linking obesity with cancer through their altered expression/production either systemically (endocrine pathway) or locally (paracrine/autocrine pathway). Using quantitative PCR, mRNA expression of adiponectin (AdipoQ) and leptin (Ob) in mammary adipose tissue (MAT), intratumoral leptin and associated ligand receptors (ObR, AdipoR1, and AdipoR2) was examined in 77 patients with complete anthropomorphic and serological data. Expression of Ob in MAT, and ObR in matched tumor tissue was significantly higher in patients with MetS compared to obese only or normal weight cancer patients (P < 0.005). There was no difference in intratumoral leptin adiponectin or its ligand receptors in the same groups. Individual features of MetS correlated with Ob and ObR expression, but not obesity markers (BMI, waist circumference). mRNA expression of leptin (Ob) and ObR, in adipose tissue and matched tumor samples, respectively, appear to be associated with obesity status in breast cancer. Increasing insulin resistance is a predominant feature of this higher Ob/ObR expression observed. These novel data indicate that the MetS may be an amenable risk factor for breast cancer. Copyright © 2011 Wiley-Liss, Inc.

  4. Distinct roles of free leptin, bound leptin and soluble leptin receptor during the metabolic-inflammatory response in patients with liver cirrhosis

    NARCIS (Netherlands)

    Ockenga, J.; Tietge, U. J. F.; Boeker, K. H. W.; Manns, M. P.; Brabant, G.; Bahr, M. J.

    2007-01-01

    Background Alteration of the leptin system appears to play a role in the inflammatory-metabolic response in catabolic diseases such as chronic liver diseases. Aim To investigate the association between leptin components, inflammatory markers and hepatic energy and substrate metabolism. Methods We

  5. [The importance of leptin in oncology--hypothesis or facts?].

    Science.gov (United States)

    Gaja, A; Churý, Z

    2001-04-01

    Leptin was described as a protein produced mostly by adipocytes which participates in regulation of caloric intake. This protein has further many physiological regulatory functions especially in hematopoesis and reproduction. The role of leptin in diseases is also considered. Maybe leptin is a part of the pathogenic mechanism or its metabolism can be influenced secondary to disease. Malignant tumours are the important area where leptin can acts. This imagination is supported by recent in vitro studies and some clinical observations. It is consider that some parameters of leptin metabolism can serve as usable marker for diagnosis and monitoring of some malignant tumours--especially breast cancer or some types of leukemia. The authors give a review of actual information of leptin metabolism changes in oncological diseases.

  6. Serum leptin levels in female patients with niddm

    International Nuclear Information System (INIS)

    Haque, Z.; Rahman, M.A.

    2003-01-01

    Objective: To compare serum leptin levels of diabetic and non-diabetic female subjects and also assess the relationship of hyperglycemia with serum insulin, C-peptide and leptin levels. Results: Serum leptin levels of obese diabetic and non-diabetic subjects were significantly higher as compared with lean diabetic patients and non-diabetic subjects (P<0.05). Leptin levels were positively correlated with serum insulin and C-peptide levels. Serum leptin increased with increase in body mass index and waist hip ratio was strongly related with insulin resistance in NIDDM. Conclusion: Leptin levels are increased in obesity and may play a role in development of insulin resistance and NIDDM. (author)

  7. Structure of Leptin Receptor Related with Obesity

    DEFF Research Database (Denmark)

    Toleikis, Zigmantas

    of the receptor, while the D5 domain is the central leptin-binding domain, implicated in the first steps of activation. Both domains are characterized by a fibronectin type III fold and both contain a conserved WSXWS motif (X represents an unconserved amino acid residue), a distinct feature of the cytokine...... receptors. This motif is thought to play a major role in correct folding and activation of the receptor. The complex between leptin and the D5CA domain was analyzed using nuclear magnetic resonance spectroscopy and the amino acid residues implicated in the binding were determined. To investigate which parts...... interactions between the aromatic residues of the peptide. It may be speculated that these differences affect the ability of the full domains to form alternative structures around the WSXWS motif....

  8. Obesity-Related Hypertension: Focus on Leptin

    DEFF Research Database (Denmark)

    Asferg, Camilla Lundegaard

    Background: Hypertension is a leading cause of death worldwide. Population studies have shown that at least two-thirds of hypertension incidence can be attributed directly to overweight and obesity. The underlying mechanisms linking obesity to hypertension are not clear. Various factors have been...... suggested to play a role in obesity-related hypertension such as the renin-angiotensin-aldosterone system, the sympathetic nervous system, inflammation, insulin resistance, physical inactivity, and abnormal production of adipocytokines. Of all adipocytokines, leptin and adiponectin have received most...... attention and both hormones are considered as candidate intermediaries between adipose tissue and overweight and obesity-related disorders. Objectives: To study obesity-related hypertension with special focus on the hormone leptin. As obesity-related hypertension is multifactorial, other biological systems...

  9. Characterization of the gut microbiota in leptin deficient obese mice

    DEFF Research Database (Denmark)

    Ellekilde, Merete; Krych, Lukasz; Hansen, Camilla Hartmann Friis

    2014-01-01

    Gut microbiota have been implicated as a relevant factor in the development of type 2 diabetes mellitus (T2DM), and its diversity might be a cause of variation in animal models of T2DM. In this study, we aimed to characterise the gut microbiota of a T2DM mouse model with a long term vision of bei...... in various disease read-outs in the B6.V-Lep(ob)/J model and considering them in both quality assurance and data evaluation for the B6.V-Lep(ob)/J model may have a reducing impact on the inter-individual variation.......Gut microbiota have been implicated as a relevant factor in the development of type 2 diabetes mellitus (T2DM), and its diversity might be a cause of variation in animal models of T2DM. In this study, we aimed to characterise the gut microbiota of a T2DM mouse model with a long term vision of being...

  10. Leptin, cortisol and distinct concurrent training sequences.

    Science.gov (United States)

    Rosa, G; Dantas, E; Biehl, C; de Castro e Silva, H; Montano, M A E; de Mello, D B

    2012-03-01

    In order to investigate the effects of distinct concurrent training sequences on serum leptin and cortisol levels, 10 subjects (27.1±4.8 years, body mass index 25.38±0.09) were submitted to a control session, concurrent training 1 and concurrent training 2. Samples of leptin and cortisol were collected. Concurrent training 1 consisted of indoor cycling followed by strength training and concurrent training 2 of strength training followed by indoor cycling. No exercises were performed at the control session. Blood was collected once again to verify the same variables. Shapiro-Wilk, 2-way ANOVA and Tukey post-hoc tests were used. There was a reduction in leptin levels after concurrent training 1 (Δ%= - 16.04; p=0.05) and concurrent training 2 (Δ%= - 8.54; p=0.02). Cortisol decreased after concurrent training 1 (Δ%= - 26.32; p=0.02) and concurrent training 2 (Δ%= - 33.57; p=0.05). There was a high and significant correlation between blood variables only in CS (lep PRE X cort PRE and cort POST: r= - 0.80 and r= - 0.81; lep POST X cort PRE and cort POST: r= - 0.62 and r= - 0.62). Concurrent training promoted a reduction in leptin and cortisol levels irrespective of sequence. © Georg Thieme Verlag KG Stuttgart · New York.

  11. Renaissance of leptin for obesity therapy

    DEFF Research Database (Denmark)

    Quarta, Carmelo; Sánchez-Garrido, Miguel A; Tschöp, Matthias H

    2016-01-01

    leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Gerald Shulman and colleagues, DOI: 10.1007/s00125-016-3909-4 ) and an overview...... by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 )....

  12. Leptin and its cardiovascular effects: Focus on angiogenesis

    Directory of Open Access Journals (Sweden)

    Zoya Tahergorabi

    2015-01-01

    Full Text Available Leptin is an endocrine hormone synthesized by adipocytes. It plays a key role in the energy homeostasis in central and peripheral tissues and has additional roles are attributed to it, such as the regulation of reproduction, immune function, bone homeostasis, and angiogenesis. The plasma concentration of leptin significantly increases in obese individuals. In the present review, we give an introduction concerning leptin, its receptors, signaling pathways, and its effect on cardiovascular system, especially on angiogenesis.

  13. [Leptin and the feedback regulation of body weight].

    Science.gov (United States)

    Wang, X; Ye, G; Sun, J

    1999-09-30

    Body weight may be controlled by a negative feedback loop. Recent studies have identified that the ob gene product, leptin, apparently and exclusively expressed in adipose tissue, is a part of the negative feedback loop. Leptin is proposed to act as an afferent signal in the negative feedback loop to hypothalamus that limiting food-intake, controlling energy homeostasis and regulating the mass of adipose tissue. The dificiency of or resistance to leptin causes severe obesity.

  14. Leptin: A Novel Therapeutic Strategy for Alzheimer's Disease

    OpenAIRE

    Tezapsidis, Nikolaos; Johnston, Jane M.; Smith, Mark A.; Ashford, J. Wesson; Casadesus, Gemma; Robakis, Nikolaos K.; Wolozin, Benjamin; Perry, George; Zhu, Xiongwei; Greco, Steven J.; Sarkar, Sraboni

    2009-01-01

    Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease (AD) at the molecular and physiological level. One activity of leptin is the control of AMP-dependent kinase (AMPK). In addition to maintaining lipid levels, AMPK regulates glycogen synthase kinase-3, which modulates tau phosphorylation. Leptin has been shown to reduce the amount of extracellular amyloid-β, both in cell culture and animal models of AD, as well as reduce tau phosphorylation in neuron...

  15. Kadar leptin saliva dan kejadian karies gigi anak obesitas (Salivary leptin levels and caries incidence in obese children

    Directory of Open Access Journals (Sweden)

    Elfrida Atzmaryanni

    2013-09-01

    Full Text Available Background: Children with obesity have a lower incidence of caries. Salivary leptin levels of obese children is higher than normal children. Leptin is protein hormone, contained in saliva. Salivary proteins maintain the balance of the ecosystem in the mouth. Purpose: The article was aimed to study the correlation of salivary leptin levels with caries incidence in obese children. Review: Mouth is reflection of the health status and so many changes occur as a weight gain. Child with obesity has a low incidence of caries than normal. This condition is associated with changes in oral cavity, especially the increase in salivary leptin. Caries is a disease of hard tissues cause by the activty of microorganisms, especially Streptococcus mutans. Salivary proteins maintain the balance of the ecosystem in the mouth. Leptin is a protein saliva, produced predominantly in adipose tissue and conduct active transport to saliva. Salivary leptin works in two ways: as an antimicrobial which prevents the attachment of bacteria on tooth surface or by inducing cytokine that affect the immune system in oral cavity. Conclusion: Salivary leptin is higher in obese children than in normal children. The low incidence of caries on obesity is associated with salivary leptin. Alteration in salivary composition and flow rate also decreased caries in obesity.Latar belakang: Anak yang mengalami obesitas memiliki insiden karies yang rendah. Kadar leptin saliva anak obesitas lebih tinggi dari anak normal. Leptin merupakan salah satu protein hormon yang terdapat di saliva. Protein saliva berfungsi untuk menjaga keseimbangan ekosistem di mulut. Tujuan: Artikel ini bertujuan mempelajari hubungan antara kadar leptin di dalam saliva dengan kejadian karies anak obesitas. Tinjauan pustaka: Rongga mulut merupakan cerminan dari status kesehatan dan banyak perubahan yang terjadi seiring peningkatan berat badan seseorang. Anak Obesitas memiliki insiden karies yang rendah jika dibandingkan

  16. Association between Salivary Leptin Levels and Taste Perception in Children

    Directory of Open Access Journals (Sweden)

    Lénia Rodrigues

    2017-01-01

    Full Text Available The satiety inducing hormone leptin acts not only at central nervous system but also at peripheral level. Leptin receptors are found in several sense related organs, including the mouth. A role of leptin in sweet taste response has been suggested but, until now, studies have been based on in vitro experiments, or in assessing the levels of the hormone in circulation. The present study investigated whether the levels of leptin in saliva are related to taste perception in children and whether Body Mass Index (BMI affects such relationship. Sweet and bitter taste sensitivity was assessed for 121 children aged 9-10 years and unstimulated whole saliva was collected for leptin quantification, using ELISA technique. Children females with lower sweet taste sensitivity presented higher salivary leptin levels, but this is only in the normal weight ones. For bitter taste, association between salivary leptin and caffeine threshold detection was observed only in preobese boys, with higher levels of salivary hormone in low sensitive individuals. This study is the first presenting evidences of a relationship between salivary leptin levels and taste perception, which is sex and BMI dependent. The mode of action of salivary leptin at taste receptor level should be elucidated in future studies.

  17. Role of leptin in blood pressure regulation and arterial hypertension.

    Science.gov (United States)

    Bełtowski, Jerzy

    2006-05-01

    Leptin is a 16-kDa protein secreted by white adipose tissue that is primarily involved in the regulation of food intake and energy expenditure. Plasma leptin concentration is proportional to the amount of adipose tissue and is markedly increased in obese individuals. Recent studies suggest that leptin is involved in cardiovascular complications of obesity, including arterial hypertension. Acutely administered leptin has no effect on blood pressure, probably because it concomitantly stimulates the sympathetic nervous system and counteracting depressor mechanisms such as natriuresis and nitric oxide (NO)-dependent vasorelaxation. By contrast, chronic hyperleptinemia increases blood pressure because these acute depressor effects are impaired and/or additional sympathetic nervous system-independent pressor effects appear, such as oxidative stress, NO deficiency, enhanced renal Na reabsorption and overproduction of endothelin. Although the cause-effect relationship between leptin and high blood pressure in humans has not been demonstrated directly, many clinical studies have shown elevated plasma leptin in patients with essential hypertension and a significant positive correlation between leptin and blood pressure independent of body adiposity both in normotensive and in hypertensive individuals. In addition, leptin may contribute to end-organ damage in hypertensive individuals such as left ventricular hypertrophy, retinopathy and nephropathy, independent of regulating blood pressure. Here, current knowledge about the role of leptin in the regulation of blood pressure and in the pathogenesis of arterial hypertension is presented.

  18. [Obesity and leptin association in three Chilean aboriginal populations].

    Science.gov (United States)

    Pérez, F; Santos, J L; Albala, C; Calvillán, M; Carrasco, E

    2000-01-01

    Although there is a clear relationship between body mass index and leptin levels, few authors have addressed the possible influence of ethnic factors on these levels. To measure serum leptin in three different Chilean aboriginal populations. Fasting serum leptin and insulin levels were measured by radioimmunoassay in 345 rural mapuche individuals, 247 rural aymara subjects and 162 urban mapuche subjects. A body mass index of 27.5 kg/m2 was used as cutoff point to classify study subjects. Among the three ethnic groups, women had serum leptin levels three times higher than men. In all three ethnic groups, there was a significant association between leptin levels, body mass index and gender (r2 = 0.32 and 0.5 p mapuche, r2 = 0.32 and 0.5 p mapuche populations). No differences in leptin levels were observed for the interaction between age and insulin. The increments per quartile in leptin levels were lower among mapuche than aymara individuals. Rural mapuche individuals have a high frequency of obesity. However their leptin levels are lower than those of aymara or urban mapuche populations. The higher leptin levels observed in urban mapuche subjects could be due to environmental influences.

  19. Plasma leptin concentration in dogs with diabetes mellitus.

    Science.gov (United States)

    Nishii, Naohito; Yamasaki, Miho; Takasu, Masaki; Honjoh, Tsutomu; Shibata, Haruki; Otsuka, Yoshihiko; Takashima, Satoshi; Ohba, Yasunori; Kitagawa, Hitoshi

    2010-06-01

    The plasma leptin concentration was evaluated in dogs with diabetes mellitus. Twenty normal and sixteen diabetic dogs were divided into nonobese and obese groups based on body condition score, respectively. The obese normal dogs had significantly higher plasma leptin concentrations than the nonobese normal dogs, whereas there was no significant difference between the nonobese and obese diabetic dogs. In addition, the plasma leptin concentration in the obese diabetic dogs was significantly lower than that in the obese normal dogs. In conclusion, the plasma leptin concentrations in the diabetic dogs were affected by factors other than adiposity.

  20. Angiogenic Effect of Leptin in the Quail Chorioallantoic Membrane

    Directory of Open Access Journals (Sweden)

    Pavel Výboh

    2010-01-01

    Full Text Available Leptin, the product of ob gene, beside its key role in the control of body weight and food consumption, can be involved in the control of embryonic development. Leptin administration in ovo accelerated the embryonic and post-embryonic development in Japanese quail. Although the mechanisms of leptin effects on growth and development acceleration are not clear, stimulation of angiogenesis represents one of plausible explanations. Therefore, the aim of the present study was to investigate the pro-angiogenic effect of leptin in vivo in the quail chorioallantoic membrane (CAM. The recombinant murine leptin (10, 100, and 1000 ng was applied either ex ovo on the CAM surface of ex ovo incubated embryos at embryonic day 7 (ED7 or in ovo into the egg albumen at ED5. Changes in blood vessels were quantified by the fractal analysis providing the fractal dimension (Df estimate. Leptin administered in ovo was more efficient in stimulation of angiogenesis than the ex ovo treatment, since 10 ng dose elicited significantly higher (P ex ovo cultivation. Our study confirmed that exogenously applied leptin was able to stimulate angiogenesis in CAM. Leptin-mediated stimulation of angiogenesis may improve nutrient utilization from the yolk and explain at least partially the accelerating effect of leptin on avian embryo growth and development.

  1. Milk Leptin Surge and Biological Rhythms of Leptin and Other Regulatory Proteins in Breastmilk.

    Directory of Open Access Journals (Sweden)

    Yuriy Nozhenko

    Full Text Available A significant number of chronic diseases are linked to perinatal nutrition, and prevention may be associated to naturally occurring components of breast milk. One key hormone in breast milk is leptin, related with the protection from obesity in the adulthood, thus knowing its changes through the day or lactation is crucial. We aimed to investigate the daily rhythms in the milk levels of leptin, together with other two related hormones, ghrelin and adiponectin, during lactation (days 5, 10 and 15 in rat dams, and the relation with morphometric parameters (dams and pups. Summarizing the main results, the existence of biological rhythms, but not daily and maybe circasemidian, was confirmed for the three hormones at the earliest period of lactation. The correlations performed generally showed a possible dependence of milk hormone levels on plasma levels at the early phase of lactation, while with the progression of lactation this dependence may fade and the hormone levels are suggested to be more dependent on mammary gland production/maturation. There was also a correlation between milk leptin and adiponectin levels, especially in the first half of lactation, suggesting a possible parallel regulation. Interestingly, we describe a milk leptin surge around the mid of lactation (at day 10 which may be related with pup's growth (males and females and with the well-known (in the literature plasma leptin surge in pups. All this knowledge may be crucial for future applications in the development of formula milk and in relation with the role of leptin surge during lactation.

  2. Caloric restriction and the adipokine leptin alter the SDF-1 signaling axis in bone marrow and in bone marrow derived mesenchymal stem cells.

    Science.gov (United States)

    Periyasamy-Thandavan, Sudharsan; Herberg, Samuel; Arounleut, Phonepasong; Upadhyay, Sunil; Dukes, Amy; Davis, Colleen; Johnson, Maribeth; McGee-Lawrence, Meghan; Hamrick, Mark W; Isales, Carlos M; Hill, William D

    2015-07-15

    Growing evidence suggests that the chemokine stromal cell-derived factor-1 (SDF-1) is essential in regulating bone marrow (BM) derived mesenchymal stromal/stem cell (BMSC) survival, and differentiation to either a pro-osteogenic or pro-adipogenic fate. This study investigates the effects of caloric restriction (CR) and leptin on the SDF-1/CXCR4 axis in bone and BM tissues in the context of age-associated bone loss. For in vivo studies, we collected bone, BM cells and BM interstitial fluid from 12 and 20 month-old C57Bl6 mice fed ad-libitum (AL), and 20-month-old mice on long-term CR with, or without, intraperitoneal injection of leptin for 10 days (10 mg/kg). To mimic conditions of CR in vitro, 18 month murine BMSCs were treated with (1) control (Ctrl): normal proliferation medium, (2) nutrient restriction (NR): low glucose, low serum medium, or (3) NR + leptin: NR medium + 100 ng/ml leptin for 6-48 h. In BMSCs both protein and mRNA expression of SDF-1 and CXCR4 were increased by CR and CR + leptin. In contrast, the alternate SDF-1 receptor CXCR7 was decreased, suggesting a nutrient signaling mediated change in SDF-1 axis signaling in BMSCs. However, in bone SDF-1, CXCR4 and 7 gene expression increase with age and this is reversed with CR, while addition of leptin returns this to the "aged" level. Histologically bone formation was lower in the calorically restricted mice and BM adipogenesis increased, both effects were reversed with the 10 day leptin treatment. This suggests that in bone CR and leptin alter the nutrient signaling pathways in different ways to affect the local action of the osteogenic cytokine SDF-1. Studies focusing on the molecular interaction between nutrient signaling by CR, leptin and SDF-1 axis may help to address age-related musculoskeletal changes. Published by Elsevier Ireland Ltd.

  3. Analysis of changes of serum leptin, C-peptide levels and peripheral fat tissue leptin receptor expression in obesity

    International Nuclear Information System (INIS)

    Du Tongxin; Sun Junjiang; Wang Shukui; Fu Lei

    2002-01-01

    Objective: To explore the mechanism of obesity and obesity accompanied type two diabetes mellitus by investigating changes of serum leptin, C-peptide (C-P) levels and leptin receptor expression in peripheral adipose tissues. Methods: Peripheral leptin receptor density was measured via radio-ligand binding method, serum leptin and C - P levels were measured via radioimmunoassay in 91 cases (38 in obesity group, 23 in over weight, and 30 in normal controls). Results: With the increase of body mass index (BMI), the peripheral leptin receptor density of the over weight and obese cases decreased and was mash less than that of normal cases (both p<0.01, respectively). There was no statistical differences for Kd value among the three groups, suggesting no associated change between the binding ability of leptin receptor to its ligand. There was a negative correlation between BMI and leptin receptor density (r = -0.70, p < 0.01). The serum leptin and C-P levels in weight excess and obese subjects with type two DM were both increased, but significantly higher in obese group than those in weight excess group (p < 0.01). The increase of C-P was much marked than that of leptin. Serum C-P level was positively correlated with BMI. Conclusion: Changes of serum leptin, C-P levels and peripheral leptin receptor expression in cases with simple obesity and obesity accompanied with type two DM were related closely with BMI. Type 2 DM in obese subjects was related with leptin resistance and insulin resistance

  4. Somato-dendritic localization and signaling by leptin receptors in hypothalamic POMC and AgRP neurons.

    Directory of Open Access Journals (Sweden)

    Sangdeuk Ha

    Full Text Available Leptin acts via neuronal leptin receptors to control energy balance. Hypothalamic pro-opiomelanocortin (POMC and agouti-related peptide (AgRP/Neuropeptide Y (NPY/GABA neurons produce anorexigenic and orexigenic neuropeptides and neurotransmitters, and express the long signaling form of the leptin receptor (LepRb. Despite progress in the understanding of LepRb signaling and function, the sub-cellular localization of LepRb in target neurons has not been determined, primarily due to lack of sensitive anti-LepRb antibodies. Here we applied light microscopy (LM, confocal-laser scanning microscopy (CLSM, and electron microscopy (EM to investigate LepRb localization and signaling in mice expressing a HA-tagged LepRb selectively in POMC or AgRP/NPY/GABA neurons. We report that LepRb receptors exhibit a somato-dendritic expression pattern. We further show that LepRb activates STAT3 phosphorylation in neuronal fibers within several hypothalamic and hindbrain nuclei of wild-type mice and rats, and specifically in dendrites of arcuate POMC and AgRP/NPY/GABA neurons of Leprb (+/+ mice and in Leprb (db/db mice expressing HA-LepRb in a neuron specific manner. We did not find evidence of LepRb localization or STAT3-signaling in axon-fibers or nerve-terminals of POMC and AgRP/NPY/GABA neurons. Three-dimensional serial EM-reconstruction of dendritic segments from POMC and AgRP/NPY/GABA neurons indicates a high density of shaft synapses. In addition, we found that the leptin activates STAT3 signaling in proximity to synapses on POMC and AgRP/NPY/GABA dendritic shafts. Taken together, these data suggest that the signaling-form of the leptin receptor exhibits a somato-dendritic expression pattern in POMC and AgRP/NPY/GABA neurons. Dendritic LepRb signaling may therefore play an important role in leptin's central effects on energy balance, possibly through modulation of synaptic activity via post-synaptic mechanisms.

  5. Leptin and Pathological Indexes in Women with Breast Cancer

    Directory of Open Access Journals (Sweden)

    B Noori Alavicheh

    2015-06-01

    Full Text Available Background & aim: Breast cancer is the most common cancer among women and one of the factors threatening the health of women worldwide. Leptin is a 16 kD glycoprotein hormone produced predominantly by white adipose tissue. Leptin binds to receptors in the hypothalamus and plays a key role in regulation of metabolism. Both leptin and leptin receptor have recently been implicated in processes and progress leading to breast cancer initiation. The aim of this study was to identify if there is association between leptin and pathological indexes in patients with breast cancer Methods: 45women with breast cancer were enrolled. Serum leptin levels of patients were measured by the ELISA method. Pathological information such as stage of the breast cancer, Hormonal receptor (ER, PR and Her2 status in these patients were determined. Result: Results revealed that the patients who were in stage one and two, the mean serum leptin level was (34.18±21.22 ng/ml And patients who were in stage three and four, the mean serum leptin level was (32.21±21/93 ng/ml. Also the mean serum leptin levels in patients whose receptor status of ER, PR and HER2 positive were (35.90±23.55, 35.74±23.91and 37.02±24.25ng/ml, respectively. The Patients whose receptor status of ER, PR and HER2 negative were 26.64±13.13, 28.17±14.26and31.32±19.9ng/ml respectively. No significant association was found between leptin leveland stage of the breast cancer, hormonal receptor (ER, PR and Her2 status in Patients with Breast cancer(p>0.05. Conclusions: In this study, no association was found between serum leptin level and pathological indices in women with Breast cancer in Yasuj, Iran.

