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

The mammalian target of rapamycin (mTOR) pathway integrates insulin and nutrient signaling in numerous cell types. Recent studies also suggest that this pathway negatively modulates insulin signaling to phosphatidylinositol 3-kinase/Akt in adipose and muscle cells. However, it is still unclear whether activation of the mTOR pathway is increased in obesity and if it could be involved in the promotion of insulin resistance. In this paper we show that basal (fasting state) activation of mTOR and its downstream target S6K1 is markedly elevated in liver and skeletal muscle of obese rats fed a high fat diet compared with chow-fed, lean controls. Time-course studies also revealed that mTOR and S6K1 activation by insulin was accelerated in tissues of obese rats, in association with increased inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1) on Ser636/Ser639 and impaired Akt activation. The relationship between mTOR/S6K1 overactivation and impaired insulin signaling to Akt was also examined in hepatic cells in vitro. Insulin caused a time-dependent activation of mTOR and S6K1 in HepG2 cells. This was associated with increased IRS-1 phosphorylation on Ser636/Ser639. Inhibition of mTOR/S6K1 by rapamycin blunted insulin-induced Ser636/Ser639 phosphorylation of IRS-1, leading to a rapid (approximately 5 min) and persistent increase in IRS-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation. These results show that activation of the mTOR pathway is increased in liver and muscle of high fat-fed obese rats. In vitro studies with rapamycin suggest that mTOR/S6K1 overactivation contributes to elevated serine phosphorylation of IRS-1, leading to impaired insulin signaling to Akt in liver and muscle of this dietary model of obesity.
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PMID:Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. 1560 15

Nutrient overload leads to obesity, insulin resistance, and often type 2 diabetes. Whereas increased fat intake is commonly cited as the major factor in diet-induced dysmetabolic states, increased protein consumption also contributes, through elevated circulating amino acids. Recent studies have revealed that ribosomal protein S6 kinase 1, S6K1, an effector of mTOR, is sensitive to both insulin and nutrients, including amino acids. Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1. Moreover, rather than signaling through the class 1 PI3K pathway, amino acids appear to mediate mTOR activation through class 3 PI3K, or hVps34. Consistent with this, infusion of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance. Thus, S6K1 may mediate deleterious effects, like insulin resistance, and potentially type 2 diabetes in the face of nutrient excess.
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PMID:Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. 1675 75

Excessive supply of fatty acids to the liver might be a contributing factor to hepatic insulin resistance associated with obesity and type 2 diabetes mellitus. The aim of this study was to investigate direct effects of palmitate on insulin signaling in hepatocytes. The ability of metformin to reverse changes induced by palmitate was also studied. Rat hepatocytes in primary culture exhibited a rightward shift of the insulin dose-response curve for PKB phosphorylation during culture with palmitate. The insulin-stimulated phosphorylation of GSK-3beta, a metabolic substrate of PKB, was diminished in palmitate hepatocytes. By contrast, the mTOR protein kinase was overstimulated in cells incubated with palmitate. Hepatocytes cultured with palmitate displayed hyperphosphorylation of IRS-1 at Ser residues 632/635, known to be phosphorylated by mTOR. Metformin treatment of the hepatocytes resulted in activation of the AMP-activated kinase, attenuation of the mTOR/S6K1 pathway, reduction of IRS-1 phosphorylation, and a leftward shift in the insulin dose-response curve for PKB activation. These data suggest a link between an oversupply of fatty acid to hepatocytes, a disproportionate stimulation of mTOR/S6K1, and resistance to insulin.
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PMID:Activation of mammalian target of rapamycin complex 1 and insulin resistance induced by palmitate in hepatocytes. 1769 34

