Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance in obesity is partly due to diminished glucose transport in myocytes and adipocytes, but underlying mechanisms are uncertain. Insulin-stimulated glucose transport requires activation of phosphatidylinositol (PI) 3-kinase (3K), operating downstream of insulin receptor substrate-1. PI3K stimulates glucose transport through increases in PI-3,4,5-(PO(4))(3) (PIP(3)), which activates atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt). However, previous studies suggest that activation of aPKC, but not PKB, is impaired in intact muscles and cultured myocytes of obese subjects. Presently, we examined insulin activation of glucose transport and signaling factors in cultured adipocytes derived from preadipocytes harvested during elective liposuction in lean and obese women. Relative to adipocytes of lean women, insulin-stimulated [(3)H]2-deoxyglucose uptake and activation of insulin receptor substrate-1/PI3K and aPKCs, but not PKB, were diminished in adipocytes of obese women. Additionally, the direct activation of aPKCs by PIP(3) in vitro was diminished in aPKCs isolated from adipocytes of obese women. Similar impairment in aPKC activation by PIP(3) was observed in cultured myocytes of obese glucose-intolerant subjects. These findings suggest the presence of defects in PI3K and aPKC activation that persist in cultured cells and limit insulin-stimulated glucose transport in adipocytes and myocytes of obese subjects.
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PMID:Impaired activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 in cultured preadipocyte-derived adipocytes and myotubes of obese subjects. 1529 39

Ciliary neurotrophic factor (CNTF), originally known for its involvement in the modulation of neuronal growth, has been discovered to exert anorexigenic effects and is currently being investigated in clinical studies for the treatment of obesity and insulin resistance. This neuropeptide acts on the central nervous system. However, we have recently demonstrated direct peripheral effects on adipocyte signalling and thermogenesis. Given the emerging endocrine role of adipose tissue in the regulation of energy homeostasis and insulin resistance, we investigated potential effects of CNTF on leptin expression and secretion. Our study demonstrates a direct inhibition of leptin expression and secretion by acute and chronic CNTF treatment. Furthermore, we demonstrate a differentiation- and Janus kinase 2 (JAK2)-independent, but phosphatidylinositol 3-kinase-dependent signalling pathway mediating this negative effect. These results provide novel evidence for a role of CNTF in the selective modulation of adipocyte endocrine function which may have important implications for the regulation of energy homeostasis.
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PMID:Ciliary neurotrophic factor influences endocrine adipocyte function: inhibition of leptin via PI 3-kinase. 1535 77

A chronic increase in systemic levels of acute-phase reactants contributes to the development of insulin resistance and associated disorders such as cardiovascular disease. Recently, serum amyloid A3 (SAA3) has been characterized as an adipocyte-secreted acute-phase reactant, expression of which is dramatically increased in insulin resistance and obesity. To further clarify expression and regulation of this adipocytokine in fat, SAA3 mRNA was measured by quantitative real-time reverse transcriptase PCR during differentiation of 3T3-L1 adipocytes and after treatment with various hormones known to induce insulin resistance and contribute to atherosclerosis. SAA3 mRNA was dramatically induced up to 77-fold during differentiation of 3T3-L1 preadipocytes. Furthermore, 100 nM dexamethasone and 30 ng/ml interleukin (IL)-6 induced SAA3 mRNA by up to 11- and 4.8-fold, respectively, in a time-dependent fashion with significant stimulation observed at concentrations as low as 10 nM dexamethasone and 1 ng/ml IL-6. In contrast, insulin, isoproterenol and growth hormone did not influence SAA3 synthesis. Inhibitor studies suggested that the positive effect of IL-6 on SAA3 expression is at least in part mediated by Janus kinase 2. Taken together, our results show a differential regulation of SAA3 by glucocorticoids and IL-6 supporting an integrative role of this acute-phase reactant in the pathogenesis of insulin resistance and its link to obesity and cardiovascular disease.
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PMID:Serum amyloid A3 expression is stimulated by dexamethasone and interleukin-6 in 3T3-L1 adipocytes. 1559 Sep 82

