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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin regulates cardiovascular function. Leptin levels are elevated in obesity and hypertension and may play a role in cardiovascular dysfunctions in these comorbidities. This study was designed to determine the influence of hypertension on the cardiac contractile response of leptin. Mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix system in ventricular myocytes from spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats. The contractile properties included peak shortening (PS), duration and maximal velocity of shortening/relengthening (TPS/TR(90), +/-dL/dt), and fura-fluorescence intensity change (DeltaFFI). NO and nitric oxide synthase (NOS) activity were assessed by the Griess and the (3)H-arginine/citrulline conversion assays, respectively. The leptin receptor (Ob-R) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were evaluated by Western blot analysis. SHR animals displayed significantly elevated blood pressure and plasma leptin levels. Leptin elicited a concentration-dependent inhibition of PS and DeltaFFI in WKY, but not in SHR myocytes. Leptin did not affect TPS, TR(90), or +/- dL/dt. The difference in leptin-induced contractile response between the WKY and the SHR groups was abolished by the NOS inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), but not by elevated extracellular Ca(2+). Either the JAK2 inhibitor AG-490 or the mitogen-activated protein (MAP) kinase inhibitor SB203580 abrogated the leptin-induced response in the WKY myocytes, whereas AG-490 unmasked a negative response in PS in the SHR myocytes. SHR myocytes displayed similar Ob-R protein abundance and basal NO levels, a blunted leptin-induced increase in NOS activity as well as enhanced basal STAT3 levels compared with the WKY group. These data indicate that the leptin-induced cardiac contractile response is abolished by spontaneous hypertension, possibly because of mechanisms involving altered JAK/STAT, MAP kinase signaling, and NO response.
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PMID:Abrogated leptin-induced cardiac contractile response in ventricular myocytes under spontaneous hypertension: role of Jak/STAT pathway. 1179 81

Obesity is a risk factor of breast cancers. As leptin, a hormone mainly secreted by white adipocytes, elicits proliferative effects in some cell types, we tested the hypothesis that leptin could influence human breast cancer MCF-7 cell growth. Here we show that MCF-7 cells express leptin receptors and respond to human recombinant leptin by STAT3 and p42/p44 MAPkinase activations and by increased proliferation. These findings suggest that leptin could act in vivo as a paracrine/endocrine growth factor towards mammary epithelial cells thus contributing to explain why obesity is a risk factor of developing breast cancers.
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PMID:Leptin mediates a proliferative response in human MCF7 breast cancer cells. 1205 48

Leptin, an adipocyte-derived hormone, regulates food intake and energy expenditure in the hypothalamus via its receptor, member of the class I cytokine receptor family. Leptin resistance has been observed in rodents and in humans. However, the mechanisms could not be explained in most cases of human obesity, except for rare cases with mutations in the leptin receptor. Recent reports demonstrated that ethanol inhibited the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activated by some members of the class I cytokine receptor family. In this study, we examined the effects of ethanol on the leptin-induced JAK/STAT signaling pathway using human hepatoma cell lines transiently expressing long form of the leptin receptor. A 30 min pretreatment with ethanol dose-dependently inhibited the leptin-induced STAT3 phosphorylation. Furthermore, to determine the time course of ethanol inhibitory effects, the cells were incubated in 10 mM ethanol for various times. Partial inhibition of leptin-induced STAT3 activation was seen after 1 min of treatment with ethanol and completely inhibited after 30 min pretreatment. SB 202190, a p38 mitogen-activated protein kinase (MAPK) inhibitor, partly prevented this inhibition by ethanol of leptin-induced STAT3 activation. These findings suggest that ethanol time- and dose-dependently inhibits the leptin action, in part via p38 MAPK.
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PMID:Ethanol inhibits leptin-induced STAT3 activation in Huh7 cells. 1216 72