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. Lipid bodies (lipid droplets) are emerging as dynamic organelles with roles in lipid metabolism and inflammation. Here we investigated the roles of leptin in signaling pathways involved in cytoplasmic lipid body biogenesis and leukotriene B(4) synthesis in macrophages. Our results demonstrated that leptin directly activated macrophages and induced the formation of adipose differentiation-related protein-enriched lipid bodies. Newly formed lipid bodies were sites of 5-lipoxygenase localization and correlated with an enhanced capacity of leukotriene B(4) production. We demonstrated that leptin-induced macrophage activation was dependent on phosphatidylinositol 3-kinase (PI3K) activity, since the lipid body formation was inhibited by LY294002 and was absent in the PI3K knock-out mice. Leptin induces phosphorylation of p70(S6K) and 4EBP1 key downstream signaling intermediates of the mammalian target of rapamycin (mTOR) pathway in a rapamycin-sensitive mechanism. The mTOR inhibitor, rapamycin, inhibited leptin-induced lipid body formation, both in vivo and in vitro. In addition, rapamycin inhibited leptin-induced adipose differentiation-related protein accumulation in macrophages and lipid body-dependent leukotriene synthesis, demonstrating a key role for mTOR in lipid body biogenesis and function. Our results establish PI3K/mTOR as an important signaling pathway for leptin-induced cytoplasmic lipid body biogenesis and adipose differentiation-related protein accumulation. Furthermore, we demonstrate a previously unrecognized link between intracellular (mTOR) and systemic (leptin) nutrient sensors in macrophage lipid metabolism. Leptin-induced increased formation of cytoplasmic lipid bodies and enhanced inflammatory mediator production in macrophages may have implications for obesity-related cardiovascular diseases.
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PMID:Leptin induces macrophage lipid body formation by a phosphatidylinositol 3-kinase- and mammalian target of rapamycin-dependent mechanism. 1803 69

The biological role of macrophage infiltration into adipose tissue in obesity remains to be fully understood. We hypothesize that macrophages may act to stimulate angiogenesis in the adipose tissue. This possibility was examined by determining macrophage expression of angiogenic factor PDGF (platelet-derived growth factor) and regulation of tube formation of endothelial cells by PDGF. The data suggest that endothelial cell density was reduced in the adipose tissue of ob/ob mice. Expression of endothelial marker CD31 was decreased in protein and mRNA. The reduction was associated with an increase in macrophage infiltration. In the obese mice, PDGF concentration was elevated in the plasma, and its mRNA expression was increased in adipose tissue. Macrophages were found to be a major source of PDGF in adipose tissue, as deletion of macrophages led to a significant reduction in PDGF mRNA. In cell culture, PDGF expression was induced by hypoxia, and tube formation of endothelial cells was induced by PDGF. The PDGF activity was dependent on S6K, as inhibition of S6K in endothelial cells led to inhibition of the PDGF activity. We conclude that, in response to the reduced vascular density, macrophages may express PDGF in adipose tissue to facilitate capillary formation in obesity. Although the PDGF level is elevated in adipose tissue, its activity in angiogenesis is dependent on the availability of sufficient endothelial cells. The study suggests a new function of macrophages in the adipose tissue in obesity.
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PMID:Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity. 1849 68

The proinflammatory cytokine TNFalpha is one of the factors that links obesity-derived chronic inflammation with insulin resistance. Activation of mTOR signaling pathway has been found to suppress insulin sensitivity through serine phosphorylation and the inhibition of IRS1 by mTOR and its downstream effector, S6K1. It remains elusive that whether the mTOR pathway has a role in TNFalpha-mediated insulin resistance. In the present study, we demonstrated that TNFalpha-IKKbeta-mediated inactivation of TSC1 resulted in increasing phosphorylation of IRS1 serine 307 and serine 636/639, impaired insulin-induced glucose uptake, tyrosine phosphorylation of IRS1, and the association between IRS1 and PI3K p85. Furthermore, a higher expression of pIKKbeta (S181), pTSC1(S511), and pS6(S240/244) was found in livers obtained from both C57BL/6J mice on a high-fat diet and B6.V-Lepob/J mice. Collectively, dysregulation of the TSC1/ TSC2/mTOR signaling pathway by IKKbeta is a common molecular switch for both cancer pathogenesis and diet- and obesity-induced insulin resistance.
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PMID:IKKbeta suppression of TSC1 function links the mTOR pathway with insulin resistance. 1894 83

