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

The vascular actions of insulin may contribute to the increase in glucose uptake by skeletal muscle. We have recently shown that when capillary recruitment by insulin is blocked in vivo, an acute state of insulin resistance is induced. Another agent that may have vascular effects is the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), which has been reported to play an important role in the insulin resistance of obesity, type 2 diabetes, and sepsis in both animals and humans. Thus, in the present study, we have investigated the effect of an intravenous 3-h TNF treatment (0.5 microg x h(1) x kg(-1)) in control and euglycemic-hyperinsulinemic-clamped (10 mU x min(-1) x kg(-1) for 2 h) anesthetized rats. Hind-leg glucose uptake, muscle uptake of 2-deoxyglucose (2-DG), femoral blood flow (FBF), vascular resistance (VR), and capillary recruitment as measured by metabolism of infused 1-methylxanthine (1-MX) were assessed. Insulin alone caused a significant (P < 0.05) increase in FBF (1.7-fold) and capillary recruitment (2.5-fold), with a significant decrease in VR. In addition, hind-leg glucose uptake was increased (fourfold), as was 2-DG uptake in the soleus and plantaris muscles. TNF completely prevented the insulin-mediated changes in FBF, VR, and capillary recruitment and significantly reduced (P < 0.05) the insulin-mediated increase in total hind-leg glucose uptake (by 61%) and muscle 2-DG uptake (by at least 50%). TNF alone had no significant effect on any of these variables. It is concluded that acute administration in vivo of TNF completely blocks the hemodynamic actions of insulin on rat skeletal muscle vasculature and blocks approximately half of the glucose uptake by muscle. It remains to be determined whether these two effects are interdependent.
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PMID:Acute impairment of insulin-mediated capillary recruitment and glucose uptake in rat skeletal muscle in vivo by TNF-alpha. 1107 58

We investigated two genetic polymorphisms in the tumor necrosis factor locus (TNF-alpha -308 G-->A and LT-alpha +252 A-->G) as risk factors for coronary atherothrombotic disease (CAD) by determining its prevalence in 148 survivors of myocardial infarction (MI) with angiographically-proven severe CAD, and in 148 age-, gender- and race-matched controls. The odds ratio (OR) for MI related to the mutant TNF-alpha and LT-alpha alleles was 0.8 (CI95: 0.4-1.3) and 1. 3 (CI95: 0.8-2.0), respectively. We also sought interaction of smoking and metabolic risk factors for MI with each mutant genotype. Smokers not carrying the LT-alpha +252 A-->G mutation had a risk of MI of 2.7 (CI95: 1.4-5.4) whereas in smoking carriers the risk was 6. 9 (CI95: 3.4-14.1). An interactive effect of the LT-alpha mutation may also exist with dyslipidemia (OR for MI in non-carriers was 12 [CI95: 3.2-41.3] and in carriers the OR was 39, [CI95: 5.1-301] and with obesity (OR for MI was 2.7, [CI95: 1-7.2] in non-carriers and in carriers the OR was 6 [CI95: 2.1-16.8]). Lastly, the OR for MI in obese non-carriers of TNF-alpha -308 G-->A was 2.8 (CI95: 1.3-6) and in obese carriers the OR was 14.5 (CI95: 1.8-113). Although significant interactive effects could not be detected, the findings suggest that interaction of polymorphisms in the TNF locus with major risk factors for CAD may exist, and should be explored in larger studies.
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PMID:Gene polymorphisms in the TNF locus and the risk of myocardial infarction. 1111 69

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

Visceral fat accumulation often accompanies various complications, such as insulin resistance, hypertension, dyslipidemia and atherosclerosis. Adipose tissue has been found to secrete various biologically active adipocytokines including free fatty acids. Accumulation of visceral fat increases the portal free fatty acids concentration to cause insulin resistance and dyslipidemia. Tumor necrosis alpha (TNF alpha) deteriorates insulin resistance in obesity. The levels of plasminogen activator inhibitor(PAI)-1 increase and plasma adiponectin concentration decreases in obesity leading to the development of vascular disease. The finding of genes specifically expressed in visceral fat and new adipocytokines should facilitate clarification of the mechanism for the development and complications of visceral fat accumulation.
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PMID:[Molecular mechanism in the development of the complications associated with obesity--the physiological and pathological role of adipocytokines]. 1126 96

