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

It has been hypothesized that increased production of tumor necrosis factor-alpha (TNF-alpha) plays a role in causing the insulin resistance associated with obesity. Obesity with insulin resistance is associated with increased production of TNF-alpha by fat cells. Exposure of 3T3-L1 adipocytes to TNF-alpha for 3-4 days makes them insulin resistant. TNF-alpha has also been reported to rapidly (15-60 min) cause insulin resistance, with a decrease in insulin-stimulated tyrosine phosphorylation, in a number of cultured cell lines. Because skeletal muscle is the major tissue responsible for insulin-stimulated glucose disposal, we performed the present study to determine if acute exposure to TNF-alpha causes insulin resistance in muscle. We found that exposure of soleus muscles to 6 nmol/l TNF-alpha for 45 min in vitro had no inhibitory effect on insulin-stimulated tyrosine phosphorylation of the insulin receptor or insulin receptor substrate 1 (IRS-1) or on phosphatidylinositol 3-kinase association with IRS-1. Incubation of epitrochlearis and soleus muscles with 6 nmol/l TNF-alpha for 45 min or 4 h had no effect on insulin-stimulated 2-deoxyglucose (2-DG) uptake. Treatment of epitrochlearis muscles with 2 nmol/l TNF-alpha for 8 h also had no effect on insulin-stimulated 2-DG uptake. We conclude that in contrast to Fao hepatoma cells and 3T3-L1 fibroblasts, skeletal muscle does not become insulin resistant in response to short-term exposure to TNF-alpha.
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PMID:Short-term exposure to tumor necrosis factor-alpha does not affect insulin-stimulated glucose uptake in skeletal muscle. 958 42

While the causes of obesity remain elusive, the relationship between obesity and insulin resistance is a well-established fact [1]. Insulin resistance is defined as a smaller than normal response to a certain dose of insulin, and contributes to several pathological problems of obese patients such as hyperlipidemia, arteriosclerosis and hypertension. Several pieces of evidence indicate that the cytokine tumor necrosis factor a (TNF-alpha) is an important player in the state of insulin resistance observed during obesity. In this review we will try to summarize what is known about the function of TNF-alpha in insulin resistance during obesity and how TNF-alpha interferes with insulin signaling.
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PMID:TNF-alpha and insulin resistance: summary and future prospects. 960 26

Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant circulating adrenal steroids in humans. Administration of DHEA has been reported to have beneficial effects on obesity, hyperlipidemia, diabetes, and atherosclerosis in obese rodents, although its effects on insulin resistance have not been fully elucidated. In this study, the effects of DHEA treatment on insulin sensitivity were investigated in genetically obese Zucker rats, an animal model of insulin resistance, using the euglycemic clamp technique. After 0.4% DHEA was administered for 10 days to female obese Zucker rats aged 16 weeks, body weight and plasma insulin decreased and glucose disposal rate (GDR), which was normally reduced in obese rats, rose significantly compared with age- and sex-matched control obese rats. On the other hand, although the pair-fed obese rats also showed levels of weight reduction similar to those of DHEA-treated rats, the increase in GDR of DHEA-treated rats was significantly greater than in pair-fed rats, suggesting a direct ameliorating effect of DHEA on insulin sensitivity of obese rats. Serum concentration of tumor necrosis factor (TNF)-alpha, one of cytokines causing insulin resistance, was also reduced significantly in DHEA-treated, but not in pair-fed obese rats. In conclusion, our results suggest that DHEA treatment reduces body weight and serum TNF-alpha independently, and that both may ameliorate insulin resistance in obese Zucker fatty rats.
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PMID:Dehydroepiandrosterone decreases serum tumor necrosis factor-alpha and restores insulin sensitivity: independent effect from secondary weight reduction in genetically obese Zucker fatty rats. 964

This review addresses the general hypothesis that the pathogenesis of preeclampsia is related to an imbalance of increased oxidative stress and lipid peroxidation coupled to a deficiency of antioxidant protection. Evidence will be presented that this imbalance is present in both the maternal compartment and the placental compartment and that interactions between these two compartments result in the clinical manifestations of this disorder. We suggest the following as a scenario for the development of preeclampsia: Oxidative stress in the maternal compartment affects the placenta in such a way as to bring about a decrease in placental antioxidant enzyme protection. The oxidative stress in the maternal compartment may be preexisting (e.g., obesity, diabetes, hyperlipidemia) or may be caused by placental secretion of lipid peroxides. Decreased placental antioxidant enzyme protection leads to a cascade of events in the placenta of uncontrolled lipid peroxidation with increased thromboxane production and increased tumor necrosis factor (TNF-alpha) production. Increased placental secretion of lipid peroxides and/or TNF-alpha results in activation of leukocytes as they circulate through the intervillous space. The activated leukocytes serve as circulating mediators that link the increased oxidative stress of the placenta with a widespread increase in oxidative stress and endothelial dysfunction in the mother. In the third trimester, when the placenta is growing rapidly, the mother's antioxidant capacity is no longer able to compensate, and the clinical symptoms of preeclampsia appear.
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PMID:Maternal-placental interactions of oxidative stress and antioxidants in preeclampsia. 965 11