  6. Leptin levels in children and adults with classic galactosaemia.

    LENUS (Irish Health Repository)

    Knerr, Ina

    2012-11-07

    Among the long-term complications of Classic Galactosaemia (Gal) is premature ovarian insufficiency (POI) in female patients with subtle abnormalities of reproductive function also reported in male patients. Leptin is a circulating hormone which reflects body energy stores and which affects the neuroendocrine reproductive axis and pubertal development.We measured serum leptin in 28 children (10 girls, 18 boys; mean age 7.6 years, range 0.5-17.9 years) and in 22 adults (10 females, 12 males; mean age 23.9 years, range 18-37 years) with Gal on a strict galactose-restricted diet in comparison with control data.Leptin levels (expressed as SDS for gender and pubertal stage) were lower in Gal children than controls (mean leptin-SDS = -0.71 for girls, p < 0.05, -0.97 for boys compared with SDS = 0 for controls, p < 0.05). In an age-related analysis, leptin levels did not correlate with age in children with Gal for both sexes as it did for matched controls.As expected, females had higher leptin levels than males in either group. In adults with Gal, leptin concentrations were within normal limits for both sexes when adjusted for gender and BMI. There was a linear relationship between log-leptin and BMI in children with Gal and in controls. For Gal women, log-leptin was also associated with BMI. However, for Gal men, and hence for the entire group of adult Gal patients, this association between log-leptin and BMI was not detectable. Our findings suggest that leptin dysregulation may play a role in fertility issues in individuals with Gal from an early age.

  7. Leptin promoter variant G2548A is associated with serum leptin

    Indian Academy of Sciences (India)

    Body weight, height, waist circumference (WC), hip circumference (HC) and blood pressure (BP) were measured by standard methods and levels of fasting blood glucose (FBG), total cholesterol, triglycerides, HDLC, LDLC, and leptin were determined. Genotyping was done by polymerase chain reaction-restriction fragment ...

  8. Lateral thinking about leptin: a review of leptin action via the lateral hypothalamus.

    Science.gov (United States)

    Leinninger, Gina M

    2011-09-26

    The lateral hypothalamic area (LHA) was initially described as a "feeding center" but we are now beginning to understand that the LHA contributes to other aspects of physiology as well. Indeed, the best-characterized neuronal populations of the LHA (which contain melanin-concentrating hormone (MCH) or the hypocretins/orexins (OX)) are not strictly orexigenic, but also have roles in regulation of the autonomic and sympathetic nervous systems as well as in modulating motivated behavior. Leptin is an anorectic hormone that regulates energy homeostasis and the mesolimbic DA system (which transduces the wanting of food, drugs of abuse, and sex) in part, via actions at the LHA. At least three populations of LHA neurons are regulated by leptin: those containing MCH, OX or the long form of the leptin receptor, LepRb. The emerging picture of leptin interaction with these LHA populations suggests that the LHA is not merely regulating feeding, but is a crucial integrator of energy balance and motivated behavior. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Insulin downregulates the expression of the Ca2+-activated nonselective cation channel TRPM5 in pancreatic islets from leptin-deficient mouse models.

    Science.gov (United States)

    Colsoul, Barbara; Jacobs, Griet; Philippaert, Koenraad; Owsianik, Grzegorz; Segal, Andrei; Nilius, Bernd; Voets, Thomas; Schuit, Frans; Vennekens, Rudi

    2014-03-01

    We recently proposed that the transient receptor potential melastatin 5 (TRPM5) cation channel contributes to glucose-induced electrical activity of the β cell and positively influences glucose-induced insulin release and glucose homeostasis. In this study, we investigated Trpm5 expression and function in pancreatic islets from mouse models of type II diabetes. Gene expression analysis revealed a strong reduction of Trpm5 mRNA levels in pancreatic islets of db/db and ob/ob mice. The glucose-induced Ca(2+) oscillation pattern in db/db and ob/ob islets mimicked those of Trpm5 (-/-) islets. Leptin treatment of ob/ob mice not only reversed the diabetic phenotype seen in these mice but also upregulated Trpm5 expression. Leptin treatment had no additional effect on Trpm5 expression levels when plasma insulin levels were comparable to those of the vehicle-injected control group. In murine β cell line, MIN6, insulin downregulated TRPM5 expression in a dose-dependent manner, unlike glucose or leptin. In conclusion, our data show that increased plasma insulin levels downregulate TRPM5 expression in pancreatic islets from leptin-deficient mouse models of type 2 diabetes.

  10. Relation between obesity, lipid profile, leptin and atopic disorders in ...

    African Journals Online (AJOL)

    EL-HAKIM

    count, serum triglycerides and cholesterol, serum leptin (for control group also) and serum total immunoglobulin E (IgE) .... The DSL–10–23100 active Human Leptin ELISA was used. It is an enzymatically amplified 'two .... and the more highly allergenic foods such as eggs, peanuts, tree nuts and fish can be delayed for 2-3.

  11. Leptin gene polymorphism in Indian Sahiwal cattle by single strand ...

    African Journals Online (AJOL)

    These leptin gene variants can be sequenced and screened in the entire population to develop single nucleotide polymorphisms (SNPs) for association studies with different productive and reproductive performances and marker assisted selection. Keywords: Leptin gene, PCR-SSCP, genetic variability, dairy cattle

  12. Study of polymorphism of leptin gene receptor in Mazandaran fowls ...

    African Journals Online (AJOL)

    In chickens, leptin is expressed mainly in the liver and adipose tissue. In Iran, Mazandaran native fowls are under recording and breeding programs, but according to the action modes and importance of the leptin receptor, its polymorphisms can be related to economical traits such as body weight. In this study, in order to ...

  13. Leptin regulates proliferation and apoptosis of colorectal carcinoma ...

    Indian Academy of Sciences (India)

    The results showed that leptin could stimulate the proliferation and inhibit the apoptosis of HCT-116 colon cells through the PI3K/Akt/mTOR pathway. Ly294002 (a PI3K inhibitor) and rapamycin (an mTOR inhibitor) could prevent the regulatory effects of leptin on the proliferation and apoptosis of HCT-116 cells via abrogating ...

  14. Lipids and leptin level in natives of Kyrgyzstan.

    Science.gov (United States)

    Mirrakhimov, Erkin; Kerimkulova, Alina; Lunegova, Olga; Mirrakhimov, Aibek; Alibaeva, Nazira; Nabiev, Malik

    2014-04-01

    A possible link between obesity and impaired lipid metabolism is leptin, the 167-amino acid protein, secreted by adipocytes. The content of leptin in the body is closely associated with body mass index (BMI). Data obtained from studies on the association of leptin with dyslipidemia are contradictory. The level of leptin has not been studied in the ethnic Kyrgyz population previously. The purpose of this study was to investigate the relationship between leptin and lipid parameters in a group of ethnic Kyrgyz. The study included 322 ethnic Kyrgyz (145 males, 177 females) aged ≥30 years, living in Kyrgyzstan. Measurement of anthropometric parameters (height, weight, waist circumference [WC], hip circumference [HC]) and blood pressure (BP) was done. Laboratory tests included blood glucose (fasting) in plasma, lipid profile (total cholesterol [TC], triglycerides [TG], high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol), and serum leptin. Leptin was positively correlated with BMI, WC and TG in both sexes and with TC in males. Leptin is associated with BMI, WC and TG in both sexes of Kyrgyz and with TC in Kyrgyz males.

  15. Leptin receptor in peripheral adipose tissues of obese subjects

    International Nuclear Information System (INIS)

    Du Tongxin; Sun Junjiang; Wang Zizheng; Wang Shukui; Fu Lei; Han Liu

    2002-01-01

    Objective: To investigate the relationship between leptin receptor and obesity by studying the leptin receptor density B max and dissociation constant K d in peripheral adipose tissue in subjects with different body weight mass (BMI). Methods: Leptin receptor density B max and K d were assayed via radioligand method in 71 cases, including 32 classified as obese, 19 over-weight and 20 normal control. Results: With the escalating of BMI, the leptin receptor density significantly decreased in obese and over-weight group compared with that in normal control (both P d values were of no differences among all three groups suggesting no correlation between the binding ability of leptin to its receptor and BMI. A negative correlation between BMI and B max (r=-0.76, P<0.01) displayed after all. Conclusion: Leptin receptor density correlates with the BMI in obese cases and it suggests that the down-regulation of leptin receptor may contribute to the occurrence of leptin resistance and obesity after-wards

  16. Role of leptin in the pathogenesis of breast cancer

    Directory of Open Access Journals (Sweden)

    Thayse Fachin Cormanique

    2015-12-01

    Full Text Available Leptin is a small polypeptide codified by the Obese Gene (OB, deeply related with the body fat mass and energetic balance. Due to its diverse biological effects and downstream signal transducers, multiple classifications have been attributed to leptin, as hormone, cytokine, adypokine, growth factor, and developmental factor, among others. This scenario gives us an idea of the size of the potential biological effects generated by this molecule. The concentration of leptin in the body is determined by the amount of adipose tissue; therefore, hyperleptinemia is a common finding in obese individuals. In addition, high levels of circulating leptin may confer a poor prognosis for any pathological condition. Although leptin history has been reported for more than 20 years, its relationship with cancer has gained notoriety in the past ten years, where studies focused on discussing the issue of obesity as a strong risk factor for cancer developing. Further, growing evidences have pointed leptin as a pivotal mediator of immune response, which aggravates the scenario of cancer occurrence in the presence of obesity. Therefore, leptin can present at least two faces in the pathogenesis of breast cancer, acting by immune and non-immune mechanisms. In this paper we review the dynamic of the leptin axis in breast cancer and further discuss its role in disease, immunopathogenesis and prognosis.

  17. Early life stress experience may blunt hypothalamic leptin signalling

    Indian Academy of Sciences (India)

    2016-12-21

    Dec 21, 2016 ... Leptin-induced suppressions in food intake and weight gain was observed in NH pups, but not in MS. Leptin increased pSTAT3 ... increase energy expenditure resulting in body weight loss in rodents (Pelleymounter et ..... response to starvation: implications for the study of wasting disorders. Am. J. Physiol.

  18. Leptin as a Potential Regulator of FGF21

    Directory of Open Access Journals (Sweden)

    Mohamed Asrih

    2016-03-01

    Full Text Available Background/Aims: Fibroblast growth factor 21 (FGF21, a potent metabolic regulator, has been shown to improve insulin sensitivity in animal models of insulin resistance. Several studies have focused on identifying mediators of FGF21 effects. However, the identification of factors involved in FGF21 regulation is far from complete. As leptin is a potent metabolic modulator as well, we aimed at characterizing whether leptin may regulate FGF21. Methods: We investigated a potential regulation of FGF21 by leptin in vivo in Wistar rats and in vitro using human derived hepatocarcinoma HepG2 cells. This model was chosen as the liver is considered the main FGF21 expression site. Results: We found that leptin injections increased plasma FGF21 levels in adult Wistar rats. This was confirmed in vitro, as leptin increased FGF21 expression in HepG2 cells. We also showed that the leptin effect on FGF21 expression was mediated by STAT3 activation in HepG2 cells. Conclusion: New findings regarding a leptin-STAT3-FGF21 axis were provided in this study, although investigating the exact mechanisms linking leptin and FGF21 are still needed. These results are of great interest in the context of identifying potential new clinical approaches to treat metabolic diseases associated with insulin resistance, such as obesity and type 2 diabetes.

  19. Adiponectin, leptin and oxidative stress in preeclampsia in Egyptian ...

    African Journals Online (AJOL)

    Adiponectin and Leptin are closely related adipokines that are associated with the oxidative stresses and endothelial dysfunction and proposed to participate in preeclampsia (PE) pathogenesis. This study is to determine changes in serum levels of adiponectin, leptin and oxidative stress in PE women in order to speculate a ...

  20. Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses

    DEFF Research Database (Denmark)

    Mordstein, M; Kochs, G; Dumoutier, L

    2008-01-01

    a distinct receptor complex for signaling that is not present on all cell types. Since type I IFN receptor-deficient mice (IFNAR1(0/0)) exhibit greatly increased susceptibility to various viral diseases, it remained unclear to which degree IFN-lambda might contribute to innate immunity. To address this issue...... we performed influenza A virus infections of mice which carry functional alleles of the influenza virus resistance gene Mx1 and which, therefore, develop a more complete innate immune response to influenza viruses than standard laboratory mice. We demonstrate that intranasal administration of IFN...

  1. Leptin receptor polymorphisms and lung function decline in COPD.

    Science.gov (United States)

    Hansel, N N; Gao, L; Rafaels, N M; Mathias, R A; Neptune, E R; Tankersley, C; Grant, A V; Connett, J; Beaty, T H; Wise, R A; Barnes, K C

    2009-07-01

    Only a fraction of all smokers develop chronic obstructive pulmonary disease (COPD), suggesting a large role for genetic susceptibility. The leptin receptor (LEPR) is present in human lung tissue and may play a role in COPD pathogenesis. The present study examined the association between genetic variants in the LEPR gene and lung function decline in COPD. In total, 429 European Americans were randomly selected from the National Heart Lung and Blood Institute Lung Health Study. 36 single nucleotide polymorphisms (SNPs) in LEPR were genotyped using the Illumina GoldenGate platform (Broad Institute, Cambridge, MA, USA). Mean annual decline in forced expiratory volume in 1 s % predicted over the 5-yr period was calculated using linear regression. Linear regression models were also used to adjust for potential confounders. In addition, in vivo expression of the receptor gene was assessed with immunohistochemistry on lungs from smoke-exposed inbred mice. We identified significant associations (pCOPD pathogenesis. We identified genetic variants in the LEPR gene significantly associated with lung function decline in a population of smokers with COPD. Our results support a role for LEPR as a novel candidate gene for COPD.

  2. [CDNA cloning of human leptin and its expression].

    Science.gov (United States)

    Jia, Zhen-Yu; Fu, Xiao-Min; Jin, Ai-Hua; Cao, Jiang

    2003-07-01

    To clone cDNA of human leptin gene and obtain leptin protein for future study on leptin binding proteins. The cDNA of human leptin with 6 x his-tag was cloned by over-hang extension PCR protocol using human genomic DNA as template, and subcloned into in vitro expression vector pIVEX2.3MCS, and the fusion protein was expressed in vitro by Rapid Translation System (RTS) (RTS500 cycle primer Kit and RTS500 ProteoMaster of Roche company). The apparent molecular weight(19.46 kD) and the immuno-specificity of the fusion protein were confirmed by SDS-PAGE and Western blot, and the expressed fusion protein stayed mainly in the supernatant of the reaction mixture in soluble form. This work provides us solid basis for further study on new leptin-associated proteins.

  3. The Role of Leptin in Maintaining Plasma Glucose During Starvation.

    Science.gov (United States)

    Perry, Rachel J; Shulman, Gerald I

    2018-03-01

    For 20 years it has been known that concentrations of leptin, a hormone produced by the white adipose tissue (WAT) largely in proportion to body fat, drops precipitously with starvation, particularly in lean humans and animals. The role of leptin to suppress the thyroid and reproductive axes during a prolonged fast has been well defined; however, the impact of leptin on metabolic regulation has been incompletely understood. However emerging evidence suggests that, in starvation, hypoleptinemia increases activity of the hypothalamic-pituitary-adrenal axis, promoting WAT lipolysis, increasing hepatic acetyl-CoA concentrations, and maintaining euglycemia. In addition, leptin may be largely responsible for mediating a shift from a reliance upon glucose metabolism (absorption and glycogenolysis) to fat metabolism (lipolysis increasing gluconeogenesis) which preserves substrates for the brain, heart, and other critical organs. In this way a leptin-mediated glucose-fatty acid cycle appears to maintain glycemia and permit survival in starvation.

  4. Leptin and ghrelin: Sewing metabolism onto neurodegeneration.

    Science.gov (United States)

    de Candia, Paola; Matarese, Giuseppe

    2017-12-15

    Life expectancy has considerably increased over the last decades. The negative consequence of this augmented longevity has been a dramatic increase of age-related chronic neurodegenerative diseases, such as Alzheimer's, Parkinson's and multiple sclerosis. Epidemiology is telling us there exists a strong correlation between the neuronal loss characterizing these disorders and metabolic dysfunction. This review aims at presenting the evidence supporting the existence of a molecular system linking metabolism with neurodegeneration, with a specific focus on the role of two hormones with a key role in the regulatory cross talk between metabolic imbalance and the damage of nervous system: leptin and ghrelin. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Children's psychosocial stress and emotional eating: A role for leptin?

    Science.gov (United States)

    Michels, Nathalie; Sioen, Isabelle; Ruige, Johannes; De Henauw, Stefaan

    2017-05-01

    Psychosocial stress can be a health threat by stimulating unhealthier eating behaviors. We aim to test the role of the hormone leptin in the association between stress and diet/emotional eating as detected in primary school children. In a two-wave longitudinal study with 308 Belgian children (5-12y) in 2010-2012, the association of fasting serum leptin with reported stress (negative events and emotional problems), measured stress by salivary cortisol (overall cortisol output and awakening response), emotional eating and food consumption frequency was examined. Analyses were split by sex. Mediation and moderation by leptin change were tested. One stress marker (overall cortisol output) was significantly correlated with high leptin levels, but only in girls and cross-sectionally. Only in boys, leptin was associated with low emotional eating. Leptin was not a significant predictor of unhealthy food consumption. Leptin change was not a mediator but an enhancing moderator in the link between stress (high cortisol output and emotional problems) and emotional eating in girls: high reports of emotional eating in 2012 were present in the case of combined high 2-year leptin increase and high stress at baseline. Stress (represented by emotional problems and high daily cortisol) seems to lead to hyperleptinemia in girls; and the combination of high stress and hyperleptinemia might make girls more vulnerable to stress-induced eating. No functional data on leptin sensitivity were present, but results might suggest that stress induces lower sensitivity to the anorexigenic leptin activity. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:471-480). © 2016 Wiley Periodicals, Inc.

  6. Leptin and its potential interest in assisted reproduction cycles.

    Science.gov (United States)

    Catteau, A; Caillon, H; Barrière, P; Denis, M G; Masson, D; Fréour, T

    2016-04-01

    Leptin, an adipose hormone, has been shown to control energy homeostasis and food intake, and exert many actions on female reproductive function. Consequently, this adipokine is a pivotal factor in studies conducted on animal models and humans to decipher the mechanisms behind the infertility often observed in obese women. A systematic PubMed search was conducted on all articles, published up to January 2015 and related to leptin and its actions on energy balance and reproduction, using the following key words: leptin, reproduction, infertility, IVF and controlled ovarian stimulation. The available literature was reviewed in order to provide an overview of the current knowledge on the physiological roles of leptin, its involvement in female reproductive function and its potential interest as a prognostic marker in IVF cycles. Animal and human studies show that leptin communicates nutritional status to the central nervous system and emerging evidence has demonstrated that leptin is involved in the control of reproductive functions by acting both directly on the ovaries and indirectly on the central nervous system. With respect to the clinical use of leptin as a biomarker in IVF cycles, a systematic review of the literature suggested its potential interest as a predictor of IVF outcome, as high serum and/or follicular fluid leptin concentrations have correlated negatively with cycle outcome. However, these preliminary results remain to be confirmed. Leptin regulates energy balance and female reproductive function, mainly through its action on hypothalamic-pituitary-ovarian function, whose molecular and cellular aspects are progressively being deciphered. Preliminary studies evaluating leptin as a biomarker in human IVF seem promising but need further confirmation. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. The association between depression and leptin is mediated by adiposity.

    Science.gov (United States)

    Morris, Alanna A; Ahmed, Yusuf; Stoyanova, Neli; Hooper, William Craig; De Staerke, Christine; Gibbons, Gary; Quyyumi, Arshed; Vaccarino, Viola

    2012-06-01

    Animal models suggest that impaired leptin production, or leptin resistance despite increased leptin levels, may contribute to depression. The link between leptin and depression could be mediated by obesity, which is more common in depression and increases leptin production. We administered the Beck Depression Inventory-II (BDI-II) to 537 participants (mean [standard deviation (SD)] age = 51 [9] years; female, 61%) enrolled in the Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) study. Leptin levels were examined as continuous log-transformed values. Participants with moderate to severe depression had higher levels of leptin (median [interquartile range] 37.7 [17.6-64.9] ng/mL) than those with mild depression (22.9 [7.0-57.9] ng/mL) or minimal to no depression (19.8 ng/mL [7.8-39.1], p = .003). Participants with moderate to severe depression had higher body mass index (BMI) than those with mild or minimal depression (mean [SD] = 33 [8] versus 31 [9] versus 29 [7] kg/m(2), p = .001). After multivariate adjustment for age, sex, race, smoking status, hypertension, diabetes, blood pressure, lipids, and C-reactive protein, the BDI-II score remained a significant predictor of leptin levels (β = 0.093, p = .01). Further adjustment for BMI eliminated the association between the BDI-II score and leptin (β = 0.03, p = .3). Adjusting for waist circumference in place of BMI revealed similar findings. The association between depression and leptin seems to be mediated by increased adiposity in depressed individuals.

  8. Serum leptin concentrations, leptin mRNA expression, and food intake during the estrous cycle in rats

    DEFF Research Database (Denmark)

    Fungfuang, Wirasak; Nakada, Tomoaki; Nakao, Nobuhiro

    2013-01-01

    :00) of the 4-day estrous cycle in female rats. Serum leptin levels were measured by ELISA, and leptin mRNA expression levels were analyzed using real-time PCR on diestrous- and proestrous-stage rats. Our results revealed that during the sexual cycle, food intake was significantly higher in the dark phase......The aim of this study was to investigate food intake, serum leptin levels, and leptin mRNA expression during the sexual cycle in rats. Female Wistar-Imamichi rats aged 8-10 weeks were used in this experiment. Food intake was measured during the light and dark phases (light on at 07:00 and off at 19...... compared with the light phase. Food intake in proestrous females was significantly lower in the light and dark phases compared with the other groups. Serum leptin concentrations were significantly higher in both phases in proestrous rats compared with diestrous rats. There was a significant increase...

  9. Oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics: Immunofluorescent localization in the mouse hypothalamus.

    Science.gov (United States)

    Anderson, Brian M; Jacobson, Lauren; Novakovic, Zachary M; Grasso, Patricia

    2017-06-01

    This study describes the localization of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics, in the hypothalamus of Swiss Webster and C57BL/6J wild-type mice, leptin-deficient ob/ob mice, and leptin-resistant diet-induced obese (DIO) mice. The mice were given [D-Leu-4]-OB3 or MA-[D-Leu-4]-OB3 in 0.3% dodecyl maltoside by oral gavage. Once peak serum concentrations were reached, the mice received a lethal dose of pentobarbital and were subjected to intracardiac perfusion fixation. The brains were excised, post-fixed in paraformaldehyde, and cryo-protected in sucrose. Free-floating frozen coronal sections were cut at 25-µm and processed for imaging by immunofluorescence microscopy. In all four strains of mice, dense staining was concentrated in the area of the median eminence, at the base and/or along the inner wall of the third ventricle, and in the brain parenchyma at the level of the arcuate nucleus. These results indicate that [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 cross the blood-brain barrier and concentrate in an area of the hypothalamus known to regulate energy balance and glucose homeostasis. Most noteworthy is the localization of [D-Leu-4]-OB3 immunoreactivity within the hypothalamus of DIO mice via a conduit that is closed to leptin in this rodent model, and in most cases of human obesity. Together with our previous studies describing the effects of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on energy balance, glucose regulation, and signal transduction pathway activation, these findings are consistent with a central mechanism of action for these synthetic peptide leptin mimetics, and suggest their potential usefulness in the management of leptin-resistant obesity and type 2 diabetes in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Two divergent leptin paralogues in zebrafish (Danio rerio) that originate early in teleostean evolution.

    NARCIS (Netherlands)

    Gorissen, M.H.A.G.; Bernier, N.J.; Nabuurs, S.B.; Flik, G.; Huising, M.O.

    2009-01-01

    We describe duplicate leptin genes in zebrafish (Danio rerio) that share merely 24% amino acid identity with each other and only 18% with human leptin. We were also able to retrieve a second leptin gene in medaka (Oryzias latipes). The presence of duplicate leptin genes in these two distantly

  11. Low serum leptin predicts mortality in patients with chronic kidney disease stage 5

    DEFF Research Database (Denmark)

    Scholze, Alexandra; Rattensperger, Dirk; Zidek, Walter

    2007-01-01

    Leptin, secreted from adipose tissue, regulates food intake, energy expenditure, and immune function. It is unknown whether leptin predicts mortality in patients with chronic kidney disease stage 5 on hemodialysis therapy.......Leptin, secreted from adipose tissue, regulates food intake, energy expenditure, and immune function. It is unknown whether leptin predicts mortality in patients with chronic kidney disease stage 5 on hemodialysis therapy....

  12. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

    DEFF Research Database (Denmark)

    Kilpeläinen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A

    2016-01-01

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered...

  13. The association between leptin and depressive symptoms is modulated by abdominal adiposity

    NARCIS (Netherlands)

    Milaneschi, Y.; Sutin, A.R.; Terracciano, A.; Canepa, M.; Gravenstein, K.S.; Egan, J.M.; Vogelzangs, N.; Guralnik, J.M.; Bandinelli, S.; Penninx, B.W.J.H.; Ferrucci, L.

    2014-01-01

    Background: Evidence for a role of leptin in depression is limited and conflicting. Inconclusive findings may be explained by the complex effect of obesity on leptin signaling. In particular, both hyperleptinemia due to leptin resistance in obese persons as well as low leptin in lean persons can

  14. Effects of β-aminoisobutyric acid on leptin production and lipid homeostasis: mechanisms and possible relevance for the prevention of obesity.

    Science.gov (United States)

    Begriche, Karima; Massart, Julie; Fromenty, Bernard

    2010-06-01

    Beta-aminoisobutyric acid (BAIBA) is a catabolite of thymine and antiretroviral thymine analogues AZT and d4T. We recently discovered that this beta-amino acid is able to enhance fatty acid oxidation and reduce body weight in mice through an increased production of leptin by the white adipose tissue (WAT). Furthermore, BAIBA could have favourable effects on nonalcoholic steatohepatitis in a leptin-independent manner. In the present review, we shall recall the circumstances that led us to discover the effects of BAIBA on body fat mass and lipid homeostasis. In addition, we put forward several hypothetical mechanisms whereby BAIBA could enhance leptin secretion by WAT and present some anti-inflammatory effects in the liver. We also discuss in this review (i) the deleterious impacts caused by the absence of, or low leptin expression on lipid homeostasis and body weight in humans and animals and (ii) recent data from other investigators suggesting that increasing leptin levels and/or responsiveness may be indeed an attractive pharmacological strategy in order to prevent (and/or treat) obesity, at least in some individuals.

