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 is an important metabolic abnormality often associated with infections, cancer, obesity, and especially non-insulin-dependent diabetes mellitus (NIDDM). We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. However, the mechanism by which TNF-alpha interferes with insulin action is not known. Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. The physiological significance of the improvements in IR signaling was indicated by a concurrent reduction in plasma glucose, insulin, and free fatty acid levels. These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat.
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PMID:Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. 752 53

Tumor necrosis factor (TNF)-alpha plays a central role in the state of insulin resistance associated with obesity. It has previously been shown that one important mechanism by which TNF-alpha interferes with insulin signaling is through the serine phosphorylation of insulin receptor substrate-1 (IRS-1), which can then function as an inhibitor of the tyrosine kinase activity of the insulin receptor (IR). However, the receptors and the signaling pathway used by TNF-alpha that mediate the inhibition of IR activity are unknown. We show here that human TNF-alpha, which binds only to the murine p55 TNF receptor (TNFR), is as effective at inhibiting insulin-dependent tyrosine phosphorylation of IR and IRS-1 in adipocytes and myeloid 32D cells as murine TNF-alpha, which binds to both p55 TNFR and p75 TNFR. Likewise, antibodies that are specific agonists for p55 TNFR or p75 TNFR demonstrate that stimulation of p55 TNFR is sufficient to inhibit insulin signaling, though a small effect can also be seen with antibodies to p75 TNFR. Exogenous sphingomyelinase and ceramides, known to be formed by activation of p55 TNFR, inhibit IR and IRS-1 tyrosine phosphorylation and convert IRS-1 into an inhibitor of IR tyrosine kinase in vitro. Myeloid 32D cells expressing IR and IRS-1 are sensitive to this inhibition, but cells expressing IR and IRS-2 are resistant, pointing to an important difference in the biological function between IRS-1 and IRS-2. These data strongly suggest that TNF-alpha inhibits insulin signaling via stimulation of p55 TNFR and sphingomyelinase activity, which results in the production of an inhibitory form of IRS-1.
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PMID:Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. 866 83

Although obesity has become the most common metabolic disorder in the developed world and is highly associated with insulin resistance and noninsulin-dependent diabetes mellitus, the molecular mechanisms underlying these disorders are not clearly understood. Tumor necrosis factor-alpha (TNF-alpha) is overexpressed in obesity and is a candidate mediator of obesity-induced insulin resistance. Complete lack of TNF-alpha function through targeted mutations in TNF-alpha gene or both of its receptors results in significant improvement of insulin sensitivity in dietary, chemical, or genetic models of rodent obesity. In this study, we have analyzed the in vivo role of TNF signaling from p55 [TNF receptor (TNFR) 1] and p75 (TNFR 2) TNFR in the development of insulin resistance by generating genetically obese mice (ob/ob) lacking p55 or p75 TNFRs. In the ob/ob mice, the absence of p55 caused a significant improvement in insulin sensitivity. p75 deficiency alone did not affect insulin sensitivity but might potentiate the effects of p55 deficiency in animals lacking both TNFRs. These results indicate that TNF-alpha is a component of insulin resistance in the ob/ob model of murine obesity and p55 TNFR is the predominant receptor mediating its actions.
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PMID:Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. 983 19