The role of tumor necrosis factor (TNF)-alpha in the development of insulin resistance has repeatedly been emphasized in the past few years. The present paper summarizes the data (including the authors' observations as well) focusing on the potential role of TNF-alpha in the pathogenesis of obesity and non-insulin-dependent diabetes mellitus: alteration of insulin receptor function, lipid metabolism, expression of sulphonylurea receptors, all of them suggested to be related to the TNF-alpha. The potential clinical relevances are shortly reviewed.
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PMID:[Tumor necrosis factor-alpha; a possible pathogenic factor in obesity in insulin resistant and non-insulin-dependent diabetes mellitus?]. 968 2

In view of the recent demonstration that obesity in animals and humans is associated with an increase in tumor necrosis factor-alpha (TNFalpha) expression, that this expression falls with weight loss, and that TNFalpha may specifically inhibit insulin action, the possibility that TNFalpha may be a mediator of insulin resistance has been raised. We have undertaken this study to investigate whether serum TNFalpha concentrations are elevated in obese subjects, whether they fall after weight loss, and whether this fall parallels the fall in insulin release after glucose challenge. Obese patients (age range: 25-54, weight mean +/- SD: 96.4 +/- 13.8 kg, body mass index: 35.7 +/- 5.6 kg/m2) were started on a diet program. The mean weight fell to 84.5 +/- 11.3 (P < 0.0001) and body mass index to 31.3 +/- 4.9 (P < 0.0001). Plasma TNFalpha concentrations were markedly elevated in the obese (3.45 +/- 0.16 pg/mL), when compared with controls (0.72 +/- 0.28 pg/mL), and fell significantly (2.63 +/- 1.40 pg/mL) after weight loss (P < 0.02). The magnitude of insulin release after glucose (75 g) challenge (area under the curve) also fell significantly (P < 0.01) after weight loss. The magnitude of weight loss and fall in TNFalpha were related to basal body weight (r = 0.57, P < 0.001) and basal TNFalpha (r = 0.55, P < 0.001) concentrations, respectively, but not to each other or to the glucose-induced insulin release (area under the curve). We conclude that obesity is associated with increased plasma TNFalpha concentrations, which fall with weight loss. Because circulating TNFalpha may mediate insulin resistance in the obese, a fall in TNFalpha concentrations may contribute to the restoration of insulin resistance after weight loss, Thus, TNFalpha may be an important circulating cytokine, which may provide a potentially reversible mechanism for mediating insulin resistance.
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PMID:Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. 970 67

Human obesity is associated with an increased tumor necrosis factor-alpha (TNF-alpha) mRNA expression in adipose tissue. TNF-alpha decreases insulin-dependent glucose uptake by inhibiting autophosphorylation of the insulin receptor, suggesting that TNF-alpha may play a role in insulin resistance. In this study, we analyzed plasma levels of TNF-alpha in 40 70-year-old men with newly detected non-insulin-dependent diabetes mellitus and in 20 age-matched controls. Twenty of the patients had a moderate level of insulin resistance and 20 were severely insulin resistant. The plasma levels of TNF-alpha were higher in patients (4.00+/-1.53 pg/mL in moderately insulin resistant and 4.91+/-1.43 pg/mL in severely insulin resistant subjects) than in controls (3.27+/-0.79 pg/mL, P<0.001). TNF-alpha was significantly related to body mass index, fasting glucose levels, and serum triglyceride levels and inversely related to the high density lipoprotein cholesterol level. The finding of an association between high plasma levels of TNF-alpha and several metabolic abnormalities characteristic for the insulin resistance syndrome suggests that TNF-alpha may be involved in the pathogenesis of non-insulin-dependent diabetes mellitus.
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PMID:Relation between plasma tumor necrosis factor-alpha and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus. 971 25