  15. Leptin level and oxidative stress contribute to obesity-induced low testosterone in murine testicular tissue.

    Science.gov (United States)

    Zhao, Jian; Zhai, Lingling; Liu, Zheng; Wu, Shuang; Xu, Liping

    2014-01-01

    This study evaluated the effects of obesity on the function of reproductive organs in male mice and the possible mechanism of male secondary hypogonadism (SH) in obesity. Ninety-six mice were randomly assigned to three groups: the control group, diet-induced obesity group, and diet-induced obesity resistant group for 8 weeks and 19 weeks. The effects of short- and long-term high-fat diet on the reproductive organs were determined by measuring sperm count and motility, relative testis weight, testosterone level, pathological changes and apoptosis of Leydig cells. Oxidative stress was evaluated by determining malondialdehyde, H2O2, NO levels, and GSH in testis tissues. CAT, SOD, GSH-Px and Nrf2 mRNA were measured by real-time PCR. Short- and long-term high-fat diet decreased sperm count and motility, relative testis weight, testosterone level; decreased CAT, SOD, GSH-Px and Nrf2 mRNA expression; increased MDA, H2O2, NO and leptin levels; inhibited the activity of CAT and GSH-Px enzymes. Pathological injury and apoptosis of Leydig cells were found in testis tissue. Pathological damage of Leydig cells, oxidative stress in testis tissue, and high level of leptin may provide some evidence to clarify the mechanisms of male SH in obesity.

  16. Leptin Level and Oxidative Stress Contribute to Obesity-Induced Low Testosterone in Murine Testicular Tissue

    Directory of Open Access Journals (Sweden)

    Jian Zhao

    2014-01-01

    Full Text Available Objective. This study evaluated the effects of obesity on the function of reproductive organs in male mice and the possible mechanism of male secondary hypogonadism (SH in obesity. Methods. Ninety-six mice were randomly assigned to three groups: the control group, diet-induced obesity group, and diet-induced obesity resistant group for 8 weeks and 19 weeks. The effects of short- and long-term high-fat diet on the reproductive organs were determined by measuring sperm count and motility, relative testis weight, testosterone level, pathological changes and apoptosis of Leydig cells. Oxidative stress was evaluated by determining malondialdehyde, H2O2, NO levels, and GSH in testis tissues. CAT, SOD, GSH-Px and Nrf2 mRNA were measured by real-time PCR. Results. Short- and long-term high-fat diet decreased sperm count and motility, relative testis weight, testosterone level; decreased CAT, SOD, GSH-Px and Nrf2 mRNA expression; increased MDA, H2O2, NO and leptin levels; inhibited the activity of CAT and GSH-Px enzymes. Pathological injury and apoptosis of Leydig cells were found in testis tissue. Conclusions. Pathological damage of Leydig cells, oxidative stress in testis tissue, and high level of leptin may provide some evidence to clarify the mechanisms of male SH in obesity.

  17. Mammary gland leptin in relation to lactogenesis in the periparturient dairy goat

    DEFF Research Database (Denmark)

    Rasmussen, Alice Neess; Nielsen, Mette Olaf; Tauson, Anne-Helene

    2008-01-01

    The role of leptin in development of mammary gland secretory function was studied during the periparturient period in dairy goats. Changes in mammary leptin and leptin receptor (short cytoplasmic form) expression were evaluated by real-time RT-PCR and related to changes in milk and plasma leptin...... peak in milk leptin 2 days post-partum needs to be understood. We did not find evidence that milk leptin can be absorbed, and thus play a role in systemic regulation, of the neonatal goat....... concentrations from 5 weeks pre-partum to 7 weeks post-partum. It was further investigated if systemic leptin concentration in the neonate is affected by milk leptin intake. We found no evidence of accumulation of leptin in colostrum pre-partum. Pre- and post-partum milk leptin concentrations were similar...

  18. Leptin effects on the regenerative capacity of human periodontal cells.

    Science.gov (United States)

    Nokhbehsaim, Marjan; Keser, Sema; Nogueira, Andressa Vilas Boas; Jäger, Andreas; Jepsen, Søren; Cirelli, Joni Augusto; Bourauel, Christoph; Eick, Sigrun; Deschner, James

    2014-01-01

    Obesity is increasing throughout the globe and characterized by excess adipose tissue, which represents a complex endocrine organ. Adipose tissue secrets bioactive molecules called adipokines, which act at endocrine, paracrine, and autocrine levels. Obesity has recently been shown to be associated with periodontitis, a disease characterized by the irreversible destruction of the tooth-supporting tissues, that is, periodontium, and also with compromised periodontal healing. Although the underlying mechanisms for these associations are not clear yet, increased levels of proinflammatory adipokines, such as leptin, as found in obese individuals, might be a critical pathomechanistic link. The objective of this study was to examine the impact of leptin on the regenerative capacity of human periodontal ligament (PDL) cells and also to study the local leptin production by these cells. Leptin caused a significant downregulation of growth (TGFβ1, and VEGFA) and transcription (RUNX2) factors as well as matrix molecules (collagen, and periostin) and inhibited SMAD signaling under regenerative conditions. Moreover, the local expression of leptin and its full-length receptor was significantly downregulated by inflammatory, microbial, and biomechanical signals. This study demonstrates that the hormone leptin negatively interferes with the regenerative capacity of PDL cells, suggesting leptin as a pathomechanistic link between obesity and compromised periodontal healing.

  19. Leptin Induces an Inflammatory Phenotype in Lean Wistar Rats

    Directory of Open Access Journals (Sweden)

    Monique Allman

    2009-01-01

    Full Text Available The present study addressed the hypothesis that leptin promotes leukocyte trafficking into adipose tissue. Accordingly, male Wistar rats were treated with saline or recombinant rat leptin (1 mg/kg via the tail vein. Leukocyte trafficking in mesenteric venules was quantified by intravital microscopy. Treatment with leptin resulted in a 3- and 5-fold increases in rolling and firm adhesion, respectively. Compared to vehicle controls, leptin enhanced mRNA levels of IL-6 (8-fold and MCP-1 (5-fold in mesenteric adipose tissue (MAT. Similar increases in these markers were observed in mesenteric venules and in liver. Finally, the direct effect of leptin was assessed in C3A hepatocytes treated with leptin for 24 hours (7.8 ng/mL–125 ng/mL. Consistent with observations in vivo, production of ICAM-1, MCP-1, and IL-6 by hepatocytes was increased significantly. These findings support the hypothesis that leptin directly initiates inflammation in the local environment of mesenteric adipose tissue as well as systemically.

  20. Leptin: A Novel Therapeutic Strategy for Alzheimer's Disease

    Science.gov (United States)

    Tezapsidis, Nikolaos; Johnston, Jane M.; Smith, Mark A.; Ashford, J. Wesson; Casadesus, Gemma; Robakis, Nikolaos K.; Wolozin, Benjamin; Perry, George; Zhu, Xiongwei; Greco, Steven J.; Sarkar, Sraboni

    2010-01-01

    Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease (AD) at the molecular and physiological level. One activity of leptin is the control of AMP-dependent kinase (AMPK). In addition to maintaining lipid levels, AMPK regulates glycogen synthase kinase-3, which modulates tau phosphorylation. Leptin has been shown to reduce the amount of extracellular amyloid-β, both in cell culture and animal models of AD, as well as reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models of AD. In humans, weight loss often precedes the onset of dementia in AD and the level of circulating leptin is inversely proportional to the severity of dementia among AD patients. It is speculated that a deficiency in leptin levels or function may contribute to systemic and central nervous system abnormalities leading to AD, suggesting that a leptin replacement therapy may be beneficial for AD. This may be an attractive alternative to the drugs that are currently under development. PMID:19387109

  1. Longitudinal study of leptin levels in chronic hemodialysis patients

    Directory of Open Access Journals (Sweden)

    Averbukh Zhan

    2011-06-01

    Full Text Available Abstract Background The influence of serum leptin levels on nutritional status and survival in chronic hemodialysis patients remained to be elucidated. We conducted a prospective longitudinal study of leptin levels and nutritional parameters to determine whether changes of serum leptin levels modify nutritional status and survival in a cohort of prevalent hemodialysis patients. Methods Leptin, dietary energy and protein intake, biochemical markers of nutrition and body composition (anthropometry and bioimpedance analysis were measured at baseline and at 6, 12, 18 and 24 months following enrollment, in 101 prevalent hemodialysis patients (37% women with a mean age of 64.6 ± 11.5 years. Observation of this cohort was continued over 2 additional years. Changes in repeated measures were evaluated, with adjustment for baseline differences in demographic and clinical parameters. Results Significant reduction of leptin levels with time were observed (linear estimate: -2.5010 ± 0.57 ng/ml/2y; p Conclusions Thus leptin levels reflect fat mass depots, rather than independently contributing to uremic anorexia or modifying nutritional status and/or survival in chronic hemodialysis patients. The importance of such information is high if leptin is contemplated as a potential therapeutic target in hemodialysis patients.

  2. Leptin Influence in Craving and Relapse of Alcoholics and Smokers

    Science.gov (United States)

    Aguiar-Nemer, Aline S.; Toffolo, Mayla C. F.; da Silva, Claudio Jeronimo; Laranjeira, Ronaldo; Silva-Fonseca, Vilma A.

    2013-01-01

    Leptin inhibits signaling of dopamine in the nucleus accumbens, suggesting its role in regulating stress and its possible involvement in the neurobiology of reward system. The aim of this study was to review of the literature on the influence of leptin in the craving for alcohol and tobacco and whether there is already evidence that leptin may be a biomarker to indicate risk for craving and relapse. The review used as data bases Medline, LILACS and SciElo in the period between 2000 and 2012. Keywords were leptin, substance use disorders, craving and withdrawal, in Portuguese and English. Only 12 articles were met the inclusion criteria, relating leptin with craving in alcoholics (n = 10) and smokers (n = 2). No studies were found in the LILACS database. Leptin levels increase during abstinence and this may be related to a reduction of dopaminergic action in mesolimbic system, resulting in a greater intensity of craving and maintenance of addictive behavior. Although there are few studies, the most recent results indicate the usefulness of leptin as a marker of risk for relapse among smokers and alcoholics in abstinence. PMID:23671541

  3. Leptin distribution and metabolism in the pregnant rat: transplacental leptin passage increases in late gestation but is reduced by excess glucocorticoids.

    Science.gov (United States)

    Smith, Jeremy T; Waddell, Brendan J

    2003-07-01

    Leptin is essential for the establishment of pregnancy and appears to promote fetal growth, but the mechanisms regulating fetal leptin exposure remain unclear. In rodents, indirect evidence suggests that fetal leptin is partly derived from the maternal circulation via transplacental passage. Indeed, the placenta expresses mRNA for Ob-Ra, one of the short forms of the leptin receptor (Ob-R(S)) important in leptin transport, and this expression increases markedly in late pregnancy. Therefore, we determined the transplacental passage of maternal leptin to the fetus in the rat and whether this transport increases near term in association with a rise in placental expression of Ob-R(S) protein. Because of the proposed role of leptin in promoting fetal growth, we also assessed the effect of glucocorticoid-induced fetal growth retardation on placental leptin transport. Anesthetized rats received a constant infusion of (125)I-leptin via a jugular cannula before and at d 16 and 22 of pregnancy (term = d 23); plasma samples were obtained at 10, 20, 40, 60, 80, and 100 min, and fetuses and placentas were collected at the time of the final sample. The metabolic clearance rate of leptin fell (P pregnancy. Over this same period, Ob-R(S) protein expression in the placental labyrinth zone increased by almost 2-fold. Transplacental leptin passage was reduced (P pregnancy. Consistent with the proposed role of leptin as a fetal growth factor, transplacental leptin passage is reduced in association with glucocorticoid-induced fetal growth retardation.

  4. Relationship between Plasma Leptin Level and Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Anoop Shankar

    2012-01-01

    Full Text Available Background. Leptin is an adipose tissue-derived hormone shown to be related to several metabolic, inflammatory, and hemostatic factors related to chronic kidney disease. Recent animal studies have reported that infusion of recombinant leptin into normal rats for 3 weeks fosters the development of glomerulosclerosis. However, few studies have examined the association between leptin and CKD in humans. Therefore, we examined the association between plasma leptin levels and CKD in a representative sample of US adults. Methods. We examined the third National Health and Nutrition Examination Survey participants >20 years of age (n=5820, 53.6% women. Plasma leptin levels were categorized into quartiles (≤4.3 Fg/L, 4.4–8.7 Fg/L, 8.8–16.9 Fg/L, >16.9 Fg/L. CKD was defined as a glomerular filtration rate of <60 mL/min/1.73 m2 estimated from serum creatinine. Results. Higher plasma leptin levels were associated with CKD after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, body mass index (BMI, diabetes, hypertension, and serum cholesterol. Compared to quartile 1 of leptin (referent, the odds ratio (95% confidence interval of CKD associated with quartile 4 was 3.31 (1.41 to 7.78; P-trend = 0.0135. Subgroup analyses examining the relation between leptin and CKD by gender, BMI categories, diabetes, and hypertension status also showed a consistent positive association. Conclusion. Higher plasma leptin levels are associated with CKD in a representative sample of US adults.

  5. Creating leptin-like biofunctions by active immunization against chicken leptin receptor in growing chickens.

    Science.gov (United States)

    Lei, M M; Wu, S Q; Shao, X B; Li, X W; Chen, Z; Ying, S J; Shi, Z D

    2015-01-01

    In this study, immunization against chicken leptin receptor (cLEPR) extracellular domain (ECD) was applied to investigate leptin regulation and LEPR biofunction in growing chicken pullets. A recombinant protein (cLEPR ECD) based on the cLEPR complemenary DNA sequence corresponding to the 582nd to 796th amino acid residues of cLEPR mature peptide was prepared and used as antigen. Immunization against cLEPR ECD in growing chickens increased anti-cLEPR ECD antibody titers in blood, enhanced proportions of phosphorylated janus kinase 2 (JAK2) and served as signal transducer and activator of transcription 3 (STAT3) protein in liver tissue. Chicken live weight gain and abdominal fat mass were significantly decreased (P chickens. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Leptin signaling molecular actions and drug target in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Jiang N

    2014-11-01

    Full Text Available Nan Jiang,1,* Rongtong Sun,2,* Qing Sun3 1Shandong University School of Medicine, Jinan, Shandong Province, People’s Republic of China; 2Weihai Municipal Hospital, Weihai, Shandong Province, People’s Republic of China; 3Department of Pathology, QianFoShan Hospital Affiliated to Shandong University, Jinan, Shandong Province, People’s Republic of China *These authors contributed equally to this work Abstract: Previous reports indicate that over 13 different tumors, including hepatocellular carcinoma (HCC, are related to obesity. Obesity-associated inflammatory, metabolic, and endocrine mediators, as well as the functioning of the gut microbiota, are suspected to contribute to tumorigenesis. In obese people, proinflammatory cytokines/chemokines including tumor necrosis factor-alpha, interleukin (IL-1 and IL-6, insulin and insulin-like growth factors, adipokines, plasminogen activator inhibitor-1, adiponectin, and leptin are found to play crucial roles in the initiation and development of cancer. The cytokines induced by leptin in adipose tissue or tumor cells have been intensely studied. Leptin-induced signaling pathways are critical for biological functions such as adiposity, energy balance, endocrine function, immune reaction, and angiogenesis as well as oncogenesis. Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells; its critical roles in tumorigenesis are based on its oncogenic, mitogenic, proinflammatory, and pro-angiogenic actions. This review provides an update of the pathological effects of leptin signaling with special emphasis on potential molecular mechanisms and therapeutic targeting, which could potentially be used in future clinical settings. In addition, leptin-induced angiogenic ability and molecular mechanisms in HCC are discussed. The stringent binding affinity of leptin and its receptor Ob-R, as well as the highly upregulated expression of both

  7. Increased leptin/leptin receptor pathway affects systemic and airway inflammation in COPD former smokers

    OpenAIRE

    Profita, Mirella; Bruno,; Alessi,; Soresi,; Bonanno,; Riccobono,; Montalbano,; Albano,; Gjomarkaj,

    2011-01-01

    Andreina Bruno1, Marinella Alessi2, Simona Soresi2, Anna Bonanno1, Loredana Riccobono1, Angela Marina Montalbano1, Giusy Daniela Albano1, Mark Gjomarkaj1, Mirella Profita11Institute of Biomedicine and Molecular Immunology, Italian National Research Council, Palermo, Italy; 2Dipartimento Biomedico di Biomedicina Interna e Specialistica, University Palermo, ItalyBackground: Leptin, a hormone produced mainly by adipose tissue, regulates food intake and energy expenditure. It is involved in infla...

  8. Leptin deficiency-induced obesity exacerbates ultraviolet B radiation-induced cyclooxygenase-2 expression and cell survival signals in ultraviolet B-irradiated mouse skin

    International Nuclear Information System (INIS)

    Sharma, Som D.; Katiyar, Santosh K.

    2010-01-01

    Obesity has been implicated in several inflammatory diseases and in different types of cancer. Chronic inflammation induced by exposure to ultraviolet (UV) radiation has been implicated in various skin diseases, including melanoma and nonmelanoma skin cancers. As the relationship between obesity and susceptibility to UV radiation-caused inflammation is not clearly understood, we assessed the role of obesity on UVB-induced inflammation, and mediators of this inflammatory response, using the genetically obese (leptin-deficient) mouse model. Leptin-deficient obese (ob/ob) mice and wild-type counterparts (C57/BL6 mice) were exposed to UVB radiation (120 mJ/cm 2 ) on alternate days for 1 month. The mice were then euthanized and skin samples collected for analysis of biomarkers of inflammatory responses using immunohistochemistry, western blotting, ELISA and real-time PCR. Here, we report that the levels of inflammatory responses were higher in the UVB-exposed skin of the ob/ob obese mice than those in the UVB-exposed skin of the wild-type non-obese mice. The levels of UVB-induced cyclooxygenase-2 expression, prostaglandin-E 2 production, proinflammatory cytokines (i.e., tumor necrosis factor-α, interleukin-1β, interleukin-6), and proliferating cell nuclear antigen and cell survival signals (phosphatidylinositol-3-kinase and p-Akt-Ser 473 ) were higher in the skin of the ob/ob obese mice than the those in skin of their wild-type non-obese counterparts. Compared with the wild-type non-obese mice, the leptin-deficient obese mice also exhibited greater activation of NF-κB/p65 and fewer apoptotic cells in the UVB-irradiated skin. Our study suggests for the first time that obesity in mice is associated with greater susceptibility to UVB-induced inflammatory responses and, therefore, obesity may increase susceptibility to UVB-induced inflammation-associated skin diseases, including the risk of skin cancer.

  9. Duplicated leptin receptors in two species of eel bring new insights into the evolution of the leptin system in vertebrates

    DEFF Research Database (Denmark)

    Morini, M.; Pasquier, J.; van den Thillart, G.

    2015-01-01

    subfunctionalization. Four-month fasting had no impact on the expression of leptins and LEPRs in control European eels. This might be related to the remarkable adaptation of silver eel metabolism to long-term fasting throughout the reproductive oceanic migration. In contrast, sexual maturation induced differential...... of the duplicated LEPRs in this species. This suggests an ancient and positive role of the leptin system in the vertebrate reproductive function. This study brings new insights on the evolutionary history of the leptin system in vertebrates. Among extant vertebrates, the eel represents a unique case of duplicated...

  10. Effects of enriched environment on COX-2, leptin and eicosanoids in a mouse model of breast cancer.

    Directory of Open Access Journals (Sweden)

    Rachida Nachat-Kappes

    Full Text Available Cyclooxygenase-2 (COX-2 and adipokines have been implicated in breast cancer. This study investigated a possible link between COX-2 and adipokines in the development of mammary tumors. A model of environmental enrichment (EE, known to reduce tumor growth was used for a syngeneic murine model of mammary carcinoma. 3-week-old, female C57BL/6 mice were housed in standard environment (SE or EE cages for 9 weeks and transplanted orthotopically with syngeneic EO771 adenocarcinoma cells into the right inguinal mammary fat pad. EE housing influenced mammary gland development with a decrease in COX-2 expressing cells and enhanced side-branching and advanced development of alveolar structures of the mammary gland. Tumor volume and weight were decreased in EE housed mice and were associated with a reduction in COX-2 and Ki67 levels, and an increase in caspase-3 levels. In tumors of SE mice, high COX-2 expression correlated with enhanced leptin detection. Non-tumor-bearing EE mice showed a significant increase in adiponectin levels but no change in those of leptin, F(2-isoprostanes, PGF(2α, IL-6, TNF-α, PAI-1, and MCP-1 levels. Both tumor-bearing groups (SE and EE housing had increased resistin, IL-6, TNF-α, PAI-1 and MCP-1 levels irrespective of the different housing environment demonstrating higher inflammatory response due to the presence of the tumor. This study demonstrates that EE housing influenced normal mammary gland development and inhibited mammary tumor growth resulting in a marked decrease in intratumoral COX-2 activity and an increase in the plasma ratio of adiponectin/leptin levels.

  11. GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet.

    OpenAIRE

    Ito Yoshihiro; Banno Ryoichi; Shibata Miyuki; Adachi Koichi; Hagimoto Shigeru; Hagiwara Daisuke; Ozawa Yoshiharu; Goto Motomitsu; Suga Hidetaka; Sugimura Yoshihisa; Bettler Bernhard; Oiso Yutaka; Arima Hiroshi

    2013-01-01

    There is evidence suggesting that the GABA system in the arcuate nucleus, where orexigenic neuropeptide Y and agouti-related peptide as well as anorexigenic proopiomelanocortin (POMC) are expressed, plays an important role in energy balance. In this study, we generated POMC-specific GABAB receptor-deficient [knock-out (KO)] mice. Male KO mice on a high-fat diet (HFD) showed mild increases in body weight (BW) at the age of 9 weeks compared to wild-type (WT) mice, and the differences remained s...

  12. Involvement of Amylin and Leptin in the Development of Projections from the Area Postrema to the Nucleus of the Solitary Tract

    Directory of Open Access Journals (Sweden)

    Kathrin Abegg

    2017-11-01

    Full Text Available The area postrema (AP and the nucleus of the solitary tract (NTS are important hindbrain centers involved in the control of energy homeostasis. The AP mediates the anorectic action and the inhibitory effect on gastric emptying induced by the pancreatic hormone amylin. Amylin’s target cells in the AP project to the NTS, an integrative relay center for enteroceptive signals. Perinatal hormonal and metabolic factors influence brain development. A postnatal surge of the adipocyte-derived hormone leptin represents a developmental signal for the maturation of projections between hypothalamic nuclei controlling energy balance. Amylin appears to promote neurogenesis in the AP in adult rats. Here, we examined whether amylin and leptin are required for the development of projections from the AP to the NTS in postnatal and adult mice by conducting neuronal tracing studies with DiI in amylin- (IAPP−/− and leptin-deficient (ob/ob mice. Compared to wild-type littermates, postnatal (P10 and adult (P60 IAPP−/− mice showed a significantly reduced density of AP-NTS projections. While AP projections were also reduced in postnatal (P14 ob/ob mice, AP-NTS fiber density did not differ between adult ob/ob and wild-type animals. Our findings suggest a crucial function of amylin for the maturation of neuronal brainstem pathways controlling energy balance and gastrointestinal function. The impaired postnatal development of neuronal AP-NTS projections in ob/ob mice appears to be compensated in this experimental model during later brain maturation. It remains to be elucidated whether an amylin- and leptin-dependent modulation in neuronal development translates into altered AP/NTS-mediated functions.

  13. TNF-alpha, leptin, and lymphocyte function in human aging

    DEFF Research Database (Denmark)

    Bruunsgaard, H.; Pedersen, Agnes Nadelmann; Schroll, M.

    2000-01-01

    Aging is associated with increased inflammatory activity and concomitant decreased T cell mediated immune responses. Leptin may provide a link between inflammation and T cell function in aging. The aim of the study was to investigate if plasma levels of tumor necrosis factor (TNF)-alpha were...... there was no difference with regard to IL-2 production. Furthermore, there were no age-related differences in serum levels of leptin, However, women had higher levels than men. In the elderly people, serum levels of leptin were correlated with TNF-alpha in univariate regression analysis and in a multiple linear...... regression analysis adjusting for the effect of gender and body mass index. Furthermore, TNF-alpha, but not leptin, was positively correlated to sIL-2R and negatively correlated to IL-2 production. In conclusion, increased plasma levels of TNF-alpha in aging is associated with poor IL-2 production ex vivo...

  14. Leptin as immune mediator: Interaction between neuroendocrine and immune system.

    Science.gov (United States)

    Procaccini, Claudio; La Rocca, Claudia; Carbone, Fortunata; De Rosa, Veronica; Galgani, Mario; Matarese, Giuseppe

    2017-01-01

    Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. Initially described as an anti-obesity hormone, leptin has subsequently been shown to exert pleiotropic effects, being also able to influence haematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect both innate and adaptive immunity, by inducing a pro-inflammatory response and thus playing a key role in the regulation of the pathogenesis of several autoimmune/inflammatory diseases. In this review, we discuss the most recent advances on the role of leptin as immune-modulator in mammals and we also provide an overview on its main functions in non-mammalian vertebrates. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Serum leptin is correlated to high turnover in osteoporosis.

    Science.gov (United States)

    Hipmair, Gunter; Böhler, Nikolaus; Maschek, Wilma; Soriguer, Federico; Rojo-Martínez, Gemma; Schimetta, Wolfgang; Pichler, Robert

    2010-01-01

    Clinical data have suggested that obesity protects against osteoporosis. Leptin, mainly secreted by white adipose tissue, might be involved by mediating an effect on bone metabolism. This study was conducted to investigate a possible relationship of leptin and bone turn-over in postmenopausal women with osteoporosis. We measured bone mineral density (BMD), serum leptin levels and markers of bone metabolism, including osteocalcin and cross-laps in 44 patients with osteoporosis. The main group consisted of 32 postmenopausal women. Mean serum leptin was 13.1 microg/L and showed no statistically significant difference to the levels measured in a collective of normal persons adjusted for age and BMI. When related to serum cross-laps as markers of bone resorption, a positive correlation (pturnover serum bone markers, at least in postmenopausal women with osteoporosis.

  16. MOLECULAR CLONING OF OVINE cDNA LEPTIN GENE

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    CLAUDIA TEREZIA SOCOL

    2008-05-01

    Full Text Available An efficient bacterial transformation system suitable for cloning the coding sequence of the ovine leptin gene in E. coli DH5α host cells using the pGEMT easy vector it is described in this paper. The necessity of producing leptin is based on the fact that the role of this molecule in the animal and human organism is still unknown, leptin not existing as commercial product on the Romanian market. The results obtained in the bacterial transformation, cloning, recombinant clones selection, control of the insertion experiments and DNA computational analysis represent the first steps in further genetic engineering experiments such as production of DNA libraries, DNA sequencing, protein expression, etc., for a further contribution in elucidating the role of leptin in the animal and human organism.

