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

During the last 10 years, various adipocytokines have been described which influence insulin sensitivity profoundly and might, therefore, potentially link obesity and insulin resistance. Recently, monocyte chemoattractant protein (MCP)-1 was characterized as a novel adipose-secreted factor upregulated in obesity and insulin resistance that impairs insulin signaling in fat cells in vitro and can be found in atherosclerotic lesions. To clarify expression and regulation of this adipocytokine, MCP-1 mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction during differentiation of 3T3-L1 adipocytes and after treatment with various hormones known to induce insulin resistance. Interestingly, MCP-1 synthesis was significantly downregulated between 43% and 68% during differentiation of 3T3-L1 preadipocytes. Furthermore, 10 ng/ml tumor necrosis factor alpha, 100 nM insulin, 500 ng/ml growth hormone (GH), and 30 ng/ml interleukin (IL)-6-induced MCP-1 mRNA by up to 124-, 23-, 8-, and 2.5-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 0.5 ng/ml GH and 30 ng/ml IL-6. In contrast, the glucocorticoid dexamethasone potently downregulated MCP-1 with significant suppression detectable at concentrations as low as 3 nM and as early as 2h after effector addition. Studies using pharmacological inhibitors suggested that the positive effects of GH and IL-6 on MCP-1 synthesis are at least in part mediated by janus kinase 2 and p44/42 mitogen-activated protein kinase. Taken together, our results show a differential regulation of MCP-1 mRNA by insulin resistance-inducing hormones and support the view that this adipocytokine might be an interesting novel candidate linking insulin resistance, obesity, and atherosclerosis. This adipocytokine could thus be a potential pharmacological target for the treatment of impaired insulin sensitivity.
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PMID:Monocyte chemoattractant protein 1 expression is stimulated by growth hormone and interleukin-6 in 3T3-L1 adipocytes. 1506 99

Recently developed therapeutics for obesity, targeted against cannabinoid receptors, result in decreased appetite and sustained weight loss. Prior studies have demonstrated CB1 receptors (CB1Rs) and leptin modulation of cannabinoid synthesis in hypothalamic neurons. Here, we show that depolarization of perifornical lateral hypothalamus (LH) neurons elicits a CB1R-mediated suppression of inhibition in local circuits thought to be involved in appetite and "natural reward." The depolarization-induced decrease in inhibitory tone to LH neurons is blocked by leptin. Leptin inhibits voltage-gated calcium channels in LH neurons via the activation of janus kinase 2 (JAK2) and of mitogen-activated protein kinase (MAPK). Leptin-deficient mice are characterized by both an increase in steady-state voltage-gated calcium currents in LH neurons and a CB1R-mediated depolarization-induced suppression of inhibition that is 6-fold longer than that in littermate controls. Our data provide direct electrophysiological support for the involvement of endocannabinoids and leptin as modulators of hypothalamic circuits underlying motivational aspects of feeding behavior.
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PMID:Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit. 1636 7

Insulin resistance in skeletal muscle is found in obesity and type 2 diabetes. A mechanism for impaired insulin signaling in peripheral tissues is the inhibition of insulin action through serine phosphorylation of insulin receptor substrate (Irs) proteins that abolish the coupling of Irs proteins to the activated insulin receptor. Recently, we described serine-318 as a protein kinase C (PKC)-dependent phosphorylation site in Irs1 (Ser-318) activated by hyperinsulinemia. Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of Ser-318 in Irs1 by a janus kinase 2, Irs2, and PKC-dependent pathway. Mutation of Ser-318 to alanine abrogates the inhibitory effect of leptin on insulin-induced Irs1 tyrosine phosphorylation and glucose uptake in L6 myoblasts. In C57Bl/6 mice, Ser-318 phosphorylation levels in muscle tissue were enhanced by leptin and insulin administration in lean animals while in diet-induced obesity Ser-318 phosphorylation levels were already up-regulated in the basal state, and further stimulation was diminished. In analogy, in lymphocytes of obese hyperleptinemic human subjects basal Ser-318 phosphorylation levels were increased compared to lean individuals. During a hyperinsulinemic euglycemic clamp, the increment in Ser-318 phosphorylation observed in lean individuals was absent in obese. In summary, these data suggest that phosphorylation of Ser-318 in Irs1 mediates the inhibitory signal of leptin on the insulin-signaling cascade in obese subjects.
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PMID:Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1. 1661 34