Protein tyrosine phosphatase 1B (PTP1B) has recently been implicated in the regulation of body weight. A surprising phenotype of PTP1B-deficient mice is their resistance to diet-induced obesity. Since leptin is one of the primary hormones involved in the regulation of body weight and energy homeostasis, we investigated whether PTP1B affects leptin receptor (lepR) signaling directly. A mouse hypothalamic cell line, GT1-7, was established as a suitable cell model for the study of leptin signaling. Stimulation of GT1-7 cells by leptin caused tyrosine phosphorylation of endogenous STAT3 and activation of a STAT-dependent luciferase reporter gene. Over-expression of PTP1B in GT1-7 cells resulted in a dose-dependent decrease in endogenous JAK2 and STAT3 tyrosine phosphorylation compared with cells transfected with lepR alone. Consistent with inhibition of JAK-STAT signaling, PTP1B over-expression caused a dose-dependent decrease in leptin-induced, STAT-dependent luciferase reporter gene activation in GT1-7 cells. Furthermore, over-expression of PTP1B led to a decrease in mRNA accumulation of suppressor-of-cytokine-signalling-3 (SOCS3) and c-fos, genes that are acutely induced by leptin. Using gene microarray analysis, we confirmed that PTP1B reduces the level of gene expression of SOCS3 and showed that the expression level of other leptin-regulated genes was affected. Genes up-regulated by leptin were decreased in cells over-expressing PTP1B. Conversely, the expression of genes down-regulated by leptin was enhanced by PTP1B over-expression in GT1-7 cells. Our findings indicate that PTP1B is a negative regulator of leptin signaling and suggest that PTP1B inhibitors might be efficacious in the treatment of obesity by increasing leptin sensitivity.
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PMID:Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line. 1235 77

Glucagon-like peptide-1 (GLP-1), released from intestinal endocrine L cells, is a potent insulinotropic hormone. GLP-1 secretion is diminished in obese patients. Because obesity is linked to abnormal leptin signaling, we hypothesized that leptin may modulate GLP-1 secretion. Leptin significantly stimulated GLP-1 secretion (by up to 250% of control) from fetal rat intestinal cells, a mouse L cell line (GLUTag), and a human L cell line (NCI-H716) in a dose-dependent manner (P < 0.05-0.001). The long form of the leptin receptor was shown to be expressed, and leptin induced the phosphorylation of STAT3 in the three cell types. The leptin receptor was also expressed by rodent and human intestinal L cells, and leptin (1 mg/kg i.p.) significantly stimulated GLP-1 secretion in rats and ob/ob mice. To determine the effect of leptin resistance on GLP-1 secretion, C57BL/6 mice were fed a high-fat (45%) or low-fat (10%) diet for 8 weeks. Mice on the high-fat diet became obese; developed glucose intolerance, hyperinsulinemia, and hyperleptinemia; and were leptin resistant. Mice on the high-fat diet also had twofold lower basal plasma GLP-1 and a diminished GLP-1 response to oral glucose, by 28.5 +/- 5.0% (P < 0.05). These results show for the first time that leptin stimulates GLP-1 secretion from rodent and human intestinal L cells, and they suggest that leptin resistance may account for the decreased levels of GLP-1 found in obese humans.
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PMID:Role of leptin in the regulation of glucagon-like peptide-1 secretion. 1254 May 94

Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes. Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action. To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis.
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PMID:STAT3 signalling is required for leptin regulation of energy balance but not reproduction. 1259 16

Blood levels of the satiety hormone leptin are directly correlated to fat stores in obese and lean people. Therefore, leptin resistance is the logical explanation for the phenomenon of common obesity. However, the important question of whether or not the intrinsic leptin activity could differ between obese and lean people has not been examined before. In the present study, serum leptin activity was measured by an in vitro assay of leptin signaling in a modified culture of HEK-293 cells. The system is based on activation of a luciferase reporter gene through a leptin receptor-dependent activation of the signal transducer and activator of transcription (STAT3). Serum samples from 20 obese and 20 non-obese individuals with leptin levels ranging from 3 to 75 ng/ml, as determined by radioimmunoassay (RIA), were used. A high correlation was observed for each serum sample between leptin RIA values and leptin activity in the bioassay. The results indicate that obesity in the 20 obese patients among the 40 individuals examined cannot be accounted for by alterations in leptin activity in our assay. The assay system provides a tool to screen for possible rare cases exhibiting alteration in leptin activity either due to a change in leptin itself or through interaction with other serum factors.
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PMID:Serum leptin activity in obese and lean patients. 1260 52

Leptin, the product of the ob gene, is an adipocyte-derived hormone that plays a key role in the control of food intake and energy expenditure. Leptin acts through receptors that belong to a member of the class I cytokine receptor family. It has been demonstrated that the SH2 domain-containing tyrosine phosphatase 2 (SHP-2) negatively regulates STAT3-mediated transcriptional activation through long form leptin receptor (OBRb). Vanadate has been shown to be a potent and selective inhibitor of PTPase activity in vitro. In this study, we have demonstrated that vanadate increases leptin-induced JAK2 and STAT3 phosphorylation in CHO cells expressing OBRb. The increased leptin-dependent luciferase activity of SOCS3 gene was also seen in vanadate-treated cell. Furthermore, vanadate reversed the inhibitory effects of SOCS3 on leptin-induced STAT3 phosphorylation. The present findings suggest that PTP inhibitors including vanadate and vanadate-derived compounds could be used as a therapeutic agent in the treatment of obesity.
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PMID:Vanadate enhances leptin-induced activation of JAK/STAT pathway in CHO cells. 1264 41