  17. Leptin in milk and plasma of dairy asses

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    F. Fantuz

    2010-04-01

    Full Text Available Milk and plasma leptin levels have been studied in dairy asses machine milked according to two different routines: 20 pregnant, pluriparous asses, were divided into two groups subjected, every 28 d for 150 d, to two consecutive milkings carried out at different intervals, i.e. 20 vs. 4 hours interval, respectively for group A and group B. During the study, the declining total milk obtained by machine milking was unaffected by the different milking strategies; body condition score of asses as well did not vary between the groups. Different milking intervals did not significantly influence skimmed milk leptin content neither plasma leptin level. Moreover, we did not find significant variation in plasma leptin neither correlation with BCS, indicating that in donkey pregnancy inhibits the cross talk between hypothalamus and adipose tissue.

  18. TNF-alpha, leptin, and lymphocyte function in human aging

    DEFF Research Database (Denmark)

    Bruunsgaard, H.; Pedersen, Agnes Nadelmann; Schroll, M.

    2000-01-01

    Aging is associated with increased inflammatory activity and concomitant decreased T cell mediated immune responses. Leptin may provide a link between inflammation and T cell function in aging. The aim of the study was to investigate if plasma levels of tumor necrosis factor (TNF)-alpha were...... associated with leptin, circulating interleukin-2 receptors (sIL-2R), and phytohaemagglutinin (PHA) induced IL-2 production in whole blood in elderly humans. Circulating levels of TNF-alpha and sIL-2R were higher in elderly humans (N=42) compared to a young control group (N=37) whereas...... there was no difference with regard to IL-2 production. Furthermore, there were no age-related differences in serum levels of leptin, However, women had higher levels than men. In the elderly people, serum levels of leptin were correlated with TNF-alpha in univariate regression analysis and in a multiple linear...

  19. Serum leptin concentration in patients with type 2 diabetes

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    Malecha-Jedraszek Arleta

    2015-12-01

    Full Text Available With the increasing importance of early type 2 diabetes (DM2 and obesity detection, it is useful to reevaluate leptin role in these conditions. Our study aimed at investigating circulating leptin concentrations in a group of patients with DM2, and at assessing in detail whether leptin concentrations correlate with selected biochemical, clinical parameters and markers of systemic inflammation in patients with DM2 and in healthy volunteers. In our work, we analysed samples and data drawn from 71 patients aged 61.4 ± 11.7 years, who have been diagnosed with type 2 diabetes, as well as from a healthy control group (HC consisting of 51 healthy subjects with a mean age of 57.8 ± 13.7 years. Therein, the concentration of leptin in the DM2 patients was significantly higher than in the HC (p < 0.01, with median value of 16.59 (IQR 8.58-33.39 ng/ml in the DM2, vs median value of 6.66 (IQR 4.52-21.40 ng/ml in the HC. In the analysis of variance, higher leptin concentrations were revealed in the DM2 group as compared to the HC, and this figure remained significant after adjusting for gender and age (p < 0.001. Moreover, it was independent of HOMA-IR (p = 0.003. However, the differences in leptin levels between the groups disappeared when additional adjustments for anthropometric parameters (BMI, waist circumference were applied (p = 0.088. Beyond the aforementioned, significant positive correlations were found in the DM 2 group between leptin level and CRP (r=0.256; p < 0.05 and IL-6 (r = 0.345; p < 0.01. Among the selected variables, only gender and BMI were included in the predictive model explaining the variability of leptin, and, in total, were responsible for 72.6% of the original variation of the studied adipocytokine. The results of this study have led to conclusion that leptin may participate in the complex pathogenesis of DM2 and be a predictor of the development of this disease. As higher concentrations of leptin coexist with obesity, and this

  20. Evaluation of Serum Leptin Level in Children With Acute Leukemia

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    Iraj Shahramian

    2016-01-01

    Full Text Available Background Leptin is a multifunctional hormone plays an important role in regulating lipid, energy, homeostasis, angiogenesis, inflammation, hematopoiesis and cell cycle. This polypeptide is effective in growth and differentiation of leukemic cells through an Ob-R receptor expressed by them. Objectives The purpose of this study was to evaluate serum leptin levels in patients with acute leukemia and compare it in lymphoid and myeloid groups. Patients and Methods This analytical case-control study, conducted on 60 children in age ranged from 6 months to 16 years in two case and control groups in Ali ibn Abi Talib hospital, Zahedan. They matched based on age and gender and examined after their parent’s satisfaction according to the parental consent forms. None of patients had heart disease, digestive, glandular and metabolic problems, iron deficiency anemia and chronic kidney disease. After collecting the samples, leptin levels of both groups were measured with ELISA kit. Then, the gathered data were analyzed in SPSS-20 software, using independent t-test in considering of 95% confidence interval. Results Leptin serum levels in patients with acute leukemia and controls showed significant difference (P < 0.05. Leptin serum levels in patients with acute lymphoblastic leukemia and acute myeloblastic leukemia showed significant difference (P < 0.05. Leptin serum level in relation to age and gender groups was not statistically significant. Conclusions The findings of this study showed that in patients with acute leukemia, leptin serum levels increase independently of age and gender. In addition, leptin serum levels in acute lymphoid leukemia were higher than acute myeloid leukemia in this study.

  1. Effect of body mass index on serum leptin levels

    International Nuclear Information System (INIS)

    Paul, R.F.; Hassan, M.; Nazar, H.S.

    2012-01-01

    Background: Leptin is product of ob gene, an adipose tissue derived hormone that plays a key role in the regulation of body fat mass by regulating appetite and metabolism while balancing energy intake and energy expenditure. The objective of the study was to evaluate possible association between serum leptin levels and Body Mass Index (BMI) of gender in adult age group. Methods: Two-hundred-seventy subjects aged 20-50 years were randomly selected from general population of Abbottabad. The subjects were grouped on the basis on BMI (89 normal, 92 overweight, and 89 obese). After complete evaluation, demographic data was recorded and BMI. Non-fasting venous blood samples were drawn to measure serum leptin and serum glucose levels. The data were analysed using SPSS-15 calculating mean, percentage, independent t-test and chi-square test. Correlation and regression curve analysis were obtained, and p and r values were calculated. Results: Serum leptin levels and differences between genders were significant in all body mass indices. For normal BMI group the mean values for leptin were 2.6+-1.5 gamma g/ml in men, and 17.3+9-10.2 gamma g/ml for women. For Group-2 mean leptin levels in men were 9.9+-6.8 gamma g/ml and in women were 34.8+-13.6 gamma g/ml. For Group-3 BMI comprising obese subjects mean values for men were 21.3+-14.2 gamma g/ml and for women were 48.21+-21.2 gamma g/ml (p<0.001). Conclusion: A progressive increase in serum leptin concentration was observed with an increase in BMI. Significant difference between leptin concentrations in either gender was found in normal, overweight and obese subjects. (author)

  2. Longitudinal Analysis of Leptin Variation during Weight Regain after Weight Loss in Obese Children

    DEFF Research Database (Denmark)

    Jens-Christian, Holm; Michael, Gamborg; Leigh, Ward

    2009-01-01

    . Results: Children with the greatest increases in BMI standard deviation score (SDS) exhibited the largest leptin increments. The disproportionate reduction of leptin seen during weight loss recovered after weight loss. Leptin increases mirrored increases in BMI SDS during weight regain, and the leptin......-BMI SDS relationship seen during follow-up resembled the baseline leptin-BMI SDS relationship. Conclusion: Proportional increases of leptin and BMI SDS during weight regain suggests an intact leptin response during re-accumulation of fat. Following the pronounced reduction of leptin during weight loss......Objective: This study assessed if lower than predicted serum leptin concentrations seen during weight loss persisted during weight regain, with possible implications for weight control. Methods: 115 children were investigated during a 12-week weight loss program. 90 children completed the program...

  3. Longitudinal Analysis of Leptin Variation during Weight Regain after Weight Loss in Obese Children

    DEFF Research Database (Denmark)

    Holm, Jens-Christian; Gamborg, Michael; Ward, Leigh

    2009-01-01

    -BMI SDS relationship seen during follow-up resembled the baseline leptin-BMI SDS relationship. Conclusion: Proportional increases of leptin and BMI SDS during weight regain suggests an intact leptin response during re-accumulation of fat. Following the pronounced reduction of leptin during weight loss......Objective: This study assessed if lower than predicted serum leptin concentrations seen during weight loss persisted during weight regain, with possible implications for weight control. Methods: 115 children were investigated during a 12-week weight loss program. 90 children completed the program....... Results: Children with the greatest increases in BMI standard deviation score (SDS) exhibited the largest leptin increments. The disproportionate reduction of leptin seen during weight loss recovered after weight loss. Leptin increases mirrored increases in BMI SDS during weight regain, and the leptin...

  4. Longitudinal Analysis of Leptin Variation during Weight Regain after Weight Loss in Obese Children

    DEFF Research Database (Denmark)

    Jens-Christian, Holm; Michael, Gamborg; Leigh, Ward

    2009-01-01

    Objective: This study assessed if lower than predicted serum leptin concentrations seen during weight loss persisted during weight regain, with possible implications for weight control. Methods: 115 children were investigated during a 12-week weight loss program. 90 children completed the program....... Results: Children with the greatest increases in BMI standard deviation score (SDS) exhibited the largest leptin increments. The disproportionate reduction of leptin seen during weight loss recovered after weight loss. Leptin increases mirrored increases in BMI SDS during weight regain, and the leptin......-BMI SDS relationship seen during follow-up resembled the baseline leptin-BMI SDS relationship. Conclusion: Proportional increases of leptin and BMI SDS during weight regain suggests an intact leptin response during re-accumulation of fat. Following the pronounced reduction of leptin during weight loss...

  5. Does leptin play a cytokine-like role within the airways of COPD patients?

    Science.gov (United States)

    Bruno, A; Chanez, P; Chiappara, G; Siena, L; Giammanco, S; Gjomarkaj, M; Bonsignore, G; Bousquet, J; Vignola, A M

    2005-09-01

    The leptin-leptin receptor system might be up-regulated in the airways of chronic obstructive pulmonary disease (COPD). In bronchial biopsies obtained from normal subjects and smokers, with and without COPD, the present study examined leptin and leptin-receptor expression and their co-localisation in airway and inflammatory cells. Combining immunohistochemistry with terminal deoxynucleotidyl transferase dUTP nick end-labelling techniques, apoptosis in airway and inflammatory cells and in leptin and leptin-receptor expressing cells was investigated. In the epithelial cells both leptin and leptin-receptor expression was higher in normal subjects than in smokers and COPD subjects. By contrast, in the sub-mucosa, leptin was over-expressed in COPD when compared with normal subjects and smokers. Leptin and its receptor were co-localised, mainly with activated T cells (CD45R0) and CD8+ T lymphocytes. In smokers, apoptosis was found in some inflammatory cells, whereas in COPD inflammatory cells, leptin and leptin-receptor positive cells were not apoptotic. Leptin expression was related to COPD severity and assessed using the Global initiative for Chronic Obstructive Lung Disease classification. In conclusion, the present study shows an increased leptin expression in bronchial mucosa of chronic obstructive pulmonary disease patients, associated with airway inflammation and airflow obstruction.

  6. Hantaran Sinyal Leptin dan Obesitas: Hubungannya dengan Penyakit Kardiovaskuler

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    David Limanan

    2013-11-01

    Full Text Available Diperkirakan saat ini jumlah orang dengan obesitas melebihi 250 juta orang, yaitu 7% dari populasi orang dewasa di dunia. Mortalitas obesitas erat hubungannya dengan sindrom metabolik yang merupakan kelainan metabolik meliputi obesitas, resistensi insulin, gangguan toleransi glukosa, abnormalitas trigliserida dan hemostasis, disfungsi endotel dan hipertensi. Leptin dihasilkan adiposit dan merupakan anggota dari adipositokin; berperan dalam hantaran sinyal hormon jaringan adiposa. Kelainan leptin maupun reseptornyadapat menyebabkan seseorang mengalami obesitas, metabolik sindrom, diabetes dan penyakit kardiovaskuler. Kompleks leptin-reseptor mengaktifkan sistem transduksi sinyal, yang paling dominan adalah jalur janus kinase-signal transducer and activator of transcription-3 (JAK-STAT3, kemudian phospatidyl inositol 3- kinase (PI3K, mitogen-activated protein kinase (MAPK, 5’adenosine monophosphate-activated protein kinase (AMPK, dan mammalian target of rapamycin (mTOR. Jalur leptin-associated PI3K dengan ERK cascade berperan penting dalam proliferasi kardiomiosit dan melindungi jantung dari ischemia reperfusion injury. ERK1/2 mengaktifkan target gen seperti c-fos dan egr-1 yang berperan dalam proliferasi dan diferensiasi. Nuclear factor κB diduga sebagai target jalur p38 dan JNK MAPK. Faktor transkripsi inu berperan pentingdalam mengatur transkripsi sitokin proinflamasi seperti tumor necrosis factor (TNF-α dan interleukin (IL-1β. Leptin dapat meningkatkan pembentukan reactive oxygen species (ROS sel endotel pembuluh darah dan menstimulasi sekresi TNF-α dan IL-6 yang merupakan promotor hipertensi dan aterosklerosis.Kata Kunci: obesitas, leptin, sistem kardiovaskuler 

  7. Effect of leptin level upon lipid metabolism in climacteric women

    International Nuclear Information System (INIS)

    Peng Lijing; Yan Ruming; Sun Enhua

    2005-01-01

    To observe the relationship between leptin and obesity of climacteric women with their lipid metabolism, 110 cases of climacteric women were chosen as observation group, consisting of 69 cases obese subgroup and 45 cases non-obese group, and 60 cases of normal reproduction- age women were arranged as control group. Blood levels of leptin, INS, LDL-C, TG, HDL-C, apoA1, apoB, LH, FSH, E-2, T, and P were detected and BMI was calculated. The results showed that blood levels of leptin and INS of obese subgroup were significantly higher than those of non-obese sub-group and control group(P<0.01), and that LDL-C(5.01 mmol/L), TG(2.21mmal/L) and apoB(0.89g/L) levels in obese subgroup were significantly higher than those of control group. Furthermore, an important observation was that in climacteric women group, blood leptin level was positively and significantly correlated with insulin, BMI and several atherogenic blood lipid parameters, including LDL-C, TG and apoB. Thus, a preliminary conclusion might be reached as that the high climacteric level of leptin is associated with abnormal lipid metabolism related to atherogenity, and so leptin and lipid metabolism as a whole should be paid more attention in climateric women, especially those with obesity. (authors)

  8. Serum leptin levels in patients with coronary artery disease

    International Nuclear Information System (INIS)

    Akram, S.; Ahmed, Z.; Fayyaz, I.; Mehmood, S.; Chani, M.

    2011-01-01

    Cardiovascular diseases (CVD) are the leading cause of morbidity, mortality and disability worldwide. Leptin, a 16kDa product of ob gene, is an endocrine hormone produced by white adipose tissue. It is primarily involved in the regulation of food intake and energy expenditure. Hyperleptinemia is one of the novel risk factors contributing in many ways to CVD. Objective: The objective of the study was to find the level of leptin in patients with coronary artery disease (CAD) and compare it with healthy people in our population. Methods: Our study was an analytical and cross-sectional study. Our study included 60 patients with a history of CAD and 60 healthy controls (aged 40-60 years, both sexes). Leptin levels were measured by ELISA. Results: Mean serum leptin level in patients was 11.48+-11.25 g/ml, while control group had a mean leptin level of 8.22+-8.01 g/ml (p=0.071). Conclusion: Leptin levels were higher in patients but the difference was non-significant. More studies are needed with larger sample size in our population. (author)

  9. The relationship between umbilical and maternal blood leptin and it's effect in fetal growth

    International Nuclear Information System (INIS)

    Chen Linqi; Guo Sheng; Yu Xin; Feng Xing

    2005-01-01

    Objective: To study the correlation of leptin between maternal serum and cord blood and to know relationship between leptin and fetal growth, and the origin of leptin. Methods: The concentration of leptin in 55 cases of maternal serum and cord arterial and venous blood were measured by ELISA assay. According to the neonatal weight and gestational age, three groups were divided into small gestational age (SGA), appropriate gestational age (AGA) and large gestational age (LGA). The nutrition status of neonatal was evaluated by index of Pondernal. The comparision was made in these groups. Results: The concentration of leptin in the cord artery, venous and maternal serum among 55 cases was 16.58 ± 8.13 ng/ml, 12.05 ± 9.87 ng/ml, 13.24 ± 10.58 ng/ml respectively; The concentration of maternal serum leptin was higher than that of cord artery. The concentration of maternal serum leptin was higher than that of venous serum leptin slightly. There was significant difference between cord artery and venous in different gestational age groups. Serum leptin levels of cord artery and venous were well correlated with the one of the weight and gestational age of neonatal. Maternal serum leptin level was not correlated with birth weight, placental weight and gestational age. Conclusions: The leptin from placenta is concerned with the adjustment of fetal growth. Cord leptin can reflect the status of fetal growth. Cord venous leptin indicate that the leptin be from placenta. Cord artery leptin demonstrates a part of placenta leptin, which acts on the fetus and then induces the fetal fat tissue to produce leptin. The maternal leptin does not adjust fetal weight directly. It only adjusts fat content itself and energy metabolism. (authors)

  10. The effect of four weeks restricted diet on serum soluble leptin receptor levels and adipocyte leptin receptor density in normoweight rattus norvegicus strain Wistar

    Directory of Open Access Journals (Sweden)

    M. R. Indra

    2006-09-01

    Full Text Available One of the five possible mechanisms of leptin resistance in human obesity is the defect in the leptin receptor (Ob-R. Evidence has accumulated that leptin-binding activity in human serum is related to a soluble form of the leptin receptor, and restriction of energy intake resulted a decrease in circulating leptin levels. Aim of this study is to examine the difference of serum soluble leptin receptor level and leptin receptor density in rat adipose tissue of adventitial aorta after four weeks treated with different restricted diets. Soluble leptin receptor level was measured by ELISA and leptin receptor density by using immuno-histochemistry. The soluble leptin receptor in group treated with 40% of normal daily calori diet was found significantly lower than control (p = 0.02. There were no any significant differences among group treated with 40 % of normal daily calori diet, “1 day fast-1day eat”, and ”1day fast-2 days eat” groups, and among 1 day fast-1 day eat”, ”day fast - 2 days eat” and control groups as well. On the other hand, leptin receptor density in adipose tissues was higher in restricted diet group than control. Diet of 40 % normal daily calorie for 4 weeks decreased soluble leptin receptor level, but increased adipocyte leptin receptor density of the adipose tissue of rat adventitial aorta. These changes may be resulted from an up regulation mechanism in relation with homeostatic maintenance. (Med J Indones 2006; 15:145-50 Keywords: restricted diet, leptin receptor, soluble leptin receptor, adipocyte, obesity

  11. EPA prevents fat mass expansion and metabolic disturbances in mice fed with a Western diet[S

    Science.gov (United States)

    Pinel, Alexandre; Pitois, Elodie; Rigaudiere, Jean-Paul; Jouve, Chrystele; De Saint-Vincent, Sarah; Laillet, Brigitte; Montaurier, Christophe; Huertas, Alain; Morio, Beatrice; Capel, Frederic

    2016-01-01

    The impact of alpha linolenic acid (ALA), EPA, and DHA on obesity and metabolic complications was studied in mice fed a high-fat, high-sucrose (HF) diet. HF diets were supplemented with ALA, EPA, or DHA (1% w/w) and given to C57BL/6J mice for 16 weeks and to Ob/Ob mice for 6 weeks. In C57BL/6J mice, EPA reduced plasma cholesterol (−20%), limited fat mass accumulation (−23%) and adipose cell hypertrophy (−50%), and reduced plasma leptin concentration (−60%) compared with HF-fed mice. Furthermore, mice supplemented with EPA exhibited a higher insulin sensitivity (+24%) and glucose tolerance (+20%) compared with HF-fed mice. Similar effects were observed in EPA-supplemented Ob/Ob mice, although fat mass accumulation was not prevented. By contrast, in comparison with HF-fed mice, DHA did not prevent fat mass accumulation, increased plasma leptin concentration (+128%) in C57BL/6J mice, and did not improve glucose homeostasis in C57BL/6J and Ob/Ob mice. In 3T3-L1 adipocytes, DHA stimulated leptin expression whereas EPA induced adiponectin expression, suggesting that improved leptin/adiponectin balance may contribute to the protective effect of EPA. In conclusion, supplementation with EPA, but not ALA and DHA, could preserve glucose homeostasis in an obesogenic environment and limit fat mass accumulation in the early stage of weight gain. PMID:27307576

  12. Effect of spontaneous gestational diabetes on fetal and postnatal hepatic insulin resistance in Lepr(db/+) mice.

    Science.gov (United States)

    Yamashita, Hiroshi; Shao, Jianhua; Qiao, Liping; Pagliassotti, Michael; Friedman, Jacob E

    2003-03-01

    Infant macrosomia is a classic feature of a gestational diabetes mellitus (GDM) pregnancy and is associated with increased risk of adult obesity and type II diabetes mellitus, however mechanisms linking GDM and later disease remain poorly understood. The heterozygous leptin receptor-deficient (Lepr(db/+)) mouse develops spontaneous GDM and the fetuses display characteristics similar to infants of GDM mothers. We examined the effects of GDM on maternal insulin resistance, fetal growth, and postnatal development of hepatic insulin resistance. Fetal body weight on d 18 of gestation was 6.5% greater (p obesity and insulin resistance in the livers of the adult offspring. The specific decrease in Akt phosphorylation in livers of adult offspring suggests that this may be a mechanism for reduced insulin-dependent physiologic events, such as suppression of hepatic glucose production, a defect associated with susceptibility to type II diabetes mellitus.

  13. Diet-induced obesity has neuroprotective effects in murine gastric enteric nervous system: involvement of leptin and glial cell line-derived neurotrophic factor.

    Science.gov (United States)

    Baudry, Charlotte; Reichardt, François; Marchix, Justine; Bado, André; Schemann, Michael; des Varannes, Stanislas Bruley; Neunlist, Michel; Moriez, Raphaël

    2012-02-01

    Nutritional factors can induce profound neuroplastic changes in the enteric nervous system (ENS), responsible for changes in gastrointestinal (GI) motility. However, long-term effects of a nutritional imbalance leading to obesity, such as Western diet (WD), upon ENS phenotype and control of GI motility remain unknown. Therefore, we investigated the effects of WD-induced obesity (DIO) on ENS phenotype and function as well as factors involved in functional plasticity. Mice were fed with normal diet (ND) or WD for 12 weeks. GI motility was assessed in vivo and ex vivo. Myenteric neurons and glia were analysed with immunohistochemical methods using antibodies against Hu, neuronal nitric oxide synthase (nNOS), Sox-10 and with calcium imaging techniques. Leptin and glial cell line-derived neurotrophic factor (GDNF) were studied using immunohistochemical, biochemical or PCR methods in mice and primary culture of ENS. DIO prevented the age-associated decrease in antral nitrergic neurons observed in ND mice. Nerve stimulation evoked a stronger neuronal Ca(2+) response in WD compared to ND mice. DIO induced an NO-dependent increase in gastric emptying and neuromuscular transmission in the antrum without any change in small intestinal transit. During WD but not ND, a time-dependent increase in leptin and GDNF occurred in the antrum. Finally, we showed that leptin increased GDNF production in the ENS and induced neuroprotective effects mediated in part by GDNF. These results demonstrate that DIO induces neuroplastic changes in the antrum leading to an NO-dependent acceleration of gastric emptying. In addition, DIO induced neuroplasticity in the ENS is likely to involve leptin and GDNF.

  14. Biologically active leptin-related synthetic peptides activate STAT3 via phosphorylation of ERK1/2 and PI-3K.

    Science.gov (United States)

    Lin, Hung-Yun; Yang, Sheng-Huei; Tang, Heng-Yuan; Cheng, Guei-Yun; Davis, Paul J; Grasso, Patricia

    2014-07-01

    The effects of leptin-related synthetic peptides [d-Leu-4]-OB3 and OB3 on energy balance and glucose homeostasis in ob/ob and db/db mice have been confirmed. The molecular basis of these effects, however, remains unclear. In the present study, we examined the ability of these peptides to activate signal transduction pathways known to be involved in transduction of the leptin signal. In a specific and concentration-dependent manner, [d-Leu-4]-OB3 induced phosphorylation of ERK1/2, PI-3K, Ser-727 STAT3, and Tyr-705 of STAT3. OB3 also induced activation of STAT3 via phosphorylation of ERK1/2, STAT3 Ser-727, STAT3 Tyr-705 and PI-3K p85, but to a lesser degree. Using PD98059 and LY294002, specific inhibitors of MEK and PI-3K, respectively, we were able to identify the signal transduction pathways involved in peptide-induced STAT3 activation. [d-Leu-4]-OB3 induced serine phosphorylation of STAT3 primarily through activation of ERK1/2. Tyrosine phosphorylation of STAT3, however, was induced primarily through activation of PI-3K. Our data suggest that in db/db mice, [d-Leu-4]-OB3 binding to short isoforms of the leptin receptor induces intracellular signaling cascades which do not require OB-Rb activation. These signals may ultimately result in peptide effects on transcriptional and translational events associated with energy balance and glycemic regulation. In summary, we have shown for the first time that, similar to leptin, bioactive leptin-related synthetic peptide analogs activate STAT3 via phosphorylation of serine and tyrosine residues by multiple signal transduction pathways. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Relationship between expression of leptin receptors mRNA in breast tissue, plasma leptin level in breast cancer patients with obesity and clinical pathologic data

    International Nuclear Information System (INIS)

    Li Chunrui; Liu Wenli; Sun Hanying; Zhou Jianfeng

    2007-01-01

    In order to investigate the expression of leptin receptors mRNA in breast tissue and plasma leptin levels in breast cancer patients with obesity and their relationship with clinical pathologic data, 124 subjects who were either obesity or had suffered from breast benign disease with obesity, or breast cancer with obesity were entered into this study. The levels of plasma leptin in all subjects were determined and leptin receptors mRNA expression levels were measured by RT-PCR in breast tissue of breast cancer patients with obesity and breast benign disease with obesity. The results showed that plasma leptin levels in breast cancer patients with obesity were significantly higher than those in breast benign disease with obesity and obesity patients alone (P<0.05). The expression of the leptin receptor long form [-Lep-R(L)-] mRNA and the leptin receptor short form [-Lep-R(S)-] mRNA in breast tissue of breast cancer patients with obesity were significantly higher than that in breast tissue of breast benign disease patients with obesity (P<0.05). The plasma leptin level had remarkable positive correlation with the expressions of the Lep-R(L) mRNA and the Lep-R(S) mRNA. The plasma leptin level and leptin receptors mRNA expression levels in patients were not correlated with the axillary node metastasis, menopause, the TNM stage or pathological type. Therefore, leptin may have a promoting effect on the carcinogenesis of breast cancer. (authors)

  16. Circulating leptin and body composition in chronic obstructive pulmonary disease.

    Science.gov (United States)

    Karakas, S; Karadag, F; Karul, A B; Gurgey, O; Gurel, S; Guney, E; Cildag, O

    2005-10-01

    Nutritional depletion and weight loss are two features of chronic obstructive pulmonary disease (COPD), and the association between low body mass index (BMI) and poor prognosis in patients with COPD is a common clinical observation. Mechanisms of weight loss are still unclear in COPD. Excessive energy expenditure partly due to increased work of breathing was shown, but other mechanisms have been searched for. Leptin is a hormone secreted by adipocytes that plays an important role in energy homeostasis and regulates body weight through control of appetite and energy expenditure. The aim of this study was to evaluate the association of circulating leptin levels and measures of body composition in COPD patients. Thirty male COPD outpatients (mean age 66.3 +/- 8.4) and 20 controls (mean age 65.9 +/- 10.8) were included in the study. After standard spirometry and body composition measurements, serum leptin concentration was measured by ELISA assay. COPD patients were grouped according to BMI. Mean BMI was 19.01 +/- 2.26 kg/m2 in group 1 (COPD patients with low BMI), 26.85 +/- 4.51 in group 2 COPD (COPD patients with normal/high BMI) and 27.64 +/- 2.75 kg/m2 in healthy controls (group 3). Mean serum leptin concentration was 1.41 +/- 1.86 ng/ml in group 1, 2.60 +/- 1.38 ng/ml in group 2 and 2.82 +/- 1.46 ng/ml in group 3 (p = 0.002). Leptin correlated to not only BMI but also body weight, waist circumference, triceps and biceps skinfold thickness and body fat percent (p leptin in COPD. Instead, leptin remains regulated in COPD and further decreased in patients with low BMI, probably as a compensatory mechanism to preserve body fat content, which should be evaluated in further studies.