Expression of tumor necrosis factor-alpha(TNFalpha) in adipocytes has been reported to correlate with insulin resistance associated with obesity. The thiazolidinediones such as BRL 49653 have been reported to improve insulin sensitivity in obese animals and humans. Although its exact mechanism of action is not known, BRL 49653 has been shown to antagonize some of the inhibitory actions of TNFalpha. BRL 49653 binds and activates the peroxisome proliferator-activated receptor (PPARgamma2), an important nuclear transcription factor in adipocyte differentiation; however, its regulation of PPARgamma2 in differentiated adipocytes is unknown. In this paper, we find that BRL 49653 blocked the ability of TNFalpha to down-regulate the expression and transcription of several adipocyte genes, but BRL 49653 did not prevent TNFalpha from down-regulating PPARgamma2. Moreover, BRL 49653 alone initially decreased the expression of PPARgamma2 mRNA and protein greatly. After 24 h of treatment in 3T3-L1 adipocytes, BRL 49653 down-regulated PPARgamma2 by greater than 90% and potentiated the decrease of PPARgamma2 mRNA by TNFalpha at this time. These unexpected results prompted us to repeat the experiments for a longer time to determine whether BRL 49653 would continue to down-regulate PPARgamma2. With prolonged BRL 49653 treatment, PPARgamma2 mRNA expression was not decreased as greatly, and the protein levels were decreased 20-30% below control at 72 h compared to 90% at 24 h. Although BRL 49653 continued to prevent the inhibitory effects of TNFgamma on perilipin and aP2 mRNA, by 72 h, BRL 49653 was not as potent an inhibitor of TNFalpha's down-regulation of perilipin protein. Since PPARgamma2 protein was more abundant at this time, these results suggest that the level of PPARgamma2 protein is not the sole factor that regulates the transcriptional control by BRL 49653.
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PMID:The short- and long-term effects of tumor necrosis factor-alpha and BRL 49653 on peroxisome proliferator-activated receptor (PPAR)gamma2 gene expression and other adipocyte genes. 971 41

In earlier work, we reported that genetically obese (fa/fa) Zucker rats exhibited significantly greater anorexia than did lean (Fa/Fa) Zucker rats to intracerebroventricular infusion of interleukin (IL)-1beta. Here, we investigated the fever response of obese (fa/fa) and lean (Fa/Fa) Zucker rats to intracerebroventricular microinfusion of IL-1beta as well as to the following other cytokines: IL-2, IL-6, and tumor necrosis factor-alpha (TNF-alpha). Core body temperature was monitored by a radiotelemetry system in freely moving rats. The results show that 1) both IL-1beta and IL-6 induce fevers in obese and lean rats; 2) IL-1beta induces a significantly higher fever response in obese rats than it does in lean rats; 3) IL-6 induces a significantly higher fever response in lean rats than it does in obese rats; 4) IL-2 induces a moderate fever response in lean but not obese rats; 5) TNF-alpha induces a similar fever response in obese and lean rats; and 6) the fevers induced by each effective cytokine have different time courses. Thus obese (fa/fa) and lean (Fa/Fa) Zucker rats show differential responsiveness to the intracerebroventricular microinfusion of various classes of cytokines. This suggests that genetic obesity in the fa/fa Zucker rat is associated with differential cytokine action on thermoregulatory mechanisms.
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PMID:Cytokine-induced fever in obese (fa/fa) and lean (Fa/Fa) Zucker rats. 975 68

The risk of coronary heart disease (CHD) is influenced by family history, insulin sensitivity (IS), and diet. Adiposity affects CHD and IS. The cellular mechanism of IS is thought to involve the adipocyte cytokine tumor necrosis factor-alpha (TNF-alpha). Insulin-stimulated glucose uptake in isolated subcutaneous and omental adipocytes obtained during elective surgery was measured in 61 premenopausal women, 24 with a parental history (PH) of CHD. In vivo IS was measured using the short insulin tolerance test (SITT) in 28 women, 16 with PH-CHD, before and 3 weeks after randomization to a low glycemic index (LGI) or high glycemic index (HGI) diet. In vitro adipocyte IS and TNF-alpha production was measured following dietary modification. On the habitual diet, in vitro insulin-stimulated glucose uptake in adipocytes as a percentage increase over basal was less in women with PH-CHD than in those without it (presented as the median with 95% confidence limits: subcutaneous, 28% (17% to 39%) v 96% (70% to 120%), P < .01); omental, 40% (28% to 52%) v 113% (83% to 143%), P < .01). In vivo IS in 16 PH-CHD subjects and 12 controls before dietary randomization was similar, and increased in both groups consuming a LGI versus HGI diet (PH-CHD, 0.31 (0.26 to 0.37) v 0.14 (0.10 to 0.24) mmol/L/min, P < .01; controls, 0.31 (0.1 to 0.53) v 0.15 (0.06 to 0.23) mmol/L/min, P < .05). Adipocyte IS was greater in PH-CHD women on a LGI versus HGI diet (subcutaneous, 50% (20% to 98%) v 13% (1% to 29%); omental, 97% (47% to 184%) v 29% (4% to 84%), P < .05). Adipocyte TNF-alpha production was higher in women with versus without PH-CHD (subcutaneous, 0.3 (0.18 to 0.42) v 0.93 (0.39 to 1.30) ng/mL/min; visceral, 0.22 (0.15 to 1.30) v 0.64 (0.24 to 1.1) ng/mL/min, P < .04, respectively), but was uninfluenced by the dietary glycemic index. We conclude that in vitro adipocyte IS is reduced and adipocyte TNF-alpha production is increased in premenopausal women with PH-CHD. A LGI diet improves both adipocyte IS in women with PH-CHD and in vivo IS in women with and without PH-CHD.
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PMID:Insulin sensitivity in women at risk of coronary heart disease and the effect of a low glycemic diet. 978 29


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