The growth hormone receptor (GHR) is a critical regulator of postnatal growth and metabolism. However, the GHR signaling domains and pathways that regulate these processes in vivo are not defined. We report the first knock-in mouse models with deletions of specific domains of the receptor that are required for its in vivo actions. Mice expressing truncations at residue m569 (plus Y539/545-F) and at residue m391 displayed a progressive impairment of postnatal growth with receptor truncation. Moreover, after 4 months of age, marked male obesity was observed in both mutant 569 and mutant 391 and was associated with hyperglycemia. Both mutants activated hepatic JAK2 and ERK2, whereas STAT5 phosphorylation was substantially decreased for mutant 569 and absent from mutant 391, correlating with loss of IGF-1 expression and reduction in growth. Microarray analysis of these and GHR(-/-) mice demonstrated that particular signaling domains are responsible for the regulation of different target genes and revealed novel actions of growth hormone. These mice represent the first step in delineating the domains of the GHR regulating body growth and composition and the transcripts associated with these domains.
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PMID:In vivo analysis of growth hormone receptor signaling domains and their associated transcripts. 1560 31

Obesity, a state of apparent "leptin resistance" is well known to be associated with insulin resistance. In diet-induced obesity (DIO), hepatic insulin signaling is impaired but the link between leptin and insulin signaling pathways is only incompletely defined. The aim of the present study was to evaluate the effects of DIO on leptin and insulin cross-signaling in the liver. Leptin receptor expression was measured by in situ hybridization with pan-leptin receptor probes and by immunoblotting. Furthermore, intracellular signaling was investigated in vivo under basal conditions and at 45 and 360 min after stimulation with a bolus of human recombinant leptin (hrec-leptin; 1 mg/kg body wt) or saline. At baseline, all forms of the leptin receptor were markedly to completely down-regulated in DIO rats. Hrec-leptin bolus injection stimulated leptin-dependent signaling with a fivefold increase in JAK-2pY in lean but not in DIO rats. Basal IRpY, IRS-1pY, IRS-1p85, IRS-2pY, IRSp85, and PKBpT308 levels were reduced (P<0.01) in DIO rats as compared with lean controls. Basal GSK-3beta serine phosphorylation (S9) was higher (P<0.01) in lean animals along with lower basal PEPCK activity compared with DIO rats consistent with the insulin and leptin resistance of the latter. Only in lean animals phosphorylation of PKB (T308) and GSK-3beta (S9) was acutely stimulated by leptin at 45 min followed by inhibition at 6 h after application. AMPKalpha protein levels as well as basal and leptin-stimulated total and alpha-specific AMPK activity were comparable in both groups. These data show that in a model of dietary-induced obesity 1) leptin receptors and subsequent signaling events are down-regulated, 2) basal insulin signaling is impaired, and 3) the cross-talk between leptin and insulin signaling is differentially regulated by the nutritional status, which is sensed by AMPK in rat liver. Thus, the liver seems to play a major role in the modulation of the leptin signal and insulin resistance in obesity.
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PMID:Hepatic leptin signaling in obesity. 1578 47

Upon leptin binding, the leptin receptor is activated, leading to stimulation of the JAK/STAT signal transduction cascade. The transient character of the tyrosine phosphorylation of JAK2 and STAT3 suggests the involvement of protein tyrosine phosphatases (PTPs) as negative regulators of this signalling pathway. Specifically, recent evidence has suggested that PTP1B might be a key regulator of leptin signalling, based on the resistance to diet-induced obesity and increased leptin signalling observed in PTP1B-deficient mice. The present study was undertaken to investigate the mechanism by which PTP1B mediates the cessation of the leptin signal transduction. Leptin-induced activation of a STAT3 responsive reporter was dose-dependently inhibited by co-transfection with PTP1B. No inhibition was observed when a catalytically inactive mutant of PTP1B was used or when other PTPs were co-transfected. PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3.
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PMID:Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling. 1582 Nov 1

Derivatives of 3-guanidinopropionic acid, such as leptin, reduce body weight in obese, diabetic mice. We have assessed whether one of these analogues, BVT.12777 activates intracellular signalling pathways in the arcuate nucleus in a manner analogous to leptin and insulin. In addition, because these hormones have been shown to activate K(ATP) channels in a subset of arcuate neurones, we examined whether this channel is also a functional endpoint for BVT.12777 in the arcuate nucleus. BVT.12777 transiently increased phosphorylation of MAPK, STAT3, PKB and GSK3, in a manner identical to that observed for leptin and insulin. BVT.12777 also hyperpolarized glucose-responsive neurones by increasing the activity of K(ATP) channels. The increase in K(ATP) activity driven by BVT.12777 was PI3-kinase independent, unlike leptin and insulin activation of this channel, and could also be elicited in isolated patches. However, K(ATP) activity induced by BVT.12777 was dependent on actin filament dynamics, both in intact neurones and isolated patches. Thus, BVT.12777 modulates arcuate neurone K(ATP) activity by re-organization of the cytoskeleton, a mechanism that has also been ascribed to leptin and insulin. Consequently, BVT.12777 appears to act as a leptin and insulin mimetic with respect to at least some elements of arcuate neurone intracellular signalling and the activation of K(ATP) channels. Resistance to leptin and insulin, associated with obesity has, at least in part, been postulated to be due to aberrant intracellular signalling in arcuate neurones. The data presented here indicate that it may be possible to develop drugs, which by-pass up-stream signalling components associated with adiposity hormone resistance, such as PI3-kinase, but can still induce functional outputs from arcuate neurones by targeting downstream components of the leptin and insulin signalling cascades.
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PMID:Activation of hypothalamic ATP-sensitive K+ channels by the aminoguanidine carboxylate BVT.12777. 1584 36