  17. Serum leptin concentration during puberty in healthy nonobese adolescents

    Directory of Open Access Journals (Sweden)

    Brandão C.M.A.

    2003-01-01

    Full Text Available Data obtained during the past five years have indicated that there are important age- and gender-based differences in the regulation and action of leptin in humans. To study the physiological changes of leptin during puberty in both sexes, and its relationship with body composition and sexual maturation, we measured leptin concentrations in 175 healthy adolescents (80 girls, 95 boys, 10-18 years of age, representing all pubertal stages. We excluded individuals with a body mass index (BMI below the 5thor above the 95th percentile relative to age. Serum concentrations of leptin were determined by a monoclonal antibody-based immunofluorimetric assay, developed in our laboratory. Body composition was determined by dual-energy X-ray absorptiometry. Pubertal stage was assigned by physical examination, according to Tanner criteria for breast development in females and genital development in males. Leptin concentration in girls (N = 80 presented a positive linear correlation with age (r = 0.35, P = 0.0012, BMI (r = 0.65, P < 0.0001 and %fat mass (r = 0.76, P < 0.0001. In boys (N = 95 there was a positive correlation with BMI (r = 0.49, P < 0.0001 and %fat mass (r = 0.85, P < 0.0001, but a significant negative linear correlation with Tanner stage (r = -0.45, P < 0.0001 and age (r = -0.40, P < 0.0001. The regression equation revealed that %fat mass and BMI are the best parameters to be used to estimate leptin levels in both sexes. Thus, the normal reference ranges for circulating leptin during adolescence should be constructed according to BMI or %fat mass to assure a correct evaluation.

  18. Influence of weeks of circadian misalignment on leptin levels

    Directory of Open Access Journals (Sweden)

    June Nguyen

    2009-12-01

    Full Text Available June Nguyen, Kenneth P Wright JrDepartment of Integrative Physiology, Sleep and Chronobiology Laboratory, University of Colorado, Boulder, CO, USAAbstract: The neurobiology of circadian, wakefulness–sleep, and feeding systems interact to influence energy homeostasis. Sleep and circadian disruptions are reported to be associated with increased risk of diabetes and obesity, yet the roles of energy balance hormones in these associations are largely unknown. Therefore, in the current study we aimed to assess the influence of several weeks of circadian misalignment (sleep and wakefulness occurring at an inappropriate biological time on the anorexigenic adipocyte hormone leptin. We utilized data from a previous study designed to assess physiological and cognitive consequences of changes in day length and light exposure as may occur during space flight, including exploration class space missions and exposure to the Martian Sol (day length. We hypothesized that circadian misalignment during an exploration class spaceflight simulation would reduce leptin levels. Following a three-week ~8 hours per night home sleep schedule, 14 healthy participants lived in the laboratory for more than one month. After baseline data collection, participants were scheduled to either 24.0 or 24.6 hours of wakefulness–sleep schedules for 25 days. Changes in the phase of the circadian melatonin rhythm, sleep, and leptin levels were assessed. Half of participants analyzed exhibited circadian misalignment with an average change in phase angle from baseline of ~4 hours and these participants showed reduced leptin levels, sleep latency, stage 2 and total sleep time (7.3 to 6.6 hours and increased wakefulness after sleep onset (all P < 0.05. The control group remained synchronized and showed significant increases in sleep latency and leptin levels. Our findings indicate that weeks of circadian misalignment, such as that which occurs in circadian sleep disorders, alters leptin

  19. Associations of plasma leptin to clinical manifestations in reproductive aged female patients with panic disorder.

    Science.gov (United States)

    Masdrakis, Vasilios G; Papageorgiou, Charalambos; Markianos, Manolis

    2017-09-01

    Preclinical studies suggest the implication of the adipocyte hormone leptin in anxiety and fear processes. We explored for potential differences regarding plasma leptin, cortisol and the ratio leptin/Body Mass Index (BMI) between 27 medication-free female patients with Panic Disorder (PD) and 42 age-matched female controls, and for potential associations between plasma leptin and psychometric evaluations including number of panic attacks during last week, Clinical Global Impression-Severity of Illness (CGI-S) and Symptoms Checklist-90-Revised (SCL-90-R). Cortisol levels showed no differences between patients and controls, or correlations to leptin or to any clinical features. Both groups demonstrated a strong positive correlation between leptin and BMI and similar leptin and leptin/BMI, despite patients' lower BMI. However, patients -but not controls- demonstrated significant negative correlations of leptin to the 'somatization', 'anxiety', and 'phobic anxiety' SCL-90-R subscales. Moreover, there was a significant negative correlation of leptin and of leptin/BMI ratio to the number of panic attacks during last week, while higher CGI-S was associated with lower leptin/BMI ratio. Our results, limited to PD female patients, suggest that lower leptin serum levels are significantly associated with greater severity of psychopathological manifestations, including number of panic attacks, symptoms of somatization, anxiety and phobic anxiety and overall clinical presentation. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  20. Leptin Levels Are Higher in Whole Compared to Skim Human Milk, Supporting a Cellular Contribution

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    Sambavi Kugananthan

    2016-11-01

    Full Text Available Human milk (HM contains a plethora of metabolic hormones, including leptin, which is thought to participate in the regulation of the appetite of the developing infant. Leptin in HM is derived from a combination of de novo mammary synthesis and transfer from the maternal serum. Moreover, leptin is partially lipophilic and is also present in HM cells. However, leptin has predominately been measured in skim HM, which contains neither fat nor cells. We optimised an enzyme-linked immunosorbent assay for leptin measurement in both whole and skim HM and compared leptin levels between both HM preparations collected from 61 lactating mothers. Whole HM leptin ranged from 0.2 to 1.47 ng/mL, whilst skim HM leptin ranged from 0.19 to 0.9 ng/mL. Whole HM contained, on average, 0.24 ± 0.01 ng/mL more leptin than skim HM (p < 0.0001, n = 287. No association was found between whole HM leptin and fat content (p = 0.17, n = 287, supporting a cellular contribution to HM leptin. No difference was found between pre- and post-feed samples (whole HM: p = 0.29, skim HM: p = 0.89. These findings highlight the importance of optimising HM leptin measurement and assaying it in whole HM to accurately examine the amount of leptin received by the infant during breastfeeding.

  1. Leptin Levels Are Higher in Whole Compared to Skim Human Milk, Supporting a Cellular Contribution.

    Science.gov (United States)

    Kugananthan, Sambavi; Lai, Ching Tat; Gridneva, Zoya; Mark, Peter J; Geddes, Donna T; Kakulas, Foteini

    2016-11-08

    Human milk (HM) contains a plethora of metabolic hormones, including leptin, which is thought to participate in the regulation of the appetite of the developing infant. Leptin in HM is derived from a combination of de novo mammary synthesis and transfer from the maternal serum. Moreover, leptin is partially lipophilic and is also present in HM cells. However, leptin has predominately been measured in skim HM, which contains neither fat nor cells. We optimised an enzyme-linked immunosorbent assay for leptin measurement in both whole and skim HM and compared leptin levels between both HM preparations collected from 61 lactating mothers. Whole HM leptin ranged from 0.2 to 1.47 ng/mL, whilst skim HM leptin ranged from 0.19 to 0.9 ng/mL. Whole HM contained, on average, 0.24 ± 0.01 ng/mL more leptin than skim HM ( p < 0.0001, n = 287). No association was found between whole HM leptin and fat content ( p = 0.17, n = 287), supporting a cellular contribution to HM leptin. No difference was found between pre- and post-feed samples (whole HM: p = 0.29, skim HM: p = 0.89). These findings highlight the importance of optimising HM leptin measurement and assaying it in whole HM to accurately examine the amount of leptin received by the infant during breastfeeding.

  2. Effects of chronic leptin administration on nitric oxide production and immune responsiveness of greenfinches.

    Science.gov (United States)

    Lõhmus, Mare; Sild, Elin; Hõrak, Peeter; Björklund, Mats

    2011-04-01

    Leptin and nitric oxide (NO) are both important messengers in intra- and intercellular communication systems in vertebrates. Several studies have demonstrated an involvement of both substances in the immune response. Here we tested the effects of chronic leptin and anti-leptin treatments on the NO production and phytohaemagglutinin- (PHA) induced cutaneous inflammatory response in a wild passerine, the greenfinch (Carduelis chloris). Plasma leptin levels of individual birds were consistent in time but could be still temporarily increased by administration of recombinant chicken leptin. Increase of plasma leptin was also induced by administration of anti-leptin, which can be most likely explained by increased endogenous leptin production due to disruption of signalling pathways. Contrary to previous findings in mammals, leptin administration reduced systemic NO production. Leptin increased cutaneous swelling response to PHA. This immune-enhancing effect was observable despite the similar plasma leptin levels of leptin-treated and control birds at the time of measurement of immune responses, i.e., 9 days after start of the treatments. This provides evidence for a delayed or long-term potentiation of the cells and cytokines involved. The effects of leptin administration on NO production and immune responsiveness were age-dependent, which indicates the complexity of underlying regulatory mechanisms. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Low serum leptin predicts mortality in patients with chronic kidney disease stage 5

    DEFF Research Database (Denmark)

    Scholze, Alexandra; Rattensperger, Dirk; Zidek, Walter

    2007-01-01

    Leptin, secreted from adipose tissue, regulates food intake, energy expenditure, and immune function. It is unknown whether leptin predicts mortality in patients with chronic kidney disease stage 5 on hemodialysis therapy....

  4. High leptin levels are associated with migraine with aura.

    Science.gov (United States)

    Pisanu, Claudia; Preisig, Martin; Castelao, Enrique; Glaus, Jennifer; Cunningham, Janet L; Del Zompo, Maria; Merikangas, Kathleen R; Schiöth, Helgi B; Mwinyi, Jessica

    2017-04-01

    Background Migraine is a prevalent disorder characterised by recurrent headache attacks preceded or accompanied by aura in a subgroup of patients. Migraine often occurs together with major depressive disorder (MDD). Alterations of adipokine levels have been reported both in migraine and in MDD. In this cross-sectional study, we aimed to assess the associations between serum leptin and adiponectin levels and migraine or migraine subtypes. Analyses were adjusted for a lifetime history of MDD in order to investigate the association between adipokines and migraine under consideration of depression status. Methods We included 3025 participants from the CoLaus/PsyCoLaus study. The impact of leptin and adiponectin levels on a diagnosis of migraine was analysed by binary regression analyses, adjusting for variables known to influence adipokine levels. Subgroup analyses were conducted based on the presence of aura. Results Crude leptin levels were significantly higher in subjects with migraine than controls (Mann-Whitney U = 515,102, p = 6 × 10 -7 ). When performing adjusted analyses, leptin levels were found to be significantly higher in subjects with migraine (odds ratio = 1.22, p = 0.024) and migraine with aura (odds ratio = 1.34, p = 0.004). Conclusion High leptin levels might play a role in the pathogenesis of migraine and migraine with aura.

  5. Circulating leptin in patients with chronic obstructive pulmonary disease.

    Science.gov (United States)

    Takabatake, N; Nakamura, H; Abe, S; Hino, T; Saito, H; Yuki, H; Kato, S; Tomoike, H

    1999-04-01

    Unexplained weight loss is common in patients with chronic obstructive pulmonary disease (COPD). Since leptin, an obesity gene product, is known to play important roles in the control of body weight and energy expenditure, we investigated serum leptin levels, along with circulating tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptor (sTNF-R55 and -R75) levels, in 31 patients with COPD and 15 age-matched healthy controls. The body mass index (BMI) and percent body fat (%fat) were significantly lower in the COPD patients than in the healthy controls (BMI = 18.1 +/- 2.7 kg/m2 versus 22.8 +/- 2.2 kg/m2 [mean +/- SD]; p leptin levels were significantly lower in the COPD patients than in the healthy controls (1.14 +/- 1.17 ng/ml versus 2.47 +/- 2.01 ng/ml; p COPD patients than in the healthy controls. Importantly, circulating leptin levels (log transformed) did correlate well with BMI and %fat, but not with TNF-alpha or with sTNF-R levels in the COPD patients. These data suggest that circulating leptin is independent of the TNF-alpha system and is regulated physiologically even in the presence of cachexia in patients with COPD.

  6. Light Modulates Leptin and Ghrelin in Sleep-Restricted Adults

    Directory of Open Access Journals (Sweden)

    Mariana G. Figueiro

    2012-01-01

    Full Text Available Acute and chronic sleep restrictions cause a reduction in leptin and an increase in ghrelin, both of which are associated with hunger. Given that light/dark patterns are closely tied to sleep/wake patterns, we compared, in a within-subjects study, the impact of morning light exposures (60 lux of 633-nm [red], 532-nm [green], or 475-nm [blue] lights to dim light exposures on leptin and ghrelin concentrations after subjects experienced 5 consecutive days of both an 8-hour (baseline and a 5-hour sleep-restricted schedule. In morning dim light, 5-hour sleep restriction significantly reduced leptin concentrations compared to the baseline, 8-hour sleep/dim-light condition (1,32 = 2.9; =0.007. Compared to the 5-hour sleep/dim-light condition, the red, green, and blue morning light exposures significantly increased leptin concentrations (1,32 = 5.7; <0.0001, 1,32 = 3.6; =0.001, and 1,32 = 3.0; =0.005, resp.. Morning red light and green light exposures significantly decreased ghrelin concentrations (1,32 = 3.3; <0.003 and 1,32 = 2.2; =0.04, resp., but morning blue light exposures did not. This study is the first to demonstrate that morning light can modulate leptin and ghrelin concentrations, which could have an impact on reducing hunger that accompanies sleep deprivation.

  7. Anorexia of aging, leptin, and the Mini Nutritional Assessment.

    Science.gov (United States)

    Morley, J E; Miller, D K; Perry, H M; Patrick, P; Guigoz, Y; Vellas, B

    1999-01-01

    In this chapter we have reviewed the evidence for physiological anorexia of aging and stressed that its pathophysiology involves both central and peripheral mechanisms. Early satiation in the older person appears to involve signals predominantly arising in the stomach. The increased feeling of satiety in older persons is mainly related to changes in the central feeding drive, in particular a decrease in the opioid rewarding properties for fatty foods. Increased cytokines, secondary to inflammatory conditions which are common in old age, may further increase the anorexia seen in older persons. Leptin, the fat hormone, is an excellent indicator of fat mass in women, in whom leptin concentrations correlate with the MNA. In men, testosterone inhibits leptin, and the fall in testosterone with age results in an increase in leptin concentrations. In males the MNA is not related to leptin concentrations. Finally, we have examined the interrelation of two nutritional screening indices, MNA and SCALES. The two indices were well correlated and were both predictive of poor basic function. We conclude that the MNA is an excellent predictor of nutritional status. These findings suggest that malnutrition is a major predictor of frailty or the "failure to thrive" syndrome in older persons. Depression is a major cause of poor nutritional status in older persons.

  8. The unique cysteine knot regulates the pleotropic hormone leptin.

    Directory of Open Access Journals (Sweden)

    Ellinor Haglund

    Full Text Available Leptin plays a key role in regulating energy intake/expenditure, metabolism and hypertension. It folds into a four-helix bundle that binds to the extracellular receptor to initiate signaling. Our work on leptin revealed a hidden complexity in the formation of a previously un-described, cysteine-knotted topology in leptin. We hypothesized that this unique topology could offer new mechanisms in regulating the protein activity. A combination of in silico simulation and in vitro experiments was used to probe the role of the knotted topology introduced by the disulphide-bridge on leptin folding and function. Our results surprisingly show that the free energy landscape is conserved between knotted and unknotted protein, however the additional complexity added by the knot formation is structurally important. Native state analyses led to the discovery that the disulphide-bond plays an important role in receptor binding and thus mediate biological activity by local motions on distal receptor-binding sites, far removed from the disulphide-bridge. Thus, the disulphide-bridge appears to function as a point of tension that allows dissipation of stress at a distance in leptin.

  9. The association of serum leptin levels with metabolic diseases

    Directory of Open Access Journals (Sweden)

    Jen-Pi Tsai

    2017-01-01

    Full Text Available Leptin is a 167-amino-acid protein released by white adipose tissue and encoded by the obese gene. It has a role as a negative regulator of appetite control through sending a satiety signal to act on receptors within the hypothalamus. At normal levels, leptin can exert its effects on weight regulation according to white fat mass, induce sodium excretion, maintain vascular tone, and repair the myocardium. Beyond these effects, elevated serum leptin levels have been implicated in the pathogenesis of metabolic syndrome, diabetes mellitus, hypertension, and multiple cardiovascular diseases. In addition, hyperleptinemia had been reported to contribute to renal diseases through multiple mechanisms resulting in glomerulopathy presenting with a decreased glomerular filtration rate, increased albuminuria, and related clinical symptoms, which are pathophysiological features of chronic kidney disease. Because these cardiovascular and metabolic disorders are great challenges for physicians, understanding the related pathophysiological association with leptin might become a valuable aid in handling patients in daily clinical practice. This review will discuss the roles of leptin in the regulation of biological functions of multiple organs beyond the maintenance of feeding and metabolism.

  10. Training, leptin receptors and SOCS3 in human muscle.

    Science.gov (United States)

    Olmedillas, H; Guerra, B; Guadalupe-Grau, A; Santana, A; Fuentes, T; Dorado, C; Serrano-Sanchez, J A; Calbet, J A L

    2011-05-01

    Endurance exercise induces SUPPRESSOR of CYTOKINE SIGNALING 3 (SOCS3) mRNA expression in rodent skeletal muscle and endurance training overimposed on strength training blunts the hypertrophic response to strength training by an unknown mechanism. The aim of this study was to determine the effects of a concurrent strength and endurance training on fat mass, serum leptin concentration, muscle morphology, and muscle vastus lateralis leptin receptors (OB-Rb) and SOCS3 protein expression. 16 healthy young men were assigned to a control (C; n=7), and to a 12-week weightlifting (3 sessions/week)+endurance training program (T; n=9) group. Training enhanced maximal dynamic strength in lower and upper body exercises (18-54%), reduced fat mass by 1.8 kg and serum leptin concentration per kg of fat mass, and elicited muscle hypertrophy of type 2 (+18.5%, Ptraining. In conclusion, concurrent strength and endurance training reduces fat mass and serum leptin and the ratio leptin/fat mass without significant effects on vastus lateralis OB-Rb protein expression. Training does not increase the basal expression of SOCS3 protein in humans. © Georg Thieme Verlag KG Stuttgart · New York.

  11. FGF21 Administration Suppresses Retinal and Choroidal Neovascularization in Mice

    Directory of Open Access Journals (Sweden)

    Zhongjie Fu

    2017-02-01

    Full Text Available Pathological neovascularization, a leading cause of blindness, is seen in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Using a mouse model of hypoxia-driven retinal neovascularization, we find that fibroblast growth factor 21 (FGF21 administration suppresses, and FGF21 deficiency worsens, retinal neovessel growth. The protective effect of FGF21 against neovessel growth was abolished in adiponectin (APN-deficient mice. FGF21 administration also decreased neovascular lesions in two models of neovascular age-related macular degeneration: very-low-density lipoprotein-receptor-deficient mice with retinal angiomatous proliferation and laser-induced choroidal neovascularization. FGF21 inhibited tumor necrosis α (TNF-α expression but did not alter Vegfa expression in neovascular eyes. These data suggest that FGF21 may be a therapeutic target for pathologic vessel growth in patients with neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration.

  12. Prenatal caffeine exposure induced a lower level of fetal blood leptin mainly via placental mechanism

    International Nuclear Information System (INIS)

    Wu, Yi-meng; Luo, Han-wen; Kou, Hao; Wen, Yin-xian; Shen, Lang; Pei, Ling-guo; Zhou, Jin; Zhang, Yuan-zhen; Wang, Hui

    2015-01-01

    It's known that blood leptin level is reduced in intrauterine growth retardation (IUGR) fetus, and placental leptin is the major source of fetal blood leptin. This study aimed to investigate the decreased fetal blood leptin level by prenatal caffeine exposure (PCE) and its underlying placental mechanisms. Pregnant Wistar rats were intragastrically administered caffeine (30–120 mg/kg day) from gestational day 9 to 20. The level of fetal serum leptin and the expression of placental leptin-related genes were analyzed. Furthermore, we investigated the molecular mechanism of the reduced placental leptin's expression by treatment with caffeine (0.8–20 μM) in the BeWo cells. In vivo, PCE significantly decreased fetal serum leptin level in caffeine dose-dependent manner. Meanwhile, placental mRNA expression of adenosine A2a receptor (Adora2a), cAMP-response element binding protein (CREB), a short-type leptin receptor (Ob-Ra) and leptin was reduced in the PCE groups. In vitro, caffeine significantly decreased the mRNA expression of leptin, CREB and ADORA2A in concentration and time-dependent manners. The addition of ADORA2A agonist or adenylyl cyclase (AC) agonist reversed the inhibition of leptin expression induced by caffeine. PCE induced a lower level of fetal blood leptin, which the primary mechanism is that caffeine inhibited antagonized Adora2a and AC activities to decreased cAMP synthesis, thus inhibited the expression of the transcription factor CREB and target gene leptin in the placenta. Meantime, the reduced transportation of maternal leptin by placental Ob-Ra also contributed to the reduced fetal blood leptin. Together, PCE decreased fetal blood leptin mainly via reducing the expression and transportation of leptin in the placenta. - Highlights: • Caffeine reduced fetal blood leptin level. • Caffeine inhibited placental leptin production and transport. • Caffeine down-regulated placental leptin expression via antagonizing ADORA2. • Caffeine

  13. Role of leptin G-2548A polymorphism in age- and gender-specific ...

    Indian Academy of Sciences (India)

    2015-06-25

    Jun 25, 2015 ... ized to the hypothalamus. When the mass of adipose tissue increases, released leptin curtails appetite and stimulates energy expenditure. When the mass of adipose tissue de- creases, a lower leptin production favours an increase in appetite and less energy expenditure (Halaas et al. 1995). Thus, leptin is ...

  14. The diversity of leptin gene in Iranian native, Holstein and Brown ...

    African Journals Online (AJOL)

    STORAGESEVER

    2008-08-04

    Aug 4, 2008 ... This study describes genetic variability in the leptin in Iranian native, Brown Swiss and Holstein cattle. (Bos Indicus and Bos Taurus). This is the first study of genetic polymorphism of the leptin gene in. Iranian native cattle. We examined exon 2 of the leptin gene from 587 individuals in six different.

  15. Association between A59V polymorphism in exon 3 of leptin gene ...

    African Journals Online (AJOL)

    ONOS

    2010-09-06

    Sep 6, 2010 ... We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique to screen for DNA polymorphisms of the leptin gene in 255 cows of Iranian Holstein. Amplified region is located in exon 3 of leptin gene. The genomic bovine leptin sequences, which consist of three ...

  16. Effects of administration of glucocorticoids and feeding status on plasma leptin concentrations in dogs.

    Science.gov (United States)

    Nishii, Naohito; Takasu, Masaki; Ohba, Yasunori; Maeda, Sadatoshi; Kitoh, Katsuya; Ohtsuka, Yoshihiko; Honjo, Tsutomu; Saito, Masayuki; Kitagawa, Hitoshi

    2006-02-01

    To investigate effects of short- and long- term administration of glucocorticoids, feeding status, and serum concentrations of insulin and cortisol on plasma leptin concentrations in dogs. 20 nonobese dogs. For experiment 1, plasma leptin concentrations and serum concentrations of insulin and cortisol were monitored for 24 hours in 4 dogs administered dexamethasone (0.1 mg/kg, IV) or saline (0.9% NaCl) solution for fed and nonfed conditions. For experiment 2, 11 dogs were administered prednisolone (1 mg/kg, PO, q 24 h for 56 days [7 dogs] and 2 mg/kg, PO, q 24 h for 28 days [4 dogs]) and 5 dogs served as control dogs. Plasma leptin and serum insulin concentrations were monitored weekly. For experiment 1, dexamethasone injection with the fed condition drastically increased plasma leptin concentrations. Furthermore, injection of saline solution with the fed condition increased plasma leptin concentrations. These increases in plasma leptin concentrations correlated with increases in serum insulin concentrations. Dexamethasone injection with the nonfed condition increased plasma leptin concentrations slightly but continuously. Injection of saline solution with the nonfed condition did not alter plasma leptin concentrations. For experiment 2, prednisolone administration at either dosage and duration did not alter plasma leptin concentrations in any dogs. Dexamethasone injection and feeding increased plasma leptin concentrations in dogs. In addition, dexamethasone administration enhanced the effect of feeding on increases in plasma leptin concentrations. Daily oral administration of prednisolone (1 or 2 mg/kg) did not affect plasma leptin concentrations in dogs.