Various adipocytokines have been described which influence insulin sensitivity and vascular function profoundly and might, therefore, potentially link obesity, insulin resistance, and atherosclerosis. Among those, plasminogen activator inhibitor (PAI)-1 is an adipose-secreted factor upregulated in obesity and insulin resistance that inhibits fibrinolysis. Furthermore, recent studies in knockout mice suggest that PAI-1 directly impairs insulin sensitivity. In the current study, the impact of growth hormone (GH) and interleukin (IL)-6 on PAI-1 mRNA synthesis and secretion was determined in 3T3-L1 adipocytes. Interestingly, 500 ng/ml GH and 30 ng/ml IL-6 increased PAI-1 secretion five-fold and 3.6-fold, respectively. Furthermore, GH and IL-6 induced PAI-1 mRNA by up to 7.3-fold, and 3.6-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 5 ng/ml GH and 10 ng/ml IL-6. Other insulin resistance-inducing hormones which stimulated PAI-1 synthesis included insulin, TNFalpha, and dexamethasone. Studies using pharmacological inhibitors suggested that basal and GH-induced PAI-1 synthesis were at least in part mediated by p44/42 mitogen-activated protein kinase but not janus kinase 2 and phosphatidylinositol 3-kinase. Taken together, our results show a differential regulation of PAI-1 mRNA by insulin resistance-inducing hormones including GH and IL-6.
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PMID:Plasminogen activator inhibitor-1 expression and secretion are stimulated by growth hormone and interleukin-6 in 3T3-L1 adipocytes. 1671 70

Recently, apelin was characterised as a novel adipose-expressed factor which is upregulated in rodent and human obesity and influences cardiovascular function, as well as insulin secretion. To clarify expression and regulation of this adipokine, apelin mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction in mouse 3T3-L1 adipocytes after treatment with various hormones known to induce insulin resistance. Interestingly, apelin synthesis was significantly upregulated by growth hormone (GH) and insulin in these cells whereas TNFalpha and isoproterenol did not have any effect. Thus, 500 ng/ml GH acutely induced apelin mRNA by up to 4-fold in a time-dependent fashion with significant stimulation seen at concentrations as low as 5 ng/ml effector. Furthermore, apelin secretion was assessed by enzyme-linked immunoassay in mouse adipocytes. Here, secretion of this adipokine was induced 2.85-fold by GH. Studies using pharmacological inhibitors suggested that the positive effect of GH on apelin mRNA synthesis is at least in part mediated by janus kinase 2 and phosphatidylinositol 3-kinase. Taken together, our results show a significant induction of apelin mRNA synthesis and protein secretion by GH.
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PMID:Growth hormone induces apelin mRNA expression and secretion in mouse 3T3-L1 adipocytes. 1712 24

The adipokine tissue inhibitor of metalloproteinase (TIMP)-1 is upregulated when weight is gained and promotes adipose tissue development. In the present study, the effect of insulin resistance-inducing and proinflammatory interleukin (IL)-1 beta on TIMP-1 gene expression and secretion was investigated in 3T3-L1 adipocytes. Interestingly, protein secretion and mRNA production of TIMP-1 were significantly stimulated by IL-1 beta. Thus, IL-1 beta induced TIMP-1 secretion in a dose-dependent manner with maximal 3.5-fold upregulation seen at 0.67 ng/ml IL-1 beta relative to untreated cells. Furthermore, TIMP-1 mRNA synthesis was significantly stimulated by IL-1 beta in a dose-dependent fashion with 2.5-fold induction seen at IL-1 beta concentrations as low as 0.02 ng/ml and maximal 8.1-fold upregulation found at 20 ng/ml effector. Induction of TIMP-1 mRNA was also time dependent with maximal 9.6-fold upregulation detectable after 8 h of IL-1 beta treatment. Signaling studies suggested that janus kinase 2 is involved in IL-1 beta-induced TIMP-1 mRNA expression. Taken together, our results demonstrate that the TIMP-1 expression is selectively upregulated by proinflammatory IL-1 beta, supporting a direct association between insulin resistance, inflammation, and adipose tissue development in obesity.
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PMID:Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1 beta in 3T3-L1 adipocytes. 1857 71

Lipocalin-2 (Lcn2) has recently been isolated as an adipocyte-secreted acute phase reactant that plays a role in insulin resistance, obesity, and atherosclerotic disease. In the current study, we determined regulation of Lcn2 by the proinflammatory and insulin resistance-inducing cytokine interleukin (IL)-1beta in 3T3-L1 and brown adipocytes by relative real-time reverse transcription-polymerase chain reaction. Interestingly, IL-1beta dramatically induced Lcn2 mRNA in both adipocyte models. Furthermore, Lcn2 protein secretion was dramatically upregulated in 3T3-L1 adipocytes after 24 h of IL-1beta treatment. Experiments using pharmacological inhibitors indicated that IL-1beta-induced Lcn2 expression is mediated via nuclear factor kappaB and janus kinase 2. Taken together, our results show an upregulation of Lcn2 by IL-1beta in fat cells implicating a potential role of this adipocyte-secreted acute phase reactant in the development of insulin resistance, obesity, and associated disorders including cardiovascular disease.
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PMID:Lipocalin-2 is induced by interleukin-1beta in murine adipocytes in vitro. 1900 54

