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

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

TNF-alpha may play a role in mediating insulin resistance associated with obesity. This concept is based on studies of obese rodents and humans, and cell culture models. TNF elicits cellular responses via two receptors called p55 and p75. Our purpose was to test the involvement of TNF in glucose homeostasis using mice lacking one or both TNF receptors. C57BL/6 mice lacking p55 (p55(-)/-), p75, (p75(-)/-), or both receptors (p55(-)/-p75(-)/-) were fed a high-fat diet to induce obesity. Marked fasting hyperinsulinemia was seen for p55(-)/-p75(-)/- males between 12 and 16 wk of feeding the high-fat diet. Insulin levels were four times greater than wild-type mice. In contrast, p55(-)/- and p75(-)/- mice exhibited insulin levels that were similar or reduced, respectively, as compared with wild-type mice. In addition, high-fat diet-fed p75(-)/- mice had the lowest body weights and leptin levels, and improved insulin sensitivity. Obese (db/db) mice, which are not responsive to leptin, were used to study the role of p55 in severe obesity. Male p55(-)/-db/db mice exhibited threefold higher insulin levels and twofold lower glucose levels at 20 wk of age than control db/db expressing p55. All db/db mice remained severely insulin resistant based on fasting plasma glucose and insulin levels, and glucose and insulin tolerance tests. Our data do not support the concept that TNF, acting via its receptors, is a major contributor to obesity-associated insulin resistance. In fact, data suggest that the two TNF receptors work in concert to protect against diabetes.
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PMID:Obesity and diabetes in TNF-alpha receptor- deficient mice. 966 82

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

Recent studies have shown that the tumor necrosis factor (TNF) system is implicated in the insulin resistance of human obesity. Plasma concentrations of the soluble fraction of the TNF receptors 1 and 2 (sTNFR1 and sTNFR2) are thought to reflect the degree of activation of the TNF system. The purpose of this study was to explore whether this activation, as measured by the levels of circulating sTNFR1 and sTNFR2, is associated with insulin resistance. A total of 19 men (mean age 36.2 +/- 1.9; BMI 28.8 +/- 1.2, range 22.2-35.7) and 17 premenopausal women (age 34.9 +/- 1.4; BMI 28.1 +/- 0.8, range 19-37.9) were studied. Men showed higher levels of plasma sTNFR1 and sTNFR2 than women. However, obese men showed increased levels of sTNFR2 but similar levels of sTNFR1 in comparison with obese women. In fact, sTNFR2 levels correlated with BMI (r = 0.50, P = 0.002), fat-free mass (FFM) (r = 0.61, P < 0.0001), and waist-to-hip ratio (WHR) (r = 0.39, P = 0.02), but not with fat mass or percent fat mass. sTNFR2 levels correlated with basal glucose levels (r = 0.45, P = 0.007), area under the curve (AUC) for glucose during an oral glucose tolerance test (r = 0.42, P = 0.013), and with the quotient AUC glucose/log AUC insulin (r = 0.41, P = 0.015). sTNFR2 also correlated negatively with insulin sensitivity (S(I)), evaluated using the frequently sampled intravenous glucose tolerance test with minimal model analysis (r = -0.38, P = 0.02). Plasma sTNFR1 levels were not associated with any of these variables. Because WHR influenced both S(I) and sTNFR2 levels, we constructed a multiple linear regression to predict S(I), with WHR and sTNFR2 as independent variables. In this model, both WHR (P = 0.0078) and sTNFR2 levels (P = 0.025) contributed to 47% of the variance in S(I). In parallel with higher FFM, lean and obese men showed a lower S(I) (2.9 +/- 0.9 vs. 5.2 +/- 1.3 min(-1) x mU x l(-1), P = 0.001; and 1.15 +/- 1.1 vs. 1.8 +/- 0.8 min(-1) x mU x l(-1), P = 0.035, respectively) and higher sTNFR2 levels in comparison with lean and obese women, respectively. After controlling for FFM, the correlation between S(I) and sTNFR2 levels disappeared, indicating that FFM was significantly influencing these associations. In summary, plasma sTNFR2 levels, but not sTNFR1, were proportional to BMI, WHR, FFM (a well-known confounder in the evaluation of insulin sensitivity), basal and postload glucose levels, and insulin resistance. These findings support TNF-alpha as a system regulating insulin action in human obesity.
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PMID:Plasma levels of the soluble fraction of tumor necrosis factor receptor 2 and insulin resistance. 979 45