  17. Placental ghrelin and leptin expression and cord blood ghrelin, adiponectin, leptin, and C-peptide levels in severe maternal obesity.

    Science.gov (United States)

    Allbrand, Marianne; Åman, Jan; Lodefalk, Maria

    2017-08-08

    The purpose of this study is to investigate placental ghrelin and leptin expression as well as cord blood ghrelin and adiponectin levels in maternal obesity and associations between placental ghrelin expression, cord blood ghrelin levels and maternal and infant variables. Placental ghrelin and leptin expression were analyzed by RT-PCR in 32 severely obese and 32 matched normal-weight women. Cord blood ghrelin, adiponectin, leptin, and C-peptide concentrations were analyzed by ELISA. Neither ghrelin nor leptin expression and neither cord blood ghrelin nor adiponectin levels differed between the groups. Placental ghrelin expression was associated with BMI at delivery in the obese women (r = 0.424, p = .016) and in the infants born to normal-weight women with their weight z-scores at six (r = -0.642, p = .010), nine (r = -0.441, p = .015), and 12 months of age (r = -0.402, p = .028). Placental ghrelin and leptin expression as well as cord blood ghrelin and adiponectin levels do not seem to be altered in severe maternal obesity. Placenta-derived ghrelin may influence the infants' postnatal weight gain, but possibly only when the mother has normal weight.

  18. Plasma leptin levels in healthy children and adolescents

    DEFF Research Database (Denmark)

    Blum, W F; Englaro, P; Hanitsch, S

    1997-01-01

    difference especially in late puberty and adolescence, even after adjustment for BMI or percent body fat; 3) the lower levels in males may be explained at least in part by a suppressive effect of androgens; 4) reference ranges with BMI as the independent variable should be stratified according to gender......Leptin, the product of the ob gene, is thought to play a key role in the regulation of body fat mass. Beyond this function, it appears to be an integral component of various hypothalamo-pituitary-endocrine feedback loops. Because childhood and puberty are periods of major metabolic and endocrine...... changes, leptin levels and various hormonal parameters were investigated in a large cohort of healthy children and adolescents (312 males, 401 females, age 5.8-19.9 yr). For this purpose, a specific and sensitive RIA was developed that allowed the accurate measurement of low leptin levels in young lean...

  19. Plasma leptin levels in healthy children and adolescents

    DEFF Research Database (Denmark)

    Blum, W F; Englaro, P; Hanitsch, S

    1997-01-01

    increase in girls between 2.51 micrograms/L (median) at Tanner stage 1 to 6.24 micrograms/L at Tanner stage 5. In boys, leptin levels were highest at Tanner stage 2 (2.19 micrograms/L) and declined thereafter to 0.71 microgram/L at Tanner stage 5. A strong exponential relationship was observed for leptin...... levels with body mass index (BMI) and percentage body fat as determined by bioelectric impedance measurements in a subgroup of subjects. This relationship was similar between boys and girls at Tanner stages 1 and 2. In boys, there was a significant decline of leptin at a given BMI with further......, but not in girls, there was an inverse correlation with testosterone concentrations (r = -0.43, P model. Since BMI proved to be the major influencing variable, reference ranges were constructed using a best-fit regression...

  20. Mechanism of attenuation of leptin signaling under chronic ligand stimulation

    Directory of Open Access Journals (Sweden)

    Bamberg-Lemper Simone

    2010-01-01

    Full Text Available Abstract Background Leptin is an adipocyte-derived hormone that acts via its hypothalamic receptor (LEPRb to regulate energy balance. A downstream effect essential for the weight-regulatory action of leptin is the phosphorylation and activation of the latent transcription factor STAT3 by LEPRb-associated Janus kinases (JAKs. Obesity is typically associated with chronically elevated leptin levels and a decreased ability of LEPRb to activate intracellular signal transduction pathways (leptin resistance. Here we have studied the roles of the intracellular tyrosine residues in the negative feedback regulation of LEPRb-signaling under chronic leptin stimulation. Results Mutational analysis showed that the presence of either Tyr985 and Tyr1077 in the intracellular domain of LEPRb was sufficient for the attenuation of STAT3 phosphorylation, whereas mutation of both tyrosines rendered LEPRb resistant to feedback regulation. Overexpression and RNA interference-mediated downregulation of suppressor of cytokine signaling 3 (SOCS3 revealed that both Tyr985 and Tyr1077 were capable of supporting the negative modulatory effect of SOCS3 in reporter gene assays. In contrast, the inhibitory effect of SOCS1 was enhanced by the presence of Tyr985 but not Tyr1077. Finally, the reduction of the STAT-phosphorylating activity of the LEPRb complex after 2 h of leptin stimulation was not accompanied by the dephosphorylation or degradation of LEPRb or the receptor-associated JAK molecule, but depended on Tyr985 and/or Tyr1077. Conclusions Both Tyr985 and Tyr1077 contribute to the negative regulation of LEPRb signaling. The inhibitory effects of SOCS1 and SOCS3 differ in the dependence on the tyrosine residues in the intracellular domain of LEPRb.

  1. Leptin and body mass index in polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Nasrin Jalilian

    2016-01-01

    Full Text Available Objective: Polycystic ovary syndrome (PCOS is a common endocrine disorder associated with obesity. Human and animal studies showed a direct relationship between leptin level and obesity, however, results from different studies were mixed. This study investigated the status of leptin level in PCOS and its relationship with body mass index (BMI in a group of Iranian women with PCOS. Methods: In this cross-sectional study, 40 women with PCOS and 36 healthy women were assigned to experimental and control groups, respectively. Those in the PCOS group were not prescribed any medications for 3 months prior to the study. Fasting blood samples were then collected during the 2nd or 3rd day of menstruation for laboratory measurement of serum total leptin, blood glucose (fasting blood sugar, serum insulin, follicle-stimulating hormone, and luteinizing hormone (LH. Results: Mean BMI of the PCOS and control groups were 26.62 ± 4.03 kg/m2 and 23.52 ± 2.52 kg/m2, respectively (P = 0.006. The mean total leptin in the PCO group was also 10.69 ± 5.37 ng/mL and 5.73 ± 2.36 ng/mL in the control group (P = 0.0001. A significant relationship was found between leptin level and BMI as well as LH level among women with PCOS (P 0.05. Conclusion: The results of this study indicated an increased leptin level among women with PCOS that positively associated with BMI and LH.

  2. The detection of serum leptin in peri-menopausal woman

    International Nuclear Information System (INIS)

    Wei Tao; Ma Yongxiu; He Juan

    2001-01-01

    Serum leptin, follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E 2 ) were measured by RIA in 138 peri-menopausal women in order to clear the relations between them. The results showed that serum levels of all the four circulating hormones are all changed significantly in all subgroups. Compared with the women of childbearing age group, it changed with P < 0.05; P < 0.01 respectively. All the changes indicate: As a circulating hormone, leptin plays an important role in woman's normal physiology developing process along ages

  3. Leptin, its receptor and aromatase expression in deep infiltrating endometriosis.

    Science.gov (United States)

    Gonçalves, Helder F; Zendron, Carolina; Cavalcante, Fernanda S; Aiceles, Verônica; Oliveira, Marco Aurélio P; Manaia, Jorge Henrique M; Babinski, Márcio A; Ramos, Cristiane F

    2015-08-05

    The aim of this study was to evaluate the leptin levels in the serum and peritoneal fluid (PF) and the protein expression in three different peritoneal ectopic implants in patients who underwent surgery for deep infiltrating endometriosis. All patients had been treated at the Department of Gynecology of the Pedro Ernesto University Hospital, Rio de Janeiro. The study group consisted of 15 patients who underwent surgery for adnexal masses and infertility, while the control group consisted of ten women who underwent surgery for tubal ligation. Peritoneal fluid and samples tissues were collected during surgery. Serum samples were obtained before anesthesia. In this study, the leptin levels in the serum and peritoneal fluid (PF) were evaluated by ELISA. The protein expression of leptin and its receptors (ObR) and aromatase enzyme were evaluated by Western blot analysis of the intestine, uterosacral ligament and vaginal septum in the ectopic implants. The t-test and one-way ANOVA with Holm-Sìdak post-test were used, and p endometriosis = 19.2 ng/mL ± 1.84, p endometriosis = 7.71 ng/mL ± 0.59, p = 0.18). Comparing women with and without ovarian implants, the leptin levels in both the serum and PF were significantly higher in women without ovarian implants (serum: with ovarian implant = 15.85 ± 1.99; without ovarian implant = 23.14 ± 2.60; ng/mL, p = 0.04; PF: with ovarian implant = 4.28 ± 1.30; without ovarian implant = 11.18 ± 2.98;ng/mL, p = 0.048). The leptin, ObR and aromatase protein expression levels were increased in lesions in the vaginal septum and were decreased in the intestine lesions. This study reports several interesting associations between the leptin levels in serum, peritoneal fluid, and tissue samples and the localization of the ectopic endometrium. Although this study does not provide a clear picture of the role of leptin in the development and progression of peritoneal implants

  4. Baseline leptin and leptin reduction predict improvements in metabolic variables and long-term fat loss in obese children and adolescents: a prospective study of an inpatient weight-loss program

    NARCIS (Netherlands)

    Murer, S.B.; Knopfli, B.H.; Aeberli, I.; Jung, A.; Wildhaber, J.; Wildhaber-Brooks, J.; Zimmermann, M.B.

    2011-01-01

    Background: It is unclear whether high plasma leptin in obese individuals represents leptin resistance or whether individuals with marked reductions in leptin concentrations in response to weight loss may be at greater risk of regaining weight. Moreover, whether changes in leptin predict metabolic

  5. Effects of escin mixture from the seeds of Aesculus hippocastanum on obesity in mice fed a high fat diet.

    Science.gov (United States)

    Avci, Gülcan; Küçükkurt, Ismail; Küpeli Akkol, Esra; Yeşilada, Erdem

    2010-03-01

    Escins, a triterpene glycoside mixture obtained from the ethanol extract of Aesculus hippocastanum L. (Hippocastanaceae) seed, was evaluated for its in vivo effects on the plasma levels of some hormones (leptin, insulin, FT(3), FT(4)) and biochemical parameters (glucose, triglyceride, total cholesterol, HDL-C, LDL-C concentrations) in mice fed with a high fat diet for 5 weeks. A high fat diet induced a remarkable increment in the plasma leptin (p escins decreased leptin (31.6%) (pescins may have beneficial effects in the understanding of obesity.

  6. The association between leptin and depressive symptoms is modulated by abdominal adiposity

    Science.gov (United States)

    Milaneschi, Yuri; Sutin, Angelina R; Terracciano, Antonio; Canepa, Marco; Gravenstein, Kristofer S; Egan, Josephine M; Vogelzangs, Nicole; Guralnik, Jack M; Bandinelli, Stefania; Penninx, Brenda WJH; Ferrucci, Luigi

    2014-01-01

    Background Evidence for a role of leptin in depression is limited and conflicting. Inconclusive findings may be explained by the complex effect of obesity on leptin signaling. In particular, both hyperleptinemia due to leptin resistance in obese persons as well as low leptin in lean persons can imply that low leptin biological signaling is associated with an increased risk of significant depressive symptoms. We tested whether the relationship between leptin and depressive symptoms is modulated by abdominal adiposity in two population-based studies. Methods Data were from 851 participants (65–94 years) of the InCHIANTI Study and 1,064 (26–93 years) of the Baltimore Longitudinal Study of Aging (BLSA). Plasma concentrations of leptin, waist circumference and depressive symptoms via the Center for Epidemiological Studies-Depression scale (CES-D) were assessed. In longitudinal InCHIANTI analyses onset of depressed mood (CES-D≥20) was evaluated over a 9-year follow-up. Results In pooled cross-sectional analyses the interaction between leptin and waist circumference was significantly associated with CES-D scores ((log)leptin-by-waist interaction p=0.01). Also in longitudinal analyses, the (log)leptin-by-waist interaction term significantly (p=0.04) predicted depressed mood onset over time; depressed mood risk was especially increased for high levels of both leptin and waist circumference. Conclusions The present findings suggest that low leptin signaling rather than low leptin concentration is a risk factor for depression. Future studies should develop proxy measures of leptin signaling by combining information on abdominal adiposity and leptin level to be used for clinical and research applications. PMID:24636496

  7. Androgen receptor-deficient islet β-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse.

    Science.gov (United States)

    Xu, Weiwei; Niu, Tianhua; Xu, Beibei; Navarro, Guadalupe; Schipma, Matthew J; Mauvais-Jarvis, Franck

    2017-05-01

    Testosterone action is mediated via the androgen receptor (AR). We have reported that male mice lacking AR selectively in β-cells (βARKO -/y ) develop decreased glucose-stimulated insulin secretion (GSIS), producing glucose intolerance. We showed that testosterone action on AR in β-cells amplifies the insulinotropic action of GLP-1 on its receptor via a cAMP-dependent protein kinase-A pathway. To investigate AR-dependent gene networks in β-cells, we performed a high throughput whole transcriptome sequencing (RNA-Seq) in islets from male βARKO -/y and control mice. We identified 214 differentially expressed genes (DEGs) (158 up- and 56 down-regulated) with a false discovery rate (FDR) 2. Our analysis of individual transcripts revealed alterations in β-cell genes involved in cellular inflammation/stress and insulin secretion. Based on 312 DEGs with an FDR insulin signaling, MAPK signaling, type 2 diabetes (T2D) and pancreatic secretion. The gene ontology analysis confirmed the results of the individual DEGs and the pathway analysis in showing enriched biological processes encompassing inflammation, ion transport, exocytosis and insulin secretion. AR-deficient islets exhibit altered expression of genes involved in inflammation and insulin secretion demonstrating the importance of androgen action in β-cell health in the male with implications for T2D development in men. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Clinical significance of changes of serum leptin and insulin levels in patients with polycystic ovary syndrome

    International Nuclear Information System (INIS)

    Chen Zhaojun; Zhang Lahong; Gao Ying; Ren Xiaohua

    2007-01-01

    Objective: To explore the relationship between the serum leptin, insulin levels and development of polycystic ovary syndrome (PCOS). Methods: Serum leptin and insulin levels (with RIA) were determined in 34 patients with PCOS and 30 controls. Results: The serum leptin and insulin levels in the 34 PCOS patients were significantly higher than those in controls (P<0. 01), and those in obese patients (n=22) were significantly higher than those in non-obese ones (n=12) too(P<0.01). Conclusion: Changes of serum leptin and insulin levels were closely related to the development of PCOS and leptin might be used as a diagnostic indicator for PCOS. (authors)

  9. Study of Serum Levels of Leptin, C-Reactive Protein and Nutritional Status in Hemodialysis Patients.

    Science.gov (United States)

    Montazerifar, Farzaneh; Karajibani, Mansour; Hassanpour, Zahra; Pourmofatteh, Mahla

    2015-08-01

    Leptin is secreted by adipose tissue and decreases appetite. However, the role of leptin in the pathogenesis of hemodialysis (HD)-related malnutrition has not been fully evaluated. The aim of study was to investigate the association between the serum leptin levels, serum C-reactive protein (CRP) levels, and nutritional status in hemodialysis patients. This analytical descriptive study included 45 hemodialysis patients and 40 healthy subjects. Biochemical parameters and serum leptin levels were measured. The nutritional status was evaluated using a food frequency questionnaire (FFQ) and the calculation of the body mass index (BMI). Serum leptin (P nutritional factors in hemodialysis patients.

  10. The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways.

    Science.gov (United States)

    Wijesuriya, Tishani Methsala; De Ceuninck, Leentje; Masschaele, Delphine; Sanderson, Matthea R; Carias, Karin Vanessa; Tavernier, Jan; Wevrick, Rachel

    2017-11-01

    In Prader-Willi syndrome (PWS), obesity is caused by the disruption of appetite-controlling pathways in the brain. Two PWS candidate genes encode MAGEL2 and necdin, related melanoma antigen proteins that assemble into ubiquitination complexes. Mice lacking Magel2 are obese and lack leptin sensitivity in hypothalamic pro-opiomelanocortin neurons, suggesting dysregulation of leptin receptor (LepR) activity. Hypothalamus from Magel2-null mice had less LepR and altered levels of ubiquitin pathway proteins that regulate LepR processing (Rnf41, Usp8, and Stam1). MAGEL2 increased the cell surface abundance of LepR and decreased their degradation. LepR interacts with necdin, which interacts with MAGEL2, which complexes with RNF41 and USP8. Mutations in the MAGE homology domain of MAGEL2 suppress RNF41 stabilization and prevent the MAGEL2-mediated increase of cell surface LepR. Thus, MAGEL2 and necdin together control LepR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of MAGEL2 and necdin may uncouple LepR from ubiquitination pathways, providing a cellular mechanism for obesity in PWS. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKbeta and ER stress inhibition.

    Directory of Open Access Journals (Sweden)

    Eduardo R Ropelle

    2010-08-01

    Full Text Available Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKbeta activation and endoplasmic reticulum (ER stress in the hypothalamus. Here we show that physical exercise suppresses hyperphagia and associated hypothalamic IKKbeta/NF-kappaB activation by a mechanism dependent upon the pro-inflammatory cytokine interleukin (IL-6. The disruption of hypothalamic-specific IL-6 action blocked the beneficial effects of exercise on the re-balance of food intake and insulin and leptin resistance. This molecular mechanism, mediated by physical activity, involves the anti-inflammatory protein IL-10, a core inhibitor of IKKbeta/NF-kappaB signaling and ER stress. We report that exercise and recombinant IL-6 requires IL-10 expression to suppress hyperphagia-related obesity. Moreover, in contrast to control mice, exercise failed to reverse the pharmacological activation of IKKbeta and ER stress in C3H/HeJ mice deficient in hypothalamic IL-6 and IL-10 signaling. Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin.

  12. Molecular cloning, characterization and evolutionary analysis of leptin gene in Chinese giant salamander, Andrias davidianus

    Directory of Open Access Journals (Sweden)

    Tian Hai-feng

    2017-11-01

    Full Text Available Leptin is an important hormone possessing diverse physiological roles in mammals and teleosts. However, it has been characterized only in a few amphibian species, and its evolutions are still under debate. Here, the full length of the leptin (Adlep cDNA of Chinese giant salamander (Andrias davidianus, an early diverging amphibian species, is characterized and according to the results of the primary sequence analysis, tertiary structure reconstruction and phylogenetic analysis is confirmed to be an ortholog of mammalian leptin. An intron was identified between the coding exons of A. davidianus leptin, which indicated that the leptin is present in the salamander genome and contains a conserved gene structure in vertebrates. Adlep is widely distributed but expression levels vary among different tissues, with highest expression levels in the muscle. Additionally, the leptin receptor and other genes were mapped to three known leptin signaling pathways, suggesting that the leptin signaling pathways are present in A. davidianus. Phylogenetic topology of leptins are consistent with the generally accepted evolutionary relationships of vertebrates, and multiple leptin members found in teleosts seem to be obtained through a Cluopeocephala-specific gene duplication event. Our results will lay a foundation for further investigations into the physiological roles of leptin in A. davidianus.

  13. Enhanced pulmonary leptin expression in patients with severe COPD and asymptomatic smokers.

    Science.gov (United States)

    Vernooy, J H J; Drummen, N E A; van Suylen, R J; Cloots, R H E; Möller, G M; Bracke, K R; Zuyderduyn, S; Dentener, M A; Brusselle, G G; Hiemstra, P S; Wouters, E F M

    2009-01-01

    Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory reaction of the lungs involving activation of epithelial cells. Leptin is a pleiotropic cytokine important in the regulation of immune responses via its functional receptor Ob-Rb. This study was undertaken to test the hypothesis that severe COPD is associated with increased leptin expression in epithelial cells. Immunohistochemistry for leptin was performed on peripheral lung specimens from 20 patients with COPD (GOLD stage 4), 14 asymptomatic ex-smokers and 13 never smokers. Leptin and Ob-Rb mRNA expression were determined by rtPCR in cultured primary bronchial epithelial cells and primary type II pneumocytes. NCI-H292 and A549 cell lines were used to study functional activation of leptin signalling. Leptin immunoreactivity in lung tissue was observed in bronchial epithelial cells, type II pneumocytes, macrophages (tissue/alveolar) and interstitial lymphocytic infiltrates. rtPCR analysis confirmed pulmonary leptin and Ob-Rb mRNA expression in primary bronchial epithelial cells and pneumocytes. Leptin-expressing bronchial epithelial cells and alveolar macrophages were markedly higher in patients with severe COPD and ex-smokers than in never smokers (pleptin and Ob-Rb (pLeptin induced phosphorylation of STAT3 in both NCI-H292 and A549 cells. Leptin expression is increased in bronchial epithelial cells and alveolar macrophages of ex-smokers with or without severe COPD compared with never smokers. A functional leptin signalling pathway is present in lung epithelial cells.

  14. Fasting and postprandial levels of ghrelin, leptin and insulin in lean, obese and anorexic subjects

    Science.gov (United States)

    Krauss, Hanna; Gibas-Dorna, Magdalena; Kupsz, Justyna; Piątek, Małgorzata; Piątek, Jacek

    2013-01-01

    Introduction Ghrelin, leptin and insulin are involved in neurohormonal regulation of energetic homeostasis. Aim We investigated the correlation between nutritional status and plasma levels of leptin, ghrelin and insulin in lean, obese and anorexic subjects. Material and methods Nineteen obese and 18 anorexic adults were enrolled in the study. Seventeen adults with normal body mass index (BMI) served as controls. Blood samples were taken twice: before breakfast and 2 h after breakfast. Fasting and postprandial ghrelin, leptin and insulin were examined. The following correlations were estimated: between BMI and basal level of tested hormones, between insulin and ghrelin, and between insulin and leptin. The threshold level of significance was p ≤ 0.05 for all calculations. Results Basal insulin level was lowest in anorexic patients and greatest in obese subjects. Fasting plasma ghrelin was lower in obesity and higher in anorexia as compared with the controls. Comparing with controls, fasting leptin levels were higher in obese and lower in anorexic subjects. There was positive correlation between BMI and basal leptin level in obesity. A significant postprandial increase was noted for insulin in all studied groups. Increased leptin and decreased ghrelin levels were detected 2 h after a meal in the control group. In obese patients, postprandial leptin was lower than before food intake, and fasting leptin showed positive correlation with basal insulin level. Conclusions Basal plasma ghrelin, leptin and insulin levels differ according to nutritional status. Impaired ghrelin and leptin secretion and insulin sensitivity may be involved in the pathogenesis of eating disorders. PMID:24868288

  15. Role of leptin as a link between metabolism and the immune system.

    Science.gov (United States)

    Pérez-Pérez, Antonio; Vilariño-García, Teresa; Fernández-Riejos, Patricia; Martín-González, Jenifer; Segura-Egea, Juan José; Sánchez-Margalet, Víctor

    2017-06-01

    Leptin is an adipocyte-derived hormone not only with an important role in the central control of energy metabolism, but also with many pleiotropic effects in different physiological systems. One of these peripheral functions of leptin is a regulatory role in the interplay between energy metabolism and the immune system, being a cornerstone of the new field of immunometabolism. Leptin receptor is expressed throughout the immune system and the regulatory effects of leptin include cells from both the innate and adaptive immune system. Leptin is one of the adipokines responsible for the inflammatory state found in obesity that predisposes not only to type 2 diabetes, metabolic syndrome and cardiovascular disease, but also to autoimmune and allergic diseases. Leptin is an important mediator of the immunosuppressive state in undernutrition status. Placenta is the second source of leptin and it may play a role in the immunomodulation during pregnancy. Finally, recent work has pointed to the participation of leptin and leptin receptor in the pathophysiology of inflammation in oral biology. Therefore, leptin and leptin receptor should be considered for investigation as a marker of inflammation and immune activation in the frontier of innate-adaptive system, and as possible targets for intervention in the immunometabolic mediated pathophysiology. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Leptin receptor (Ob-R) mRNA expression and serum leptin concentration in patients with colorectal and metastatic colorectal cancer

    International Nuclear Information System (INIS)

    Erkasap, N.; Ozkurt, M.; Erkasap, S.; Yasar, F.; Uzuner, K.; Ihtiyar, E.; Uslu, S.; Kara, M.; Bolluk, O.