Similar to leptin, ciliary neurotrophic factor (CNTF) suppresses appetite and selectively reduces body fat in leptin-deficient ob/ob mice. To assess the relative importance of specific regions of the hypothalamus in mediating these effects, we administered a CNTF analogue (CNTFAx15) or leptin to mice made obese by administration of gold thioglucose (GTG), which destroys a well-defined portion of the medial basal hypothalamus. CNTFAx15 treatment reduced appetite and body weight in obese GTG-lesioned C57BL/6 mice, whereas leptin failed to effect similar changes regardless of whether treatment was initiated before or after the lesioned mice had become obese. Because leptin does not reduce food intake or body weight in most forms of obesity (a condition termed 'leptin resistance'), we also investigated the actions of leptin in GTG-lesioned leptin-deficient (ob/ob) mice. By contrast to C57BL/6 mice, leptin treatment reduced food intake and body weight in GTG-lesioned ob/ob mice, although the effect was attenuated. To further compare the neural substrates mediating the anorectic actions of leptin and CNTF, we determined the patterns of neurone activation induced by these proteins in the hypothalamus of intact and GTG-lesioned mice by staining for phosphorylated signal transducer and activator of transcription 3 (pSTAT3). CNTFAx15 stimulated robust pSTAT3 signalling in neurones of the medial arcuate nucleus in both intact and lesioned C57BL/6 and ob/ob mice. Leptin administration stimulated pSTAT3 signalling in only a few neurones of the medial arcuate nucleus in intact or lesioned C57BL/6 mice, but elicited a robust response in intact or lesioned ob/ob mice. By contrast to CNTFAx15, leptin treatment also resulted in prominent activation of STAT3 in several areas of the hypothalamus outside the medial arcuate nucleus. This leptin-induced pSTAT3 signal was at least as prominent in intact and GTG-lesioned C57BL/6 mice as it was in ob/ob mice, and thus was not correlated with appetite suppression or weight loss. These results indicate that the medial arcuate nucleus is a key mediator of appetite suppression and weight loss produced by CNTF and leptin, whereas GTG-vulnerable regions play a role only in leptin-induced weight loss. Other regions of hypothalamus in which pSTAT3 signal is induced by leptin may regulate energy metabolism through mechanisms other than appetite reduction.
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PMID:Activation of the hypothalamic arcuate nucleus predicts the anorectic actions of ciliary neurotrophic factor and leptin in intact and gold thioglucose-lesioned mice. 1278 49

The metabolic syndrome in association with obesity is a major clinical problem inducing hypertension, diabetes mellitus, and atherosclerosis. Leptin induces angiogenesis by its proliferative effects on endothelial cells (ECs) via OB receptor (OB-Rb) gene. We evaluated the growth of ECs and intracellular signalings in response to leptin in vitro and the angiogenic effects of leptin in the cornea in vivo with and without adenovirus-mediated transfer of the OB-Rb gene in Zucker fatty (ZF) rats as a model for the metabolic syndrome. Recombinant adenovirus vector encoding rat OB-Rb (Ad.OB-Rb) or Escherichia coli. LacZ (Ad.LacZ) was transfected into cultured ECs from Zucker lean (ZL) rats and ZF rats. Leptin increased DNA synthesis dose-dependently in ECs from ZL rats but not ZF rats. Infection with Ad.OB-Rb, but not with Ad.LacZ, improved the growth effects of leptin in ECs from ZF rats. Leptin induced phosphorylation of Janus kinase (JAK)2, signal transducer and activator of transcription (STAT)3, and extracellular signal-regulated kinase (ERK) in ECs from ZL rats but not ZF rats. Infection with Ad.OB-Rb restored phosphorylation of JAK2 and STAT3 in ECs from ZF rats. Leptin induced angiogenesis in cornea from ZL rats, but not from ZF rats. Coadministration of leptin and Ad.OB-Rb induced angiogenesis in cornea from ZF rats. Ad.LacZ did not influence the angiogenic effects of leptin. The impaired endothelial function with the leptin resistance may be one of causes of the atherosclerosis in the metabolic syndrome.
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PMID:Effects of leptin on endothelial function with OB-Rb gene transfer in Zucker fatty rats. 1292 73


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