Insulin resistance is an early and major feature in the development of non-insulin-dependent diabetes mellitus(NIDDM). It is also associated with hyperlipidemia, hypertension, obesity and cardiovascular disease. It is the clustor of the risk factors for atherosclerosis and recognized as 'insulin-resistance syndrome' (Syndrome X). Central (abdominal) obesity is much more strongly associated with insulin resistance than overall obesity. The increase of both the influx of free fatty acid to liver and the production of TNF-alpha in adipose tissue may play an important role in mechanism of insulin resistance associated with central obesity. Calorie restriction and weight loss improve insulin sensitivity in overweight humans. Exercise training also improves insulin sensitivity via increased oxidative enzymes, glucose transporters (GLUT4) and capillarity in muscle as well as by reducing abdominal fat. The new 'glitazones' (thiazolidinediones) is used clinically to improve insulin sensitivity.
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PMID:[Syndrome X]. 1019 44

Elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels, responsible for reduced fibrinolysis, are associated with animal and human obesity and with increased cardiovascular disease. The expression of PAI-1 has been found recently in animal and human adipose tissue. Factors and mechanisms regulating such an expression remain to be elucidated. In omental and/or subcutaneous biopsies from obese non-diabetic patients, incubated in Medium 199, we have confirmed that human adipose tissue expresses PAI-1 protein and mRNA; furthermore we have demonstrated that such an expression is clearly evident also in collagenase isolated human adipocytes and that it is stimulated by incubation itself and enhanced by exogenous human tumor necrosis factor-alpha (h-TNF-alpha). Since human adipose tissue produces TNF-alpha, to further characterize the relationship of PAI-1 to TNF-alpha, human fat biopsies were also incubated with Pentoxifylline (PTX) or Genistein, both known to inhibit endogenous TNF-alpha through different mechanisms. PTX caused a dose-dependent decrease of basal PAI-1 protein release, reaching 80% maximal inhibitory effect at 10(-3)M, the same inhibitory effect caused by Genistein at 100 microg/ml. This was associated to a marked inhibition of PAI-1 mRNA and of endogenous TNF-alpha production. Furthermore, when human fat biopsies were incubated in the presence of polyclonal rabbit neutralizing anti-human TNF-alpha antibody (at a concentration able to inhibit 100 UI/ml human TNF-alpha activity), a modest but significant decrease of the incubation induced expression of PAI-1 mRNA was observed (19.8+/-19.0% decrease, P = 0.04, n = 7). In conclusion, the results of this study demonstrate that PAI-I expression is present in human isolated adipocytes and that it is enhanced in human adipose tissue in vitro by exogenous TNF-alpha. Furthermore our data support the possibility of a main role of endogenous TNF-alpha on human adipose tissue PAI-1 expression. This cytokine, produced by human adipose tissue and causing insulin resistance, may be a link in the clinical relationship between insulin-resistance syndrome and increased PAI-1 plasma levels.
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PMID:Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-alpha? 1020 82

There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems. We explored the relationship between TNF-alpha and insulin resistance using knockout mice deficient for either TNF-alpha or one or both of its receptors, p55 and p75. In studies of TNF-alpha-deficient knockout mice with diet-induced obesity, obese TNF-alpha knockouts responded to an exogenous dose of insulin or glucose much more efficiently than TNF-alpha wild-type animals. This finding suggests that deletion of TNF-alpha leads to increased insulin sensitivity, ie decreased insulin resistance. In studies using genetically obese ob/ob mice, TNF-alpha receptor wild-type and p75 receptor knockout animals developed a pronounced hyperinsulinemia and transient hyperglycaemia, whereas p55 receptor and double-knockout animals did not. Moreover, in glucose and insulin tolerance tests, we found that p75 knockout animals exhibited profiles identical to those of the wild-type animals, but that p55 knockout animals and double mutants showed a mild improvement in insulin sensitivity, relative to the wild type. Since the improvement in sensitivity was slightly greater with double mutants, p55 alone cannot be responsible for TNF-alpha's promotion of insulin resistance in obese mice, despite the likelihood that it is more important than p75. How TNF-alpha-related insulin resistance is mediated is not fully clear, although phosphorylation of serine residues on IRS-1 has previously been shown to be important. When we monitored Glut 4 expression in obese TNF-alpha wild-type and knockout mice, we found no convincing evidence that TNF-alpha mediation of the down-regulation of Glut 4 mRNA expression is responsible for insulin resistance. However, we found an approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNF-alpha knockout mice, suggesting that insulin receptor signalling is an important target for TNF-alpha. Other possible mediators of TNF-alpha-induced insulin resistance include circulating free fatty acids (FFAs) and leptin.
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PMID:Mechanisms of TNF-alpha-induced insulin resistance. 1032 50