    2013-01-01

    The objective of the present study was to investigate the effect of leptin on the progression of colorectal carcinoma to metastatic disease by analyzing the serum leptin concentration and Ob-R gene expression in colon cancer tissues. Tissue samples were obtained from 31 patients who underwent surgical resection for colon (18 cases) and metastatic colon (13 cases) cancer. Serum leptin concentration was determined by an enzyme-linked immunosorbent assay (ELISA) and Ob-R mRNA expression by real-time polymerase chain reaction (RT-PCR) for both groups. ELISA data were analyzed by the Student t-test and RT-PCR data were analyzed by the Mann-Whitney U-test. RT-PCR results demonstrated that mRNA expression of Ob-R in human metastatic colorectal cancer was higher than in local colorectal cancer tissues. On the other hand, mean serum leptin concentration was significantly higher in local colorectal cancer patients compared to patients with metastatic colorectal cancer. The results of the present study suggest a role for leptin in the progression of colon cancer to metastatic disease without weight loss. In other words, significantly increased Ob-R mRNA expression and decreased serum leptin concentration in patients with metastatic colon cancer indicate that sensitization to leptin activity may be a major indicator of metastasis to the colon tissue and the determination of leptin concentration and leptin gene expression may be used to aid the diagnosis

  17. The observation of leptin levels in pregnant women newborn and newborn's weight and its clinical significance

    International Nuclear Information System (INIS)

    Yuan Gengbiao; Xiao Jin; Shi Xin; Chen Xuehong

    2002-01-01

    To study the relationship of leptin quantity of placenta, amniotic fluid, umbilical blood, maternal blood and newborn's weight, leptin levels of placenta, amniotic fluid, umbilical blood and maternal blood of 59 pregnant women were detected by RIA. Results were: (1) leptin was be detected from placenta, amniotic fluid, umbilical blood and maternal blood; (2) there was an obvious difference between leptin quantities of placenta, amniotic fluid, umbilical blood and maternal blood (P < 0.01); (3) there was an obvious difference between leptin quantities of placenta, amniotic fluid, umbilical blood and maternal blood for normal pregnant women and pregnancy induced hypertension (P < 0.01); (4) there was an obvious difference between leptin quantities of maternal blood and placenta (P < 0.01). It may be of important significance to detect eh leptin quantity of amniotic fluid and maternal blood in pregnant women for predicting the weight and growth of newborns and treat pregnancy induced hypertension

  18. Changes of serum leptin and other related hormones levels in simple obese children

    International Nuclear Information System (INIS)

    Xiao Jinhua; Wang Yaping; Xu Yan; Gao Yufeng

    2001-01-01

    Objective: To measure the serum leptin concentration in simple obese children together with other four kinds of related hormones. Methods: Serum Leptin, Ins, T 3 , T 4 and GH levels were measured by radioimmunoassay in thirty-eight obese children and thirty healthy controls. Results: The levels of serum leptin, Ins and T 3 in obese group were dramatically higher than those in control group (all P 4 concentration between simple obese children and control group (P > 0.05), Serum GH levels was significantly decreased in simple obese children (P < 0.01). There was a positive correlation between serum leptin levels and lns levels (r = 0.46, P < 0.01). Conclusion: In simple obese children there were leptin resistance and endocrine metabolic disturbances, the later might be correlated with the increasing of serum leptin levels; It is suggested that Leptin resistance might play a key role in the development of obesity

  19. Does tibolone affect serum leptin levels and body weight in postmenopausal women?

    Science.gov (United States)

    Gol, Mert; Ozsener, Serdar; Sendag, Fatih; Uretmen, Sevinç; Oztekin, Kemal; Tanyalcin, Tijen; Bilgin, Onur

    2005-07-01

    Leptin has a significant role in body weight regulation and energy balance. We examined the effect of tibolone on the body weight and serum leptin levels in postmenopausal women. Twenty women (aged 43-60 years) participated in this prospective study. All women in this study protocol received 2.5 mg/day of tibolone. Absolute and body mass index (BMI)-corrected serum leptin concentrations and BMI values were measured at baseline, after 3 months, and after 6 months of the tibolone therapy. Tibolone did not affect absolute and BMI-corrected serum leptin levels, and BMI values during the treatment. A significant linear correlation between BMI values and serum leptin levels was observed (p<0.05, r=0.67). Tibolone seems not to affect serum leptin levels, body weight and BMI values of postmenopausal women. There is a significant correlation between serum leptin levels and BMI values.

  20. The plasma leptin concentration is closely associated with the body fat mass in nondiabetic uremic patients

    DEFF Research Database (Denmark)

    Clausen, P; Nielsen, P K; Olgaard, K

    1999-01-01

    filtration rate seemed to have a limited influence on the plasma leptin concentration in nondiabetic uremic subjects matched by body fat mass to controls. The plasma leptin concentration was closely associated with the body fat mass, and the leptin level might, therefore, be useful as an indicator of the fat......Plasma leptin is associated with the body mass index and, more precisely, with the body fat mass. Plasma leptin has been found to be elevated in uremic patients. This study aimed at investigating the plasma leptin concentration and associations between plasma leptin, body fat mass, and glomerular.......4 (3.1-59.5) ng/ml versus 5.4 (1.6-47.5) ng/ml (median and range in parentheses; p

  1. Serum leptin levels in pregnant women with type 1 diabetes mellitus

    DEFF Research Database (Denmark)

    Lauszus, F F; Schmitz, O; Vestergaard, H

    2001-01-01

    BACKGROUND: Leptin is an important weight regulator and during pregnancy leptin is not only synthesized in adipose tissue but also in the placenta. AIM: To examine changes in serum leptin levels in women with type 1 diabetes mellitus during pregnancy and post delivery in relation to concomitant...... changes in maternal body weight, birth weight, glycemic control, and blood pressure. METHODS: Non-fasting serum leptin from 45 women with type 1 diabetes mellitus were studied consecutively throughout pregnancy and 3 months post partum. RESULTS: Serum leptin was positively associated with HbA1c in week 18...... of serum leptin throughout pregnancy and it changed significantly differently from the women with higher blood pressure (pserum leptin levels of pregnant women with type 1 diabetes mellitus were associated with parallel changes in maternal body weight and glycemic control...

  2. Postnatal leptin promotes organ maturation and development in IUGR piglets.

    Science.gov (United States)

    Attig, Linda; Brisard, Daphné; Larcher, Thibaut; Mickiewicz, Michal; Guilloteau, Paul; Boukthir, Samir; Niamba, Claude-Narcisse; Gertler, Arieh; Djiane, Jean; Monniaux, Danielle; Abdennebi-Najar, Latifa

    2013-01-01

    Babies with intra-uterine growth restriction (IUGR) are at increased risk for experiencing negative neonatal outcomes due to their general developmental delay. The present study aimed to investigate the effects of a short postnatal leptin supply on the growth, structure, and functionality of several organs at weaning. IUGR piglets were injected from day 0 to day 5 with either 0.5 mg/kg/d leptin (IUGRLep) or saline (IUGRSal) and euthanized at day 21. Their organs were collected, weighed, and sampled for histological, biochemical, and immunohistochemical analyses. Leptin induced an increase in body weight and the relative weights of the liver, spleen, pancreas, kidneys, and small intestine without any changes in triglycerides, glucose and cholesterol levels. Notable structural and functional changes occurred in the ovaries, pancreas, and secondary lymphoid organs. The ovaries of IUGRLep piglets contained less oogonia but more oocytes enclosed in primordial and growing follicles than the ovaries of IUGRSal piglets, and FOXO3A staining grade was higher in the germ cells of IUGRLep piglets. Within the exocrine parenchyma of the pancreas, IUGRLep piglets presented a high rate of apoptotic cells associated with a higher trypsin activity. In the spleen and the Peyer's patches, B lymphocyte follicles were much larger in IUGRLep piglets than in IUGRSal piglets. Moreover, IUGRLep piglets showed numerous CD79(+) cells in well-differentiated follicle structures, suggesting a more mature immune system. This study highlights a new role for leptin in general developmental processes and may provide new insight into IUGR pathology.

  3. Leptin receptor polymorphisms and lung function decline in COPD

    OpenAIRE

    Hansel, N.N.; Gao, L.; Rafaels, N.M.; Mathias, R.A.; Neptune, E.R.; Tankersley, C.; Grant, A.V.; Connett, J.; Beaty, T.H.; Wise, R.A.; Barnes, K.C.

    2009-01-01

    Only a fraction of all smokers develop chronic obstructive pulmonary disease (COPD), suggesting a large role for genetic susceptibility. The leptin receptor (LEPR) is present in human lung tissue and may play a role in COPD pathogenesis. The present study examined the association between genetic variants in the LEPR gene and lung function decline in COPD.

  4. Role of leptin and adiponectin in gestational diabetes mellitus: a ...

    African Journals Online (AJOL)

    One of the mechanisms underlying glucose metabolism in pregnancy are a group of substances, which includes leptin and adiponectin, produced mainly in the adipose tissue; in this paper we analyze the role of these mediators in women with GDM. This case control study was performed in 90 females (30 GDM patients ...

  5. Early life stress experience may blunt hypothalamic leptin signalling

    Indian Academy of Sciences (India)

    2016-12-21

    Dec 21, 2016 ... showed binge-like eating with increased HPA axis activity when they were ..... brain. Many studies have reported that leptin is a stress- response hormone and its action may be related with the. HPA axis activity (Heiman et al. 1997 .... a cancer cell line, and the STAT3 target genes included ones that were ...

  6. The Effect of EPH- Gestosis on Plasma Leptin concentration | Ajayi ...

    African Journals Online (AJOL)

    Edema-proteinuria-hypertension-gestosis complex develops in late pregnancy and is usually associated with placenta hypoxia and dysfunction. Leptin, the obsess gene product, is adipocyte-derived hormone that reduces calorie intake and body fat consequently results in weight lost. Recently it had been shown to be ...

  7. BLOOD METABOLIC HORMONES AND LEPTIN IN GROWING LAMBS

    Directory of Open Access Journals (Sweden)

    Zvonko Antunović

    2010-12-01

    Full Text Available The aim of this paper is to determine the concentration of blood metabolic hormones and leptin levels in growing lambs. The research was carried out on Tsigai lambs in two periods (suckling and fattening during the winter feeding season. Lambs were suckling and ate a food mixture and alfalfa hay ad libitum, while during the fattening period they were fed only with the above mentioned mixture and alfalfa hay ad libitum. Their blood was analyzed on 35th and 75th day of age. Concentrations of minsulin, leptin and thyroid hormones were determined in the blood serum of lambs during both periods. In the blood of fattening lambs significantly higher (P0.05 insulin concentrations (1.05 and 0.54 μU/mL, were determined, compared to suckling lambs. A significant strong positive correlation between serum leptin and insulin (r = 0.85, P0.05. The concentration of thyroid hormones did not significantly differ depending on the period of measurement. These changes indicate that the measurement concentrations of metabolic hormones and leptin in blood are very important in order to understand the changes of metabolism and nutrient supply in growing lambs.

  8. Leptin, Adiponectin, and Obesity among Caucasian and Asian Women

    Directory of Open Access Journals (Sweden)

    Shannon M. Conroy

    2011-01-01

    Full Text Available Ethnic differences in adipose tissue distribution may contribute to different chronic disease risks across ethnic groups, and adipokines may mediate the risk. In a cross-sectional study, we examined ethnic differences in adipokines and inflammatory markers as related to body mass index (BMI among 183 premenopausal women with Caucasian and Asian ancestry. General linear models were used to estimate adjusted mean levels of leptin, adiponectin, interleukin-6, and C-reactive protein (CRP. Asian women had significantly lower serum levels of leptin, adiponectin, and CRP than Caucasian participants (P≤.01 across all levels of BMI. Among overweight and obese women, Asians showed a stronger association of CRP with leptin (β=1.34 versus β=0.64 and with adiponectin (β=−0.95 versus β=−0.75 than Caucasians. Compared to Caucasians of similar BMI, Asians may experience a higher chronic disease risk due to lower levels of adiponectin despite their lower levels of leptin.

  9. Physiology and genetics of leptin in periparturient dairy cows

    NARCIS (Netherlands)

    Liefers, S.C.

    2004-01-01

    In dairy cattle, the increase in milk yield has been accompanied by a decrease in fertility and a more negative energy balance. As the hormone leptin is involved in regulation of nutritional status and reproductive function (Chapter 2) this is an

  10. Plasma leptin levels in healthy children and adolescents

    DEFF Research Database (Denmark)

    Blum, W F; Englaro, P; Hanitsch, S

    1997-01-01

    Leptin, the product of the ob gene, is thought to play a key role in the regulation of body fat mass. Beyond this function, it appears to be an integral component of various hypothalamo-pituitary-endocrine feedback loops. Because childhood and puberty are periods of major metabolic and endocrine...... increase in girls between 2.51 micrograms/L (median) at Tanner stage 1 to 6.24 micrograms/L at Tanner stage 5. In boys, leptin levels were highest at Tanner stage 2 (2.19 micrograms/L) and declined thereafter to 0.71 microgram/L at Tanner stage 5. A strong exponential relationship was observed for leptin...... levels with body mass index (BMI) and percentage body fat as determined by bioelectric impedance measurements in a subgroup of subjects. This relationship was similar between boys and girls at Tanner stages 1 and 2. In boys, there was a significant decline of leptin at a given BMI with further...

  11. Relation between obesity, lipid profile, leptin and atopic disorders in ...

    African Journals Online (AJOL)

    Background: Obesity has become a disease of great importance affecting children and adolescents. Obesity can cause atopy or inflammation, where there are some common factors that predispose to both obesity and atopy. Objective: To study the factors contributing to allergic disorders in obese children, the role of leptin ...

  12. Plasma leptin levels in healthy children and adolescents

    DEFF Research Database (Denmark)

    Blum, W F; Englaro, P; Hanitsch, S

    1997-01-01

    Leptin, the product of the ob gene, is thought to play a key role in the regulation of body fat mass. Beyond this function, it appears to be an integral component of various hypothalamo-pituitary-endocrine feedback loops. Because childhood and puberty are periods of major metabolic and endocrine...

  13. Serum Leptin Is a Biomarker of Malnutrition in Decompensated Cirrhosis

    Science.gov (United States)

    Rachakonda, Vikrant; Borhani, Amir A.; Dunn, Michael A.; Andrzejewski, Margaret; Martin, Kelly; Behari, Jaideep

    2016-01-01

    Background and Aims Malnutrition is a leading cause of morbidity and mortality in cirrhosis. There is no consensus as to the optimal approach for identifying malnutrition in end-stage liver disease. The aim of this study was to measure biochemical, serologic, hormonal, radiographic, and anthropometric features in a cohort of hospitalized cirrhotic patients to characterize biomarkers for identification of malnutrition. Design In this prospective observational cohort study, 52 hospitalized cirrhotic patients were classified as malnourished (42.3%) or nourished (57.7%) based on mid-arm muscle circumference malnutrition. Results Subjects with and without malnutrition differed in several key features of metabolic phenotype including wet and dry BMI, skeletal muscle index, visceral fat index and HOMA-IR. Serum leptin levels were lower and INR was higher in malnourished subjects. Serum leptin was significantly correlated with HOMA-IR, wet and dry BMI, mid-arm muscle circumference, skeletal muscle index, and visceral fat index. Logistic regression analysis revealed that INR and log-transformed leptin were independently associated with malnutrition. Conclusions Low serum leptin and elevated INR are associated with malnutrition in hospitalized patients with end-stage liver disease. PMID:27583675

  14. Plumbagin Inhibits Leptin-Induced Proliferation of Hepatic Stellate ...

    African Journals Online (AJOL)

    HP

    plumbagin treatment in HSC-LX2 (p < 0.01). p-ERK1/2 expression markedly decreased in plumbagin-treated. HSCs (p < 0.01). Plumbagin significantly increased MMP-1 expression in leptin-treated HSCs (p < 0.01). Conclusion: Plumbagin has an anti-fibrotic effect and may decrease the protein expressions of components.

  15. Adrenomedullin and leptin levels in diabetic retinopathy and retinal diseases.

    Science.gov (United States)

    Er, Hamdi; Doğanay, Selim; Ozerol, Elif; Yürekli, Muhittin

    2005-01-01

    Proliferative and vascular retinal diseases are important cause of irreversible blindness. Consistent features of these diseases are endothelial dysfunction and angiogenesis. Adrenomedullin (ADM) is a multifunctional vasorelaxant peptide. Leptin is a recently discovered metabolic peptide that regulates energy metabolism in human. In the present study, we aimed to investigate the possible roles of adrenomedullin and leptin in the pathophysiology of diabetic and proliferative diseases. Ten patients with proliferative diabetic retinopathy (57.1 years, 5 female and 5 male) and 8 patients (51 years, 5 female and 3 male) with other retinal diseases including macular hole and epiretinal membrane were included in this study. All the patients had undergone pars plana vitrectomy for complications of the diseases. Vitreous samples were collected by vitreous tap during the vitrectomy. Adrenomedullin analysis was made by using reverse-phase high-performance liquid chromatography (HPLC). Leptin was measured by enzyme-linked immunosorbent assay (ELISA). Body mass index (BMI) [weight (kg)/height (m2)] was calculated for each group. The Mann-Whitney U test was used for statistics. The age, gender ratio and BMI were not substantially different between the two groups. The mean vitreous adrenomedullin levels (63.9+/-7.1 pmol/l) were significantly higher (pdiabetic retinopathy than in those without diabetes (1.83+/-0.5 ng/ml). Increased adrenomedullin and leptin levels in vitreous humor might be a possible newly associated factor in the course of vascular and proliferative retinal diseases. Copyright (c) 2005 S. Karger AG, Basel.

  16. Correlation Between Insulin, Leptin and Polycystic Ovary Syndrome ...

    African Journals Online (AJOL)

    Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of fertile age. Insulin can stimulate ovarian androgen production in normal women and in women with PCOS. Leptin levels were reduced among women with PCOS treated with insulin sensitizers. Aim: This study aims to ...

  17. Correlation Between Insulin, Leptin and Polycystic Ovary Syndrome

    African Journals Online (AJOL)

    Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of fertile age. Insulin can stimulate ovarian androgen production in normal women and in women with PCOS. Leptin levels were reduced among women with PCOS treated with insulin sensitizers. Aim: This study aims to ...

  18. Expression of Leptin (Ob Gene Product) in Reproductive System ...

    African Journals Online (AJOL)

    Purpose: To determine serum leptin and its ob mRNA expression both in the PCOS and non-PCOS ovary, endometrium and adipose tissue in normal or polycystic ovary syndrome (PCOS) in South Indian population. PCOS (Polycystic Ovary Syndrome) and non-PCOS subject's endometrium, ovary and adipose tissue were ...

  19. The association between leptin, body composition and physical ...

    African Journals Online (AJOL)

    This study investigated the association between leptin, body composition and physical fitness in black adolescents from two selected schools in Ikageng, in the North West Province of South Africa. Baseline measurements were obtained from 124 boys and 148 girls between the ages of 13 and 20 years, which participated in ...

  20. Allelic polymorphism of Makoei sheep leptin gene identified by ...

    African Journals Online (AJOL)

    use

    2011-12-05

    Dec 5, 2011 ... intake, energy expenditure and whole-body energy balance in animals. In the present study, the polymorphism of the leptin gene (LEP) of Makoei sheep was investigated by polymerase chain reaction and single strand conformation polymorphism technique (PCR–SSCP). Genomic DNA was extracted.

  1. Leptin responses to bovine interferon- α and insulin in cattle

    African Journals Online (AJOL)

    Egyptian Journal of Biochemistry and Molecular Biology ... IFN- α injection produced a rapid increase in glucose and insulin levels but leptin levels did not show any alteration after the injection. ... Insulin levels rapidly increased in the blood and consequently a significant decrease in blood glucose level was recorded.

  2. Leptin regulates proliferation and apoptosis of colorectal carcinoma ...

    Indian Academy of Sciences (India)

    Furthermore, HCT-116 colon cancer cells were used to elucidate the effect of PI3K/Akt/. mTOR signalling pathway on the leptin's regulation on colon cancer. 2. Materials and ... prior knowledge of the patients' clinical data using Olympus. CX42 microscope ..... and clinicopathologic characteristics of colorectal cancer.

  3. Leptin and Anthropometric Indices in Adolescents with Sickle Cell ...

    African Journals Online (AJOL)

    Background: Leptin is a peptide hormone secreted by adipocytes and acts to promote weight loss by decreasing food intake, increasing metabolic rate and energy expenditure. In sickle cell anaemia (SCA), poor growth and nutritional status are common clinical features. Adolescence is a period of rapid growth; in sickle cell ...

  4. Adaptation of enterovirus 71 to adult interferon deficient mice.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Caine

    Full Text Available Non-polio enteroviruses, including enterovirus 71 (EV71, have caused severe and fatal cases of hand, foot and mouth disease (HFMD in the Asia-Pacific region. The development of a vaccine or antiviral against these pathogens has been hampered by the lack of a reliable small animal model. In this study, a mouse adapted EV71 strain was produced by conducting serial passages through A129 (α/β interferon (IFN receptor deficient and AG129 (α/β, γ IFN receptor deficient mice. A B2 sub genotype of EV71 was inoculated intraperitoneally (i.p. into neonatal AG129 mice and brain-harvested virus was subsequently passaged through 12 and 15 day-old A129 mice. When tested in 10 week-old AG129 mice, this adapted strain produced 100% lethality with clinical signs including limb paralysis, eye irritation, loss of balance, and death. This virus caused only 17% mortality in same age A129 mice, confirming that in the absence of a functional IFN response, adult AG129 mice are susceptible to infection by adapted EV71 isolates. Subsequent studies in adult AG129 and young A129 mice with the adapted EV71 virus examined the efficacy of an inactivated EV71 candidate vaccine and determined the role of humoral immunity in protection. Passive transfer of rabbit immune sera raised against the EV71 vaccine provided protection in a dose dependent manner in 15 day-old A129 mice. Intramuscular injections (i.m. in five week-old AG129 mice with the alum adjuvanted vaccine also provided protection against the mouse adapted homologous strain. No clinical signs of disease or mortality were observed in vaccinated animals, which received a prime-and-boost, whereas 71% of control animals were euthanized after exhibiting systemic clinical signs (P<0.05. The development of this animal model will facilitate studies on EV71 pathogenesis, antiviral testing, the evaluation of immunogenicity and efficacy of vaccine candidates, and has the potential to establish correlates of protection

  5. Leptin, Leptin Soluble Receptor, and the Free Leptin Index following a Diet and Physical Activity Lifestyle Intervention in Obese Males and Females

    Directory of Open Access Journals (Sweden)

    Jeffrey E. Herrick

    2016-01-01

    Full Text Available Leptin (LEP is associated with appetite regulation and metabolism. Concentration is linear with adiposity, suggesting LEP resistance. LEP circulates freely and bound with its soluble receptor (sOB-r; the ratio is the free leptin index (FLI, an index of leptin resistance; lower FLI suggests reduced biological action. Purpose. The aim was to determine the effect of changes in adipose tissue distribution on LEP, sOB-r, and FLI following 6 months (6 M of a diet/exercise weight loss program (WLP. In addition, we aim to identify predictors of the FLI. Methods. 6 M WLP consisted of diet/lifestyle interventions following ADA guidelines. Body composition was assessed by DXA. LEP and sOB-r analysis were done via ELISA. Results. 10 adults completed the WLP. Significant reductions were seen in total fat percentage (% fat, nontrunk fat, (NTF, and trunk fat (TF from base to 3 m and 6 M (p≤0.05. The FLI were reduced at 3 M and 6 M for males and 6 M for females. Total body fat and body weight predicted the FLI in both sexes. Conclusions. LEP and FLI reductions following 6 M of WLP were achieved independent of sOB-r changes. We also demonstrate that the FLI can be predicted noninvasively through total fat mass and body weight in kilograms.

  6. Leptin levels in different forms of Chagas' disease

    Directory of Open Access Journals (Sweden)

    F. Fernandes

    2007-12-01

    Full Text Available Leptin is produced primarily by adipocytes. Although originally associated with the central regulation of satiety and energy metabolism, increasing evidence indicates that leptin may be an important mediator in cardiovascular pathophysiology. The aim of the present study was to investigate plasma leptin levels in patient with Chagas' heart disease and their relation to different forms of the disease. We studied 52 chagasic patients and 30 controls matched for age and body mass index. All subjects underwent anthropometric, leptin and N-terminal pro-brain natriuretic peptide (NT-proBNP measurements and were evaluated by echocardiography, 12-lead electrocardiogram (ECG, and chest X-ray. All patients had fasting blood samples taken between 8:00 and 9:00 am. Chagasic patients were divided into 3 groups: group I (indeterminate form, IF group consisted of 24 subjects with 2 positive serologic reactions for Chagas' disease and no cardiac involvement as evaluated by chest X-rays, ECG and two-dimensional echocardiography; group II (showing ECG abnormalities and normal left ventricular systolic function, ECG group consisted of 14 patients; group III consisted of 14 patients with congestive heart failure (CHF group and left ventricular dysfunction. Serum leptin levels were significantly lower (P < 0.001 in the CHF group (1.4 ± 0.8 ng/mL when compared to the IF group (5.3 ± 5.3 ng/mL, ECG group (9.7 ± 10.7 ng/mL, and control group (8.1 ± 7.8 ng/mL. NT-proBNP levels were significantly higher (P < 0.001 in the CHF group (831.8 ± 800.1 pg/mL when compared to the IF group (53.2 ± 33.3 pg/mL, ECG group (83.3 ± 57.4 pg/mL, and control group (32 ± 22.7 pg/mL. Patients with Chagas' disease and an advanced stage of CHF have high levels of NT-ProBNP andlow plasma levels of leptin. One or more leptin-suppressing mechanisms may operate in chagasic patients.