Tumor necrosis factor-alpha (TNF-alpha) has been shown to induce insulin resistance in cultured cells as well as in animal models. The aim of this study was to map the in vivo mechanism whereby TNF-alpha contributes to the pathogenesis of impaired insulin signaling, using obese and lean Zucker rats in which TNF-alpha activity was inhibited through adenovirus-mediated gene transfer. We employed a replication-incompetent adenovirus-5 (Ad5) vector to endogenously express a TNF inhibitor (TNFi) gene, which encodes a chimeric protein consisting of the extracellular domain of the human 55-kDa TNF receptor joined to a mouse IgG heavy chain. Control animals consisted of rats infected with the same titer of adenovirus carrying the lac-z complementary DNA, encoding for beta-galactosidase. There was a significant reduction in plasma insulin and free fatty acid levels in TNFi obese rats 2 days following Ad5 administration. The peripheral insulin sensitivity index was 50% greater, whereas hepatic glucose output was completely suppressed during hyperinsulinemic glucose clamps in TNFi obese animals, with no differences observed between the two lean groups. The improvement in peripheral and hepatic sensitivity to insulin seen in the obese animals was independent of insulin receptor (IR) number and insulin binding affinity for IR. However, TNF-alpha neutralization led to a 2.5-fold increase in tyrosine phosphorylation of IR in skeletal muscle, whereas this was unchanged in liver. There was also a 4-fold increase in particulate protein tyrosine phosphatase activity of skeletal muscle in TNFi obese animals vs. beta-galactosidase controls, whereas protein tyrosine phosphatase activity in liver was unchanged. These results suggest that TNF-alpha is a mediator of insulin resistance in obesity and may modulate IR signaling in skeletal muscle and liver through different pathways. TNF-alpha may affect insulin action in the liver either at sites distal to the IR or indirectly, possibly because of increased provision of gluconeogenic substrates or altered counterregulation. In addition, the Ad5-mediated gene delivery system employed here provides an in vivo model that is efficient and economical for exploring mechanisms involved in TNF-alpha-induced insulin resistance in various genetic models of obesity-linked diabetes.
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PMID:An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: evidence for differential regulation of insulin signaling by TNF-alpha. 983 30

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 < 0.0001; %fat = 16.9 +/- 5.8% versus 24.3 +/- 4.9%; p < 0.001). Serum 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 < 0.05). In contrast, serum TNF-alpha levels (6.59 +/- 1.92 pg/ml versus 5.41 +/- 1.60 pg/ml; p < 0.05), plasma sTNF-R55 (1.16 +/- 0.47 ng/ml versus 0.67 +/- 0.13 ng/ml; p < 0.0001) and sTNF-R75 (3.65 +/- 1.29 ng/ml versus 2.25 +/- 0.43 ng/ml; p < 0.0001) levels were significantly higher in the 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.
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PMID:Circulating leptin in patients with chronic obstructive pulmonary disease. 1019 68

Insulin resistance is associated with many common diseases including diabetes mellitus, hyperlipidemia and hypertension, and plays an important role for determining their clinical courses. Obesity is a multifactorial syndrome characterized by an excessive adipose tissue accumulation, and is associated with acquired insulin resistance. Adipose tissue, acting as one of the endocrine organs, has been revealed to produce and secrete some bioactive molecules, "adipocytokines", which regulate cell growth and/or metabolic pathways. Tumor necrosis factor(TNF)-alpha is also synthesized by adipocytes, and is involved in the expression of peripheral insulin resistance. This review deals with molecular mechanisms of the TNF/TNF receptor system promoting insulin resistance, and its prevention by the insulin-sensitizing drugs, thiazolidinediones.
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PMID:[Insulin resistance and cytokine, cytokine receptor]. 1070 52

Inhibition of tumor necrosis factor (TNF)-alpha results in a marked increase in insulin sensitivity in obese rodents. We investigated the influence of a TNF antagonist [Ro 45-2081, a recombinant fusion protein that consists of the soluble TNF-receptor (p55) linked to the Fc portion of human IgG1] on insulin sensitivity of patients with android obesity. Seven patients (five women and two men; mean +/- SD age, 41 +/- 4 yr; body mass index, 36.1 +/- 4.7 kg/m2; waist to hip ratio, 0.99 +/- 0.11) were studied (three patients with normal glucose tolerance and four patients with impaired glucose tolerance or mild diabetes; all were hyperinsulinemic). Each patient underwent two consecutive euglycemic hyperinsulinemic glucose-clamp tests: 48 h after injection of placebo and 48 h after a single i.v. injection of 50 mg Ro 45-2081. In both tests, steady-state plasma glucose and insulin levels were similar. Insulin-mediated glucose disposal (2.23 +/- 0.74 vs. 2.38 +/- 0.99 mg/kg(-1) x min(-1)) and glucose metabolic clearance rate (2.28 +/- 0.85 vs. 2.48 +/- 1.03 mL/kg(-1) x min(-1)) were similar after placebo and after the drug. Indirect calorimetry showed no difference in substrate oxidation rates between the two experimental conditions. In conclusion, under the conditions of this study, no improvement in insulin sensitivity was observed in obese insulin-resistant patients following a single i.v. administration of a recombinant TNF receptor: Fc fusion protein.
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PMID:No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients. 1072 82