Protein-tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and leptin signaling and a novel therapeutic target for the treatment of type 2 diabetes, obesity, and other associated metabolic syndromes. Because PTP1B regulates multiple signal pathways and it can both enhance and antagonize a cellular event, it is important to establish the physiological relevance of PTP1B in these processes. In this study, we utilize potent and selective PTP1B inhibitors to delineate the role of PTP1B in integrin signaling. We show that down-regulation of PTP1B activity with small molecule inhibitors suppresses cell spreading and migration to fibronectin, increases Tyr(527) phosphorylation in Src, and decreases phosphorylation of FAK, p130(Cas), and ERK1/2. In addition, PTP1B "substrate-trapping" mutants bind Tyr(527)-phosphorylated Src and protect it from dephosphorylation by endogenous PTP1B. These results establish that PTP1B promotes integrin-mediated responses in fibroblasts by dephosphorylating the inhibitory pTyr(527) and thereby activating the Src kinase. We also show that PTP1B forms a complex with Src and p130(Cas), and that the proline-rich motif PPRPPK (residues 309-314) in PTP1B is essential for the complex formation. We suggest that the specificity of PTP1B for Src pTyr(527) is mediated by protein-protein interactions involving the docking protein p130(Cas) with both Src and PTP1B in addition to the interactions between the PTP1B active site and the pTyr(527) motif.
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PMID:The role of protein-tyrosine phosphatase 1B in integrin signaling. 1586 71

Obesity is associated with impaired insulin-stimulated glucose disposal in the skeletal muscle, but whether this is an intrinsic or acquired factor is unknown. In many patients with type 2 diabetes mellitus (T2D) and their nondiabetic relatives, who have a genetic predisposition for diabetes, insulin resistance is maintained in cultured muscle cells. To study the association of obesity with defects in insulin action, we investigated insulin stimulation of both insulin receptor (IR) autophosphorylation and subsequent glucose transport in primary skeletal muscle cell cultures obtained from both nonobese and obese nondiabetic subjects. In these 2 groups, there was no difference in the ability of insulin to induce autophosphorylation of the IR, phosphorylation of the downstream serine kinase Akt/PKB, or stimulation of glucose transport. Moreover, there were no major differences in cultured muscle cell content of either the IR, the IR antagonist PC-1, or GLUT 1 and GLUT 4. These data therefore indicate that the insulin resistance associated with obesity is not maintained in cultured muscle cells and suggest that this insulin resistance is an acquired feature of obesity.
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PMID:Analysis of insulin-stimulated insulin receptor activation and glucose transport in cultured skeletal muscle cells from obese subjects. 1587 89

An elevated circulating level of the adipocyte-derived satiety hormone leptin is an independent risk factor for cardiovascular disease. Because thrombus formation is a major cause of acute coronary events and leptin was shown previously to facilitate ADP-induced platelet aggregation, we chose to define the signaling events involved in leptin-mediated platelet activation. Using pharmacological, biochemical, and cell biological approaches, we show that leptin-induced platelet activation required activation of a signaling cascade that included the long form of the leptin receptor, three kinases [Janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (PKB/Akt)], the insulin receptor substrate-1 (IRS-1), and the major human platelet cAMP phosphodiesterase phosphodiesterase 3A (PDE3A). Moreover, we identify a role for an intraplatelet LEPR/JAK2/IRS-1/PI3K/PKB/PDE3A molecular complex that allows for the selective leptin-mediated activation of platelets. Our data demonstrate that leptin promotes platelet activation, provides a mechanistic basis for the prothrombotic effect of this hormone, and identifies a potentially novel therapeutic avenue to limit obesity-associated cardiovascular disease.
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PMID:Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex. 1588 25


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