  7. Regulation of chick bone growth by leptin and catecholamines.

    Science.gov (United States)

    Mauro, L J; Wenzel, S J; Sindberg, G M

    2010-04-01

    Leptin and the sympathetic nervous system have a unique role in linking nutritional status to skeletal metabolism in mammals. Such a regulatory mechanism has not been identified in birds but would be beneficial to signal information about energy reserves to an organ system essential for locomotion, reproduction, and survival. To explore this potential role of leptin and the sympathetic nervous system in birds, an ex vivo chick tibiotarsal model was used to test the effects of leptin and sympathetic activity on longitudinal bone growth and the expression of chondrocyte markers. Reverse transcription-PCR analysis revealed the expression of chicken leptin receptor mRNA as well as both alpha-adrenergic (alpha1A, alpha2A, alpha2B, alpha2C) and beta adrenergic (beta1, beta2) receptor subtype mRNA in the whole bone. Incubation with norepinephrine (NE; 0, 10, or 100 microM for 4 d) caused a significant increase in distal condyle length as compared with vehicle-treated, contralateral tibiotarsi. In contrast, no change in condyle length was detected after leptin treatment (0 or 10 nM or 1 microM for 4 d). Analysis of cell proliferation by bromodeoxyuridine incorporation revealed no increase in bromodeoxyuridine-positive cells in the condyles in response to leptin or NE treatments. Real-time PCR analysis showed that NE enhanced type X collagen mRNA expression, a marker of mature hypertrophic chondrocytes, with no effect on type II collagen mRNA, the matrix protein secreted by proliferating chondrocytes. Leptin treatment had no effect on the expression of either matrix protein. Treatment with agonists specific for alpha- or beta-adrenergic receptors indicates that the activation of alpha-adrenergic receptors is most likely responsible for the sympathetic effect on type X collagen gene expression. These results suggest that NE and other sympathetic agonists have positive effects on bone elongation and the changes in critical genes associated with this process. These

  8. The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Eiichi [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Hosokawa, Masaya [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Faculty of Human Sciences, Tezukayama Gakuin University, Osaka (Japan); Harada, Norio; Yamane, Shunsuke; Hamasaki, Akihiro; Toyoda, Kentaro; Fujimoto, Shimpei; Fujita, Yoshihito; Fukuda, Kazuhito [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Tsukiyama, Katsushi; Yamada, Yuichiro [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Department of Internal Medicine, Division of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, Akita (Japan); Seino, Yutaka [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Kansai Electric Power Hospital, Osaka (Japan); Inagaki, Nobuya, E-mail: inagaki@metab.kuhp.kyoto-u.ac.jp [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); CREST of Japan Science and Technology Cooperation (JST), Kyoto (Japan)

    2011-01-07

    Research highlights: {yields} Exogenous GIP inhibits intestinal motility through a somatostatin-mediated pathway. {yields} Exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility. {yields} The GIP-receptor-mediated action in intestine does not involve in GLP-1-mediated pathway. -- Abstract: Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic {beta} cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucose absorption in vivo was measured by single-pass perfusion method. Incorporation of [{sup 14}C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [{sup 14}C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin

  9. The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice

    International Nuclear Information System (INIS)

    Ogawa, Eiichi; Hosokawa, Masaya; Harada, Norio; Yamane, Shunsuke; Hamasaki, Akihiro; Toyoda, Kentaro; Fujimoto, Shimpei; Fujita, Yoshihito; Fukuda, Kazuhito; Tsukiyama, Katsushi; Yamada, Yuichiro; Seino, Yutaka; Inagaki, Nobuya

    2011-01-01

    Research highlights: → Exogenous GIP inhibits intestinal motility through a somatostatin-mediated pathway. → Exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility. → The GIP-receptor-mediated action in intestine does not involve in GLP-1-mediated pathway. -- Abstract: Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic β cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucose absorption in vivo was measured by single-pass perfusion method. Incorporation of [ 14 C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [ 14 C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin-mediated pathway rather

  10. Serum Leptin Levels in Asthma, COPD and Bronchiectasis

    Directory of Open Access Journals (Sweden)

    Ercan Kurtipek

    2016-01-01

    Full Text Available Aim: The aim of the present study is to compare body mass indexes (BMI and serum leptin levels of most frequently observed three chronic airway diseases; namely, Asthma, Chronic Obstructive Pulmonary Disease (COPD and bronchiectasis. Material and Method: The study included a total of 216 people, 78 asthma, 67 COPD, and 37 bronchiectasis patients who were in stable period and 34 healthy individuals all aged above 18. Control group consisted of non-smokers and non-corticosteroid users. Of all the participants, the blood samples were taken in order to determine serum leptin levels and BMI were calculated, and pulmonary function tests measured at rest. Results: The BMI levels of all the groups was above >25 kg/m2. There were no statistical differences between the control and patient groups with regard to BMI (p>0.05. Comparing patient groups, the BMI of asthma patients was higher than those with COPD and bronchiectasis (29.84±6.46, 25.78±4.96, 27.64±5.19, p=0.0001, p=0.20. FEV1 results of COPD patients were lower than those with asthma and bronchiectasis (63.25±19.26, 76.73±20.35, 72.75±20.17 and p=0.0001, p=0.06. Serum leptin levels of asthma patients were higher than the COPD, bronchiectasis patients, as well as that of the control group (12.36±11.16 ng/ml, 3.35±4.71 ng/ml, 8.49±7.85 ng/ml and 5.21±6.83 ng/ml, p=0.0001, p=0.09 and p=0.0001, respectively. Serum leptin level of COPD patients was lower than control group, but it was not statistically significant (p=0.71. Serum leptin levels of the patients with bronchiectasis were higher than healthy control group members; yet , not statistical significant (p=0.34. However serum leptin levels of the patients with bronchiectasis were higher than the patient COPD groups and this was statisticaly significant (p=0.01. Istatistically significant different emerge on comparing serum leptin levels and BMI of the asthma, COPD and bronchiectasis patients in the Lineear regression analysis made (beta

  11. [Preliminary investigation of effect of serum leptin on nutritional state of COPD patients].

    Science.gov (United States)

    Yuan, Y; Wang, Z; Liu, C

    2000-05-01

    To explore the significance of serum leptin and TNF-alpha in malnutrition of COPD. Serum leptin and TNF-alpha concentrations were measured by radioimmunoassay. Body mass index (BMI), percent normal body weight (NW%), triceps skin-fold thickness (TSF), subscapular skin-fold thickness (SSF), mid-upper arm circumference (MAC), serum albumin (ALB) and total lymphocytes count (LYM) were determined in 31 patients with COPD and in 11 healthy controls. The correlation between leptin and nutritional parameters was analysed. (1) Serum leptin concentrations (3.0 +/- 2.5) micrograms/L in 42 subjects were significantly correlated with BMI, NW%, TSF, SSF and MAC (P leptin concentrations were significantly correlated with BMI in both malnourished patients with COPD and non-malnourished patients (P leptin level was significantly lower in malnourished group (1.3 +/- 1.0) micrograms/L than in non-malnourished group (4.5 +/- 2.6) micrograms/L, (P leptin level and BMI between non-malnourished group and healthy group were not significant. (3) Serum TNF-alpha level was significantly higher in COPD group (1.8 +/- 0.3) micrograms/L than in healthy group (1.0 +/- 0.5) microgram/L (P leptin levels didn't significantly correlate with TNF-alpha levels in COPD patients. Serum leptin levels correlate with nutritional parameters in COPD patients and leptin may contribute to the malnutrition in COPD patients.

  12. Effect of Technological Treatments on Human-Like Leptin Level in Bovine Milk for Human Consumption

    Directory of Open Access Journals (Sweden)

    Damiano Magistrelli

    2014-07-01

    Full Text Available In this experiment, raw milk and commercially available full-cream UHT milk, semi-skimmed UHT milk, skimmed UHT milk, full-cream pasteurized milk, semi-skimmed pasteurized milk and infant formulas for babies between 6 and 12 months of age were analyzed by RIA, with a method using an antibody directed against human leptin and human leptin as reference standard. Raw milk and full-cream UHT milk did not differ for human-like leptin. Leptin content of full-cream pasteurized milk was not different to that of full-cream UHT milk, but it was 14% lower (p < 0.05 than that observed in raw milk. Human-like leptin level of semi-skimmed UHT milk was not different to that of semi-skimmed pasteurized milk, but it was 30% lower (p < 0.0001 than those of full-cream UHT and full-cream pasteurized milks. In skimmed UHT milk, leptin was 40% lower (p < 0.0001 than in full-cream UHT milk. Leptin was correlated (p < 0.001 with lipid content. Leptin level of infant formulas was not different to that of skimmed milks. Results suggest that the heat treatment (pasteurization or UHT is not a modifier of human-like leptin content of edible commercial bovine milks, whereas the skimming process significantly reduces milk leptin level.

  13. Serum Leptin Concentrations during the Menstrual Cycle in Iranian Healthy Women

    Directory of Open Access Journals (Sweden)

    Nahid Einollahi

    2010-09-01

    Full Text Available "nLeptin, a circulating 16-kd polypeptide consisting of 167 amino acids, appears to be involved in the body weight homeostasis. Moreover leptin plays an important role for the reproductive system, early embryogenesis, and fat metabolism during pregnancy and puberty. Significant correlations have been found between leptin and sexual hormones, which is a cytokine and has hormonal properties. The aim of this study was to determine serum leptin levels during the menstrual cycle, and the association between serum leptin and reproductive hormones in young, healthy Iranian women. 42 healthy women volunteered for the study. They all had regular menstrual cycles, with cycle length varying between 26 and 32 days. None of them used oral contraceptives. All were of normal weight, with body mass index ( BMI < 25 Kg/m2. Fasting blood samples were collected during the follicular phase, mid cycle and luteal phase of the menstrual cycle. FSH and LH were measured with coated tube immunoradiometric assay. Estrogen and progesterone were measured using antibody -coated tubes. Serum Leptin concentration were measured by Leptin (sandwich ELISA. In menstruating women, serum leptin increased from 13.15+/-1.60 ng/ml in the early follicular phase to 16.57+/-1.68 ng/ml (P<0.01 at the luteal phase. Serum leptin concentration negatively correlated with LH and progesterone (P<0.05. Mean serum leptin levels correlated with body mass index (BMI (r =0.78, P<0.001.

  14. Seminal plasma leptin and spermatozoon apoptosis in patients with varicocele and leucocytospermia.

    Science.gov (United States)

    Wang, H; Lv, Y; Hu, K; Feng, T; Jin, Y; Wang, Y; Huang, Y; Chen, B

    2015-08-01

    Excessive apoptotic spermatozoon death is associated with male infertility. Leptin regulates apoptosis in several cell types. We prospectively investigated if seminal plasma leptin mediates spermatozoon apoptosis in 74 varicocele (VC) patients and 70 leucocytospermia patients. Spermatozoa from 40 normospermic men were used as controls. Routine semen analysis, spermatozoon apoptosis rate, seminal plasma leptin, reactive oxygen species (ROS) and tumour necrosis factor-alpha (TNF-α) levels were measured. In VC and leucocytospermia patients, seminal plasma leptin levels and spermatozoon apoptosis rates were significantly higher compared with controls. In the VC group, seminal plasma ROS levels were significantly higher compared with controls; there were no significant differences in TNF-α levels. In the leucocytospermia group, both ROS and TNF-α levels were significantly higher compared with controls. In both the VC and leucocytospermia groups, there was a significant positive correlation between the spermatozoon apoptosis rate and leptin levels and ROS and leptin levels. There was a significant correlation between leptin and TNF-α levels in the leucocytospermia group. Seminal plasma leptin levels correlate significantly with spermatozoon apoptosis rate, and leptin may be a spermatozoon pro-apoptotic factors. The generation of ROS is a possible mechanism. Leptin may induce apoptosis via TNF-α in leucocytospermia patients. © 2014 Blackwell Verlag GmbH.

  15. Rhythmic leptin is required for weight gain from circadian desynchronized feeding in the mouse.

    Directory of Open Access Journals (Sweden)

    Deanna Marie Arble

    Full Text Available The neuroendocrine and metabolic effects of leptin have been extensively researched since the discovery, and the later identification, of the leptin gene mutated within the ob/ob mouse. Leptin is required for optimal health in a number of physiological systems (e.g. fertility, bone density, body weight regulation. Despite the extensive leptin literature and many observations of leptin's cyclical pattern over the 24-hour day, few studies have specifically examined how the circadian rhythm of leptin may be essential to leptin signaling and health. Here we present data indicating that a rhythmic leptin profile (e.g. 1 peak every 24 hours leads to excessive weight gain during desynchronized feeding whereas non-rhythmic leptin provided in a continuous manner does not lead to excessive body weight gain under similar feeding conditions. This study suggests that feeding time can interact with leptin's endogenous rhythm to influence metabolic signals, specifically leading to excessive body weight gains during 'wrongly' timed feeding.

  16. Beneficial Effect of Leptin on Spatial Learning and Memory in Streptozotocin-Induced Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Mohsen Ghasemi

    2016-02-01

    Full Text Available Background: Diabetes mellitus is a chronic disease which may be accompanied by cognitive impairments. The expression of the obesity gene (ob is decreased in insulin-deficient diabetic animals and increased after the administration of insulin or leptin. Plasma leptin levels are reduced in the streptozotocin (STZ-induced diabetic rats. Therefore, the deleterious effects of diabetes on memory may be due to the reduction of leptin. Aims: Investigate the effect of subcutaneous injection of leptin on spatial learning and memory in STZ-induced diabetic rats. Study Design: Animal experimentation. Methods: The rats were divided into three groups: 1- control, 2- diabetic, and 3- diabetic-leptin. Diabetes was induced in groups 2 and 3 by STZ injection (55 mg/kg intraperitoneally (i.p. The animals received leptin (0.1 mg/kg or saline subcutaneously (s.c for 10 days before behavioral studies. Then, they were examined in the Morris water maze over 3 blocks after 3 days of the last injection of leptin. Results: The travelled path length and time spent to reach the platform significantly increased in the diabetic group (p<0.001 and decreased with leptin treatment (p<0.01 & p<0.001 respectively; also, a significant increase in path length and time was observed between the diabetic-leptin group and the diabetic group (p<0.01, p<0.001, respectively in the probe test. Conclusion: Leptin can exert positive effects on memory impairments in diabetic rats.

  17. Maternal leptin and body composition in the first trimester of pregnancy.

    LENUS (Irish Health Repository)

    Fattah, Chro

    2012-02-01

    BACKGROUND: Leptin is produced mainly by adipocytes. Levels are increased in women with obesity and during pregnancy. Increased levels are also associated with pregnancy complications such as, pre-eclampsia and gestational diabetes mellitus. OBJECTIVE: We studied what component of body composition correlated best with maternal leptin in the first trimester of pregnancy and, whether maternal leptin correlated better with visceral fat rather than fat distributed elsewhere. SUBJECTS AND METHODS: Women were recruited in the first trimester. Maternal adiposity was measured using body mass index and advanced bioelectrical impedance analysis. Maternal leptin was measured using an enzyme-linked immunosorbent assay technique. RESULTS: Of the 100 subjects studied, the mean leptin concentration was 37.7 ng\\/ml (range: 2.1-132.8). Leptin levels did not correlate with gestational age in the first trimester, maternal age, parity or birth weight. Serum leptin correlated positively with maternal weight and body mass index, and with the different parameters of body composition. On multiple regression analysis, serum leptin correlated with visceral fat but not fat distributed elsewhere. CONCLUSIONS: Visceral fat is the main determinant of circulating maternal leptin in the first trimester of pregnancy. This raises the possibility that maternal leptin in early pregnancy may be a marker for the development of metabolic syndrome, including diabetes mellitus.

  18. Low leptin levels predict amenorrhea in underweight and eating disordered females.

    Science.gov (United States)

    Köpp, W; Blum, W F; von Prittwitz, S; Ziegler, A; Lübbert, H; Emons, G; Herzog, W; Herpertz, S; Deter, H C; Remschmidt, H; Hebebrand, J

    1997-07-01

    Evidence that leptin plays an important role in reproductive function is accumulating rapidly. We hypothesized that low leptin synthesis is associated with amenorrhea. We therefore determined serum leptin levels in 43 underweight female students, who were screened for lifetime occurrence of amenorrhea. We assessed the predictive value of leptin, body mass index (BMI), fat mass and percent body fat, respectively, for lifetime occurrence of amenorrea. Factors predicting amenorrhea were tested for their capability to predict current amenorrhea in a second cohort of 63 inpatients with anorexia nervosa (AN) or bulimia nervosa (BN). Furthermore, the relationships between serum leptin levels and of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol and progesterone, respectively, were evaluated. Only leptin predicted lifetime occurrence of amenorrhea in the student cohort. The critical leptin level was in the range of 1.85 micrograms L-1. This level served to largely separate anorectic from bulimic patients. In patients with AN mean serum log10 leptin levels over the first 4 weeks of inpatient treatment were correlated with mean FSH, LH and estradiol levels, respectively. Evidently, a critical leptin level is needed to maintain menstruation. In affluent populations eating disorders are likely to be a major cause of a low leptin synthesis.

  19. Leptin Overexpression in Bone Marrow Stromal Cells Promotes Periodontal Regeneration in a Rat Model of Osteoporosis.

    Science.gov (United States)

    Zheng, Baoyu; Jiang, Jun; Chen, Yuling; Lin, Minkui; Du, Zhibin; Xiao, Yin; Luo, Kai; Yan, Fuhua

    2017-08-01

    Osteoporosis is associated with widespread periodontitis and impaired periodontal healing. However, there is a lack of information about the outcomes of regenerative approaches under the influence of osteoporosis. This study investigates the effect of leptin (LEP) overexpression on the regenerative potential of bone marrow stromal cells (BMSCs) in an osteoporotic rat periodontal fenestration defect model. Rat BMSCs were transfected with adenoviruses harboring the human (h)LEP gene. Cell proliferation and osteogenic differentiation were evaluated. A β-tricalcium phosphate scaffold seeded with transfected cells was implanted into nude mice to investigate ectopic osteogenesis and into an osteoporotic rat defect to study periodontal regeneration. Regenerated periodontal and bone-like tissues were analyzed by histologic methods. hLEP overexpression induced osteogenic differentiation of BMSCs as evidenced by the upregulation of osteogenesis-related genes such as Runt-related transcription factor 2, alkaline phosphatase (ALP), and collagen Type I, as well as increased ALP activity and enhanced mineralization. Mice implanted with hLEP-BMSC-containing scaffolds showed more extensive formation of bone-like tissue than those in other groups. Periodontal defects were also filled to a greater degree when treated with hLEP-BMSCs and contained cementum and a well-organized periodontal ligament after 10 and 28 days. hLEP overexpression in BMSCs can stimulate periodontal regeneration in osteoporotic conditions and might be a promising strategy for periodontal regeneration in patients with osteoporosis.

  20. Interleukin-17A increases leptin production in human bone marrow mesenchymal stem cells.

    Science.gov (United States)

    Noh, Minsoo

    2012-03-01

    Lineage commitment of human bone marrow mesenchymal stem cells (hBM-MSCs) to adipocytes or osteoblasts has been suggested as a model system to study the relationship between type II diabetes and abnormal bone metabolism. Leptin and IL-17A inhibit adipogenesis whereas they promote osteogenesis in MSCs. Due to pathophysiologic roles of IL-17A in human metabolic diseases and bone metabolism, it was evaluated whether IL-17A-dependent inverse regulation on adipogenesis and osteogenesis was related to endogenous leptin production in hBM-MSCs. In the analysis of adiponectin and leptin secretion profiles of hBM-MSCs in response to various combinations of differentiation inducing factors, it was found that dexamethasone, a common molecule used for both adipogenesis and osteogenesis, increased leptin production in hBM-MSCs. Importantly, the level of leptin production during osteogenesis in hBM-MSCs was higher than that during adipogenesis, implicating a significant leptin production in extra-adipose tissues. IL-17A increased leptin production in hBM-MSCs and also under the condition of osteogenesis. In spite of direct inhibition on adipogenesis, IL-17A up-regulated leptin production in hBM-MSC-derived adipocytes. Anti-leptin antibody treatment partially antagonized the IL-17A dependent inhibition of adipogenesis in hBM-MSCs, suggesting a role of leptin in mediating the inverse regulation of IL-17A on osteogenesis and adipogenesis in hBM-MSCs. Therefore, the IL-17A-induced leptin production may provide a key clue to understand a molecular mechanism on the lineage commitment of hBM-MSCs into adipocytes or osteoblasts. In addition, leptin production in extra-adipose tissues like MSCs and osteoblasts should be considered in future studies on leptin-associated human diseases. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Evidence that plasma leptin and insulin levels are associated with body adiposity via different mechanisms.

    Science.gov (United States)

    Schwartz, M W; Prigeon, R L; Kahn, S E; Nicolson, M; Moore, J; Morawiecki, A; Boyko, E J; Porte, D

    1997-09-01

    Like insulin, the adipocyte hormone, leptin, circulates at levels proportionate to body adiposity. Because insulin may regulate leptin secretion, we sought to determine if plasma leptin levels are coupled to body adiposity via changes in circulating insulin levels or insulin sensitivity and whether leptin secretion from adipocytes is impaired in subjects with NIDDM. We used multiple linear regression to analyze relationships between BMI (a measure of body adiposity) and fasting plasma levels of leptin and insulin in 98 nondiabetic human subjects (68 men/30 women) and 38 subjects with NIDDM (27 men/11 women). The insulin sensitivity index (Si) was also determined in a subset of nondiabetic subjects (n = 38). Fasting plasma leptin concentrations were correlated to both BMI (r = 0.66, P = 0.0001) and fasting plasma insulin levels (r = 0.65, P = 0.0001) in nondiabetic men and women (r = 0.58, P = 0.0009 for BMI; r = 0.47, P = 0.01 for insulin). While the plasma leptin level was also inversely related to Si (r = -0.35; P = 0.03), this association was dependent on BMI, whereas the association between insulin and Si was not. Conversely, the relationship between plasma leptin and BMI was independent of Si, whereas that between insulin and BMI was dependent on Si. The relationship between plasma leptin levels and BMI did not differ significantly among NIDDM subjects from that observed in nondiabetic subjects. We conclude that 1) body adiposity, sex, and the fasting insulin level are independently associated with plasma leptin level; 2) because NIDDM does not influence leptin levels, obesity associated with NIDDM is unlikely to result from impaired leptin secretion; and 3) insulin sensitivity contributes to the association between body adiposity and plasma levels of insulin, but not leptin. The mechanisms underlying the association between body adiposity and circulating levels of these two hormones, therefore, appear to be different.

  2. Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase

    Directory of Open Access Journals (Sweden)

    Stefanou Nikolaos

    2010-08-01

    Full Text Available Abstract Background Numerous epidemiological studies have documented that obesity is associated with hepatocellular carcinoma (HCC. The aim of this study was to investigate the biological actions regulated by leptin, the obesity biomarker molecule, and its receptors in HCC and the correlation between leptin and human telomerase reverse transcriptase (hTERT, a known mediator of cellular immortalization. Methods We investigated the relationship between leptin, leptin receptors and hTERT mRNA expression in HCC and healthy liver tissue samples. In HepG2 cells, chromatin immunoprecipitation assay was used to study signal transducer and activator of transcription-3 (STAT3 and myc/mad/max transcription factors downstream of leptin which could be responsible for hTERT regulation. Flow cytometry was used for evaluation of cell cycle modifications and MMP1, 9 and 13 expression after treatment of HepG2 cells with leptin. Blocking of leptin's expression was achieved using siRNA against leptin and transfection with liposomes. Results We showed, for the first time, that leptin's expression is highly correlated with hTERT expression levels in HCC liver tissues. We also demonstrated in HepG2 cells that leptin-induced up-regulation of hTERT and TA was mediated through binding of STAT3 and Myc/Max/Mad network proteins on hTERT promoter. We also found that leptin could affect hepatocellular carcinoma progression and invasion through its interaction with cytokines and matrix mettaloproteinases (MMPs in the tumorigenic microenvironment. Furthermore, we showed that histone modification contributes to leptin's gene regulation in HCC. Conclusions We propose that leptin is a key regulator of the malignant properties of hepatocellular carcinoma cells through modulation of hTERT, a critical player of oncogenesis.

  3. Reference values for serum leptin in healthy non-obese children and adolescents.

    Science.gov (United States)

    Lausten-Thomsen, Ulrik; Christiansen, Michael; Louise Hedley, Paula; Esmann Fonvig, Cilius; Stjernholm, Theresa; Pedersen, Oluf; Hansen, Torben; Holm, Jens-Christian

    2016-11-01

    Adipokines are biologically active, low-molecular weight peptides, which play a major role in metabolic homeostasis in humans. Leptin has gained increasing attention in pediatrics as a biomarker for various metabolic pathologies. Yet, its usefulness is hampered by the relative lack of reference values from pediatric settings. Accordingly, this study aims to evaluate serum concentrations of leptin, soluble leptin receptor (sOB-R), and free leptin index (FLI) in healthy Danish schoolchildren aged 6-18 years and subsequently to establish reference intervals across sex and age groups. A total of 1193 healthy, non-obese Danish schoolchildren (730 girls, 463 boys) aged 6-18 years (median 11.9) were examined by trained medical staff. Serum leptin and sOB-R concentrations in venous fasting blood samples were quantitated by immunoassay. Percentile curves of leptin, sOB-R, and free leptin index were calculated using the General Additive Model for Location Scale and Shape (GAMLSS). Significant age and sex-dependent differences in circulating leptin levels were found. In boys, the median leptin concentration for all ages combined was 3.35 μg/L (95%-interval: 0.71-22.47) and in girls, it was 9.89 ng/L (95%-interval: 2.06-41.49). For SOB-R, no sex-specific difference was found, and the median sOB-R concentration was 8.24 μg/L (IQR: 3.58-23.74; range: < 1.56-744.15). We demonstrated an age-dependent correlation with both serum leptin concentration and free leptin index with a gradual and significant increase in girls throughout childhood and adolescence and a significantly higher leptin concentration and free leptin index bell-shaped peak in early adolescence in boys.

  4. The molecular mechanism of leptin secretion and expression induced by aristolochic acid in kidney fibroblast.

    Directory of Open Access Journals (Sweden)

    Tsung-Chieh Lin

    Full Text Available BACKGROUND: Leptin is a peptide hormone playing pivotal role in regulating food intake and energy expenditure. Growing evidence has suggested the pro-inflammatory and fibrogenic properties of leptin. In addition, patients with renal fibrosis have higher level of plasma leptin, which was due to the increased leptin production. Aristolochic acid (AA is a botanical toxin characterized to associate with the development of renal fibrosis including tubulointerstitial fibrosis. However, whether leptin is upregulated to participate in AA-induced kidney fibrosis remain completely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, leptin expression was increased by sublethal dose of AA in kidney fibroblast NRK49f determined by enzyme-linked immunosorbent assay and Western blot. Data from real-time reverse transcriptase-polymerase chain reaction revealed that leptin was upregulated by AA at transcriptional level. DNA binding activity of CCAAT enhancer binding protein α (C/EBP α, one of the transcription factors for leptin gene, was enhanced in DNA affinity precipitation assay and chromatin immunoprecipitation experiments. Knockdown of C/EBP α expression by small interfering RNA markedly reduced AA-induced leptin expression. Moreover, AA promoted Akt interaction with p-PDK1, and increased phosphorylated activation of Akt. Akt knockdown, and inhibition of Akt signaling by LY294002 and mTOR inhibitor rapamycin reduced leptin expression. Furthermore, treatment of LY294002 or rapamycin significantly suppressed AA-induced C/EBP α DNA-binding activity. These results suggest that Akt and C/EBP α activation were involved in AA-regulated leptin expression. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate the first that AA could induce secretion and expression of fibrogenic leptin in kidney fibroblasts, which reveal potential involvement of leptin in the progression of kidney fibrosis in aristolochic acid nephropathy.

  5. Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase

    International Nuclear Information System (INIS)

    Stefanou, Nikolaos; Papanikolaou, Vassilis; Furukawa, Yoichi; Nakamura, Yusuke; Tsezou, Aspasia

    2010-01-01

    Numerous epidemiological studies have documented that obesity is associated with hepatocellular carcinoma (HCC). The aim of this study was to investigate the biological actions regulated by leptin, the obesity biomarker molecule, and its receptors in HCC and the correlation between leptin and human telomerase reverse transcriptase (hTERT), a known mediator of cellular immortalization. We investigated the relationship between leptin, leptin receptors and hTERT mRNA expression in HCC and healthy liver tissue samples. In HepG2 cells, chromatin immunoprecipitation assay was used to study signal transducer and activator of transcription-3 (STAT3) and myc/mad/max transcription factors downstream of leptin which could be responsible for hTERT regulation. Flow cytometry was used for evaluation of cell cycle modifications and MMP1, 9 and 13 expression after treatment of HepG2 cells with leptin. Blocking of leptin's expression was achieved using siRNA against leptin and transfection with liposomes. We showed, for the first time, that leptin's expression is highly correlated with hTERT expression levels in HCC liver tissues. We also demonstrated in HepG2 cells that leptin-induced up-regulation of hTERT and TA was mediated through binding of STAT3 and Myc/Max/Mad network proteins on hTERT promoter. We also found that