Leptin, tumor necrosis factor-alpha (TNF-alpha), and soluble TNF receptors are involved in weight regulation. Antipsychotic agents, such as clozapine, induce weight gain and increase circulating levels of these cytokines. To assess whether obesity-inducing antidepressants have a similar effect, we measured plasma cytokine levels in depressive inpatients during the first six weeks of treatment with tricyclic agents (amitriptyline or nortriptyline, n = 12), with paroxetine (n = 10), or without medication (n = 14). There was an increase in the body mass index at week 6 of treatment with the tricyclics, which was preceded by a significant increase in soluble TNF receptor p75 plasma levels. Circulating levels of leptin were not affected. Paroxetine and drug-free treatment did not affect any of these parameters. We conclude that weight gain induced by psychotropic agents may occur without increased circulating levels of leptin. However, activation of the TNF-alpha system might be an early and sensitive marker of ensuing weight gain.
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PMID:Effects of antidepressants on weight and on the plasma levels of leptin, TNF-alpha and soluble TNF receptors: A longitudinal study in patients treated with amitriptyline or paroxetine. 1086 82

Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of diseases, including hypertension, dyslipidemias, cardiovascular problems and type 2 diabetes mellitus. However, the molecular mechanisms underlying abnormal insulin action and these other pathological states are not well understood. We have been focusing on cytokines, particularly TNFalpha and fatty acid binding proteins, as potential sites to study the molecular basis of these disorders. The role of TNFalpha in insulin resistance and other pathologies associated with obesity, have been examined in several experimental systems including obese mice with homozygous null mutations at the TNFalpha or TNF receptor loci. Analysis of these animals demonstrated that the genetic absence of TNF signaling in obesity: (i) significantly improves insulin receptor signaling capacity and consequently insulin sensitivity; (ii) prevents brown adipose tissue atrophy and beta3-adrenoreceptor deficiency and improves thermo-adaptive responses, (iii) decreases the elevated PAI-1 and TGFbeta production; and (iv) lowers hyperlipidemia and hyperleptinemia. Hence, abnormal TNFalpha action in adipocytes disturbs many aspects of metabolic homeostasis in obesity.
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PMID:Molecular mechanisms of insulin resistance and the role of the adipocyte. 1112 35

Previous studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) production from adipose tissue is elevated in obese animal models and in obese humans. It plays an important role in the induction of insulin resistance in experimental animals. In this study, we examined hypothalamic tissue expression of TNF-alpha and its receptors and TNF-alpha expression of adipose tissue in lean C57BLKSJ+/+ and obese polygenic New Zealand obese (NZO) mice. Obese animals exhibited hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and hypercholesterinemia. Using RT-PCR, we observed increased expression (2.4-fold) of TNF receptor 2 (p75) in the hypothalamus of obese mice. TNF-alpha expression in adipose tissue of obese mice was eight times higher than in controls. TNF-alpha and TNF receptor 1 (p55) expression in hypothalamic tissue was similar in obese and lean animals. These results suggest that the hypothalamic TNF receptor 2 (p75) might play a role in obesity by modulating the actions of TNF-alpha in conditions of leptin resistance.
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PMID:Increased hypothalamic expression of the p75 tumor necrosis factor receptor in New Zealand obese mice. 1156 Dec 10


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