Insulin signaling is essential for normal glucose homeostasis. Rho-kinase (ROCK) isoforms have been shown to participate in insulin signaling and glucose metabolism in cultured cell lines. To investigate the physiological role of ROCK1 in the regulation of whole body glucose homeostasis and insulin sensitivity in vivo, we studied mice with global disruption of ROCK1. Here we show that, at 16-18 weeks of age, ROCK1-deficient mice exhibited insulin resistance, as revealed by the failure of blood glucose levels to decrease after insulin injection. However, glucose tolerance was normal in the absence of ROCK1. These effects were independent of changes in adiposity. Interestingly, ROCK1 gene ablation caused a significant increase in glucose-induced insulin secretion, leading to hyperinsulinemia. To determine the mechanism(s) by which deletion of ROCK1 causes insulin resistance, we measured the ability of insulin to activate phosphatidylinositol 3-kinase and multiple distal pathways in skeletal muscle. Insulin-stimulated phosphatidylinositol 3-kinase activity associated with IRS-1 or phospho-tyrosine was also reduced approximately 40% without any alteration in tyrosine phosphorylation of insulin receptor in skeletal muscle. Concurrently, serine phosphorylation of IRS-1 at serine 632/635, which is phosphorylated by ROCK in vitro, was also impaired in these mice. Insulin-induced phosphorylation of Akt, AS160, S6K, and S6 was also decreased in skeletal muscle. These data suggest that ROCK1 deficiency causes systemic insulin resistance by impairing insulin signaling in skeletal muscle. Thus, our results identify ROCK1 as a novel regulator of glucose homeostasis and insulin sensitivity in vivo, which could lead to new treatment approaches for obesity and type 2 diabetes.
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PMID:Targeted disruption of ROCK1 causes insulin resistance in vivo. 1927 91

Adiponectin is widely known as an adipocytokine with therapeutic potential for its markedly protective function in the pathogenesis of obesity-related disorders, metabolic syndrome, systemic insulin resistance, cardiovascular disease and more recently carcinogenesis. In the present study, we show that adiponectin inhibits adhesion, invasion and migration of breast cancer cells. Further analysis of the underlying molecular mechanisms revealed that adiponectin treatment increased AMP-activated protein kinase (AMPK) phosphorylation and activity as evident by increased phosphorylation of downstream target of AMPK, acetyl-coenzyme A carboxylase and inhibition of p70S6 kinase (S6K). Intriguingly, we discovered that adiponectin treatment increases the expression of tumor suppressor gene LKB1 in breast cancer cells. Overexpression of LKB1 in breast cancer cells further increased adiponectin-mediated phosphorylation of AMPK. Using isogenic LKB1 knockdown cell line pair, we found that LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and more importantly, inhibition of adhesion, migration and invasion of breast cancer cells. Taken together these data present a novel mechanism involving specific upregulation of tumor suppressor gene LKB1 by which adiponectin inhibits adhesion, invasion and migration of breast cancer cells. Our findings indicate the possibility of using adiponectin analogues to inhibit invasion and migration of breast cancer cells.
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PMID:LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and inhibition of migration and invasion of breast cancer cells. 1948 24

Rapamycin is an immunosuppressant drug used to prevent organ rejection in transplant patients. In this study, we investigated the metabolic effects of rapamycin in an obese animal model, KK/HlJ mice. Mice were treated with a daily intraperitoneal injection of rapamycin at 2 mg/kg or vehicle for 42 days on a high-fat diet. Treated mice lost body weight and adiposity, reduced weight gain and retroperitoneal and epididymal fat pads/body weight, decreased serum leptin and plasma triglyceride levels and had lower liver fat concentration. However, treated mice had higher serum insulin levels and food intake. Dissection of rapamycin-treated mice revealed a marked reduction in fatty liver scores and fat cell size in retroperitoneal and epididymal adipocytes. Moreover, Western blot analysis revealed that rapamycin treatment resulted in decreasing adipophilin expression, as a marker of lipid accumulation, and reducing phosphorylation of mTOR downstream targets S6K1 compared to control group. Unfortunately, rapamycin-treated animals showed a marked decline in glucose tolerance as judged by the 180-min. area under the curve for plasma glucose levels, paralleled by increased generation of plasma reactive oxygen species. These results suggest that continual rapamycin administration may help to prevent diet-induced obesity, while prolonged use of rapamycin may exacerbate glucose intolerance.
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PMID:Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice. 1949 79

Insulin receptor substrates (IRS) serine phosphorylation is a time-controlled physiological feedback mechanism in insulin signaling that is hijacked by metabolic and inflammatory stresses to promote insulin resistance. Kinases, including IKKbeta, JNK, ERK, mTOR, and S6K, activated by the inducers of insulin resistance induce uncontrolled IRS serine phosphorylation. Studies with genetically modified mice reveal that these kinases integrate signals from metabolic and inflammatory stresses in adipose tissue, liver, and hypothalamus leading to peripheral and central insulin resistance. Moreover, IKKbeta/NF-kappaB and JNK1 pathways in myeloid cells represent a core mechanism involved in inflammation linked to obesity. These kinases are thus potential drug targets against insulin resistance and the targeting of the IKKbeta/NF-kappaB or the JNK pathway may evolve into future diabetes medication.
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PMID:Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. 1968 71


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