Tumor necrosis factor-alpha (TNF alpha) can decrease adipose tissue mass, but in obesity, adipose tissue hypertrophy persists despite increased TNF alpha expression. The hormonal milieu of obesity may antagonize the adipostat effects of TNF alpha. We examined the effects of insulin and the synthetic glucocorticoid, dexamethasone (Dex), on TNF alpha-induced apoptosis and gene expression in human adipocytes and preadipocytes. Using RT multiplex PCR, the expression of the proapoptotic genes interleukin-1 beta (IL-1 beta)-converting enzyme (ICE) and TNF alpha and the antiapoptotic genes bcl-2, nuclear factor-kappa B (NF kappa B), and NF kappa B inhibitory subunit, I kappa B, were examined. The expression and release of IL-1 beta, a postulated downstream effector of ICE-mediated apoptosis, were also determined. TNF alpha increased the messenger ribonucleic acid levels of ICE, TNF alpha, IL-1 beta, bcl-2, and NF kappa B in preadipocytes and adipocytes (P < 0.01). Dex inhibited TNFalpha-induced messenger ribonucleic acid expression of ICE, TNF alpha, and IL-1 beta (P < 0.01), but not that of bcl-2 and NF kappa B. TNF alpha stimulated IL-1 beta release from preadipocytes and adipocytes up to 20-fold, but the effect was abrogated by Dex. Apoptosis induced by TNF alpha was reduced to control levels (P < 0.01) by Dex. Insulin had no significant effect on TNF alpha-induced apoptosis and gene expression. In obesity, glucocorticoids may reduce TNF alpha actions in adipose tissue by inhibiting TNF alpha-induced apoptosis, IL-1 beta release, and TNF alpha expression.
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PMID:Dexamethasone inhibits tumor necrosis factor-alpha-induced apoptosis and interleukin-1 beta release in human subcutaneous adipocytes and preadipocytes. 1139 93

Tumor necrosis factor-alpha (TNF alpha) is involved in the physiological and biological abnormalities found in two opposite metabolic situations: cachexia and obesity. In an attempt to identify novel genes and proteins that could mediate the effects of TNFalpha on adipocyte metabolism and development, we have used a differential display technique comparing 3T3-L1 cells exposed or not to the cytokine. We have isolated a novel adipose cDNA encoding a TNF alpha-inducible 470-amino acid protein termed TIARP, with six putative transmembrane regions flanked by a large amino-terminal and a short carboxyl-terminal domain, a structure reminiscent of channel and transporter proteins. Commitment into the differentiation process is required for cytokine responsiveness. The differentiation process per se is accompanied by a sharp emergence of TIARP mRNA transcripts, in parallel with the expression of the protein at the plasma membrane. Transcripts are present at high levels in white and brown adipose tissues, and are also detectable in liver, kidney, heart, and skeletal muscle. Whereas the biological function of TIARP is presently unknown, its pattern of expression during adipose conversion and in response to TNF alpha exposure as a transmembrane protein mainly located at the cell surface suggest that TIARP might participate in adipocyte development and metabolism and mediate some TNF alpha effects on the fat cell as a channel or a transporter.
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PMID:Tumor necrosis factor-alpha-induced adipose-related protein (TIARP), a cell-surface protein that is highly induced by tumor necrosis factor-alpha and adipose conversion. 1144 37

Obesity is related to cardiovascular disease (CVD) morbidity and mortality, however, the mechanisms for the development of obesity-induced CVD risk remain unclear. Hyperinsulinemia and insulin resistance are considered key components in the metabolic cardiovascular syndrome and as independent risk factors for CVD. Plasma leptin and tumor necrosis factor-alpha (TNF-alpha), two adipocyte products, are also proposed to be associated with the development of CVD risk. The purpose of this study is to evaluate the association of plasma leptin, soluble TNF receptors (sTNF-R), and insulin levels as possible mediators of the effect of obesity on atherogenic and thrombogenic CVD risk factors among men. From the Health Professionals Follow-up Study (HPFS), we selected 268 men, aged 47--83 years, who were free of CVD, diabetes, and cancer (except non-melanoma skin cancer), and who had provided a fasting blood sample in 1994. We measured plasma insulin and leptin levels by radioimmunoassay and sTNF-R levels by ELISA. Men in the highest quintile of body mass index (BMI, mean=30.5 kg/m(2)) were less physically active and had a more adverse cardiovascular lipid and homeostatic profile, as indicated by levels of insulin, triglyceride (TG), tissue plasminogen activator (t-PA) antigen levels, and apolipoprotein A1 (Apo-A1). In a multivariate regression model controlling for age, smoking, alcohol intake, physical activity and diet, BMI was inversely associated with HDL-cholesterol (HDL-C) and Apo-A1 and positively associated with TG, Apo-B and t-PA antigen levels. The associations between BMI and these CVD risk factors were only slightly changed after adjusting for leptin and/or sTNF-R; but were substantially attenuated after controlling for insulin levels. These data suggest that the association between obesity and biological predictors of CVD may be mediated through changes in plasma insulin, rather than leptin or sTNF-R levels. However, plasma leptin may still play a role in CVD through independent effects on lipid metabolism.
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PMID:Plasma insulin, leptin, and soluble TNF receptors levels in relation to obesity-related atherogenic and thrombogenic cardiovascular disease risk factors among men. 1147 52