Insulin resistance is central to the pathophysiology of type 2 diabetes. It has been known for some time that down-regulation and reduced kinase activity of the insulin receptor play a role in insulin resistance; however, it has recently emerged that defects in the intracellular responses to insulin are also very important. We studied the molecular basis of insulin resistance in mice in which injection with gold thioglucose led to the development of hyperphagia, obesity and insulin resistance over a 4-month period. We found that the insulin-stimulated activation of MAP kinase was defective in obese, insulin-resistant mice. Similarly, we investigated insulin-stimulated PI3-kinase activation in the isolated soleus muscle of lean and obese mice, and found a marked reduction in the PI3-kinase activation of obese animals. The magnitude of the effect was greater than the reduction in insulin receptor activation, suggesting that impairment of PI3-kinase activation is a very important element in the development of insulin resistance in obese mice. In keeping with this, we found that the defect in PI3-kinase activation developed in young obese mice before the emergence of overt insulin resistance. We investigated different mechanisms by which defects in the components of the insulin signalling cascade could emerge, including down-regulation and abnormal phosphorylation of signal molecules. In adipocytes from young obese mice in which insulin resistance had not yet developed, we found that there were already marked defects in IRS-1 tyrosine phosphorylation. Increased IRS-1 phosphorylation on serine and threonine residues affects tyrosine phosphorylation. Such a process could contribute to the defective IRS-1 tyrosine phosphorylation in insulin-resistant animals. We found that brief exposure of 3T3-L1 adipocytes to platelet-derived growth factor led to IRS-1 serine/threonine phosphorylation through a PI3-kinase-dependent pathway, and that this prevented phosphorylation of the tyrosine residues of IRS-1. Such a mechanism, induced by growth factors, TNF-alpha or some other agent, may play an important role in the development of insulin resistance in obese mice.
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PMID:Molecular mechanisms of insulin action in normal and insulin-resistant states. 1032 50

1. Insulin resistance has been highlighted as a common causal factor for hypertension, hyperlipidaemia, diabetes mellitus and obesity, all of which are recognized to occur simultaneously, and a distinct clinical entity is defined as 'multiple risk factor syndrome'. 2. Recently, a new class of antidiabetic agents, thiazolidinediones (TZD) has been developed and has been shown to improve insulin resistance by binding and activating a nuclear receptor, peroxisome proliferator-activated receptor (PPAR) gamma. 3. cDNA of rat PPAR gamma 1 and gamma 2 were cloned and gene regulation of PPAR gamma in rat mature adipocytes was examined. Hydrogen peroxide, an oxygen radical, which is recognized to be the common intracellular signal for multiple risk factors, potently down-regulated PPAR gamma mRNA expression in rat mature adipocytes. 4. Tumour necrosis factor (TNF)-alpha, which is considered to play a role in obesity-induced non-insulin-dependent diabetes mellitus and to augment oxidative stress, also suppressed PPAR gamma expression. 5. Thiazolidinediones dose-dependently recovered TNF-alpha-induced down-regulation of PPAR gamma mRNA expression. 6. The modulation of PPAR gamma expression by TZD can be one mechanism for the improvement of insulin resistance by TZD. 7. Vascular tone and remodelling are controlled by several vasoactive autocrine/paracrine factors produced by endothelial cells in response to several vascular injury stimuli, including hypertension. The PPAR gamma gene transcript was detected in cultured endothelial cells. 8. The administration of TZD stimulated the endothelial secretion of type-C natriuretic peptide, which is one of the natriuretic peptide family and is demonstrated by us to act as a novel endothelium-derived relaxing peptide. 9. Concomitantly, TZD significantly suppressed the secretion of endothelin, a potent endothelium-derived vasoconstricting peptide. 10. Thiazolidinediones can affect vascular tone and growth by modulating the production of endothelium-derived vasoactive substances to influence occurrence and progression of hypertension and atherosclerosis.
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PMID:Hypertension and insulin resistance: role of peroxisome proliferator-activated receptor gamma. 1040 88

TNF-alpha (so-called cachectin), IL-1 and 6 are important regulating agents in the homeostasis of energy in the organism, as among others they control processes of apoptosis and thus also the volume of adipose and muscular tissues. They are produced not only in immunocompetent cells but also in adipocytes and muscle cells. The cytokine system is then activated not only in tumours and infections but elevated values were found also in obesity, NIDDM, in myocardial infarction and in advanced decompensated cardiac patients. By acting on phosphorylation of IRS-1 and PI-3 kinase TNF-alpha promotes significantly insulin resistance, causes deterioration of diabetes, as well as elevated body temperature, sleepiness and anorexia. In a group of 65 patients, mostly with android obesity, in hyperleptinaemic and insulin