To examine whether obesity-associated leptin resistance could be due to down-regulation of leptin receptors (OB-Rs) and/or up-regulation of suppressor of cytokine signalling 3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B) in skeletal muscle, which blunt janus kinase 2-dependent leptin signalling and signal transducer and activator of transcription 3 (STAT3) phosphorylation and reduce AMP-activated protein kinase (AMPK) and acetyl-coenzyme A carboxylase (ACC) phosphorylation. Deltoid and vastus lateralis muscle biopsies were obtained from 20 men: 10 non-obese control subjects (mean +/- s.d. age, 31 +/- 5 years; height, 184 +/- 9 cm; weight, 91 +/- 13 kg; and percentage body fat, 24.8 +/- 5.8%) and 10 obese (age, 30 +/- 7 years; height, 184 +/- 8 cm; weight, 115 +/- 8 kg; and percentage body fat, 34.9 +/- 5.1%). Skeletal muscle OB-R170 (OB-R long isoform) protein expression was 28 and 25% lower (both P < 0.05) in arm and leg muscles, respectively, of obese men compared with control subjects. In normal-weight subjects, SOCS3 protein expression, and STAT3, AMPKalpha and ACCbeta phosphorylation, were similar in the deltoid and vastus lateralis muscles. In obese subjects, the deltoid muscle had a greater amount of leptin receptors than the vastus lateralis, whilst SOCS3 protein expression was increased and basal STAT3, AMPKalpha and ACCbeta phosphorylation levels were reduced in the vastus lateralis compared with the deltoid muscle (all P < 0.05). In summary, skeletal muscle leptin receptors and leptin signalling are reduced in obesity, particularly in the leg muscles.
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PMID:Leptin receptor 170 kDa (OB-R170) protein expression is reduced in obese human skeletal muscle: a potential mechanism of leptin resistance. 1971 88

In common forms of obesity, animals and humans become leptin resistant associated with impaired regulation of energy homeostasis. Over the last decade, significant advances in delineating the underlying mechanisms have been achieved. As well as the obvious scientific progress obtained by novel transgenic animals, natural and physiological models of leptin resistance such as the Siberian hamster (Phodoups sungorus), the field vole (Microtus agrestis) or the rat during pregnancy have also provided invaluable insight into the dynamic long-term control of energy homeostasis. Seasonal (in the hamster) and pregnancy-induced leptin resistance are characterised by a modulation of the leptin signalling cascade downstream of its receptor in the hypothalamus. In this state, leptin-induced phosphorylation of the important transcription factor, signal transducer and activator of transcription 3 (STAT3), is impaired in the arcuate nucleus and the ventromedial hypothalamus (only during pregnancy). This is accompanied by elevated levels of leptin signalling inhibitors such as the suppressor of cytokine signalling (SOCS3) and the protein tyrosine phosphatase 1B (PTP1B). The janus kinase 2 (JAK2)-STAT3 signalling pathway might be modulated by a dual function of the tyrosine residue Tyr(985) in the intracellular domain of the leptin receptor. In seasonal animals, SOCS3, most importantly seems to act as a 'molecular switch' enabling a photoperiod-induced alteration in leptin signalling and subsequent adjustments in energy homeostasis to allow attainment of a new body weight set-point. These physiological models show that animals can exhibit leptin resistance as an adaptive response to meet new physiological or environmental challenges, promoting the survival of the species during times of increased metabolic demand. The molecular mechanisms mediating physiological and/or pathological leptin resistance, like during diet induced obesity, might be very similar involving hypothalamic SOCS3. Investigation of these models might further provide new insight into the dynamic complexity of energy homeostasis.
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PMID:Physiological models of leptin resistance. 1973 87

SH2B1 is a multidomain protein that serves as a key adaptor to regulate numerous cellular events, such as insulin, leptin, and growth hormone signaling pathways. Many of these protein-protein interactions are mediated by the SH2 domain of SH2B1, which recognizes ligands containing a phosphorylated tyrosine (pY), including peptides derived from janus kinase 2, insulin receptor, and insulin receptor substrate-1 and -2. Specificity for the SH2 domain of SH2B1 is conferred in these ligands either by a hydrophobic or an acidic side chain at the +3 position C-terminal to the pY. This specificity for chemically disparate species suggests that SH2B1 relies on distinct thermodynamic or structural mechanisms to bind to peptides. Using binding and structural strategies, we have identified unique thermodynamic signatures for each peptide binding mode, and several SH2B1 residues, including K575 and R578, that play distinct roles in peptide binding. The high-resolution structure of the SH2 domain of SH2B1 further reveals conformationally plastic protein loops that may contribute to the ability of the protein to recognize dissimilar ligands. Together, numerous hydrophobic and electrostatic interactions, in addition to backbone conformational flexibility, permit the recognition of diverse peptides by SH2B1. An understanding of this expanded peptide recognition will allow for the identification of novel physiologically relevant SH2B1/peptide interactions, which can contribute to the design of obesity and diabetes pharmaceuticals to target the ligand-binding interface of SH2B1 with high specificity.
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PMID:Diversity in peptide recognition by the SH2 domain of SH2B1. 2912 27


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