SOCS (suppressor of cytokine signaling) proteins are inhibitors of cytokine signaling involved in negative feedback loops. We have recently shown that insulin increases SOCS-3 mRNA expression in 3T3-L1 adipocytes. When expressed, SOCS-3 binds to phosphorylated Tyr(960) of the insulin receptor and prevents Stat 5B activation by insulin. Here we show that in COS-7 cells SOCS-3 decreases insulin-induced insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation and its association with p85, a regulatory subunit of phosphatidylinositol-3 kinase. This mechanism points to a function of SOCS-3 in insulin resistance. Interestingly, SOCS-3 expression was found to be increased in the adipose tissue of obese mice, but not in the liver and muscle of these animals. Two polypeptides known to be elevated during obesity, insulin and tumor necrosis factor-alpha (TNF-alpha), induce SOCS-3 mRNA expression in mice. Insulin induces a transient expression of SOCS-3 in the liver, muscle, and the white adipose tissue (WAT). Strikingly, TNF-alpha induced a sustained SOCS-3 expression, essentially in the WAT. Moreover, transgenic ob/ob mice lacking both TNF receptors have a pronounced decrease in SOCS-3 expression in the WAT compared with ob/ob mice, providing genetic evidence for a function of this cytokine in obesity-induced SOCS-3 expression. As SOCS-3 appears as a TNF-alpha target gene that is elevated during obesity, and as SOCS-3 antagonizes insulin-induced IRS-1 tyrosine phosphorylation, we suggest that it is a player in the development of insulin resistance.
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PMID:SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. 1160 92

Potent activation of PPAR gamma by thiazolidinediones(TZD) increases TG content of WAT, thereby decreasing TG content of liver/muscle, leading to amelioration of insulin resistance at the expense of obesity. Moderate reduction of PPAR gamma activity by PPAR gamma/RXR inhibitors decreases TG content of WAT/muscle/liver due to increased leptin and increase in fatty-acid combustion and decrease in lipogenesis, thereby ameliorating HF diet-induced obesity and insulin resistance. Moreover, PPAR gamma/RXR inhibitors decrease lipogenesis in WAT, while TZD stimulate adipocyte differentiation and apoptosis, thereby both preventing adipocyte hypertrophy, which is associated with alleviation of insulin resistance presumably due to decreases in FFA, and TNF alpha, and upregulation of adiponectin. We conclude that although by different mechanisms, both PPAR gamma/RXR inhibitors and PPAR gamma agonist improve insulin resistance, which is associated with decreased TG content of muscle/liver and prevention of adipocyte hypertrophy.
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PMID:[The molecular mechanisms by which PPAR gamma/RXR inhibitors improve insulin resistance]. 1171 15

There is accumulating evidence for a role of tumor necrosis factor-alpha (TNF-alpha) in insulin resistance induced by obesity. The purpose of this study was to investigate whether the TNF alpha/G-308A polymorphism was associated with responses to oral glucose and fat tolerance tests in a case--control study comparing male offspring with a paternal history of premature myocardial infarction (cases, n=335) to age-matched controls (n=340) recruited from 14 European university populations. Genotype frequencies did not significantly differ between cases and controls. Among cases, those carrying the A allele exhibited a higher area under the curve for insulin (64.5 vs 55.9 mU h/l, P=0.009), a higher increment between baseline concentration and peak of insulin (63.1 vs 52.8 mU/l, P=0.005) and a greater decrease between peak and insulin at 120 min (49.1 vs 36.8 mU/l, P=0.003) than those with the GG genotype. No such effect was observed in control subjects. No association was observed with response to a fat tolerance test either in cases or in controls. The present results suggest that the TNF alpha/G-308A polymorphism might interact with other susceptibility factors to coronary heart disease to predispose to insulin resistance, and that the ability of TNF-alpha to induce insulin resistance may extend beyond obesity.
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PMID:The TNF alpha/G-308A polymorphism influences insulin sensitivity in offspring of patients with coronary heart disease: the European Atherosclerosis Research Study II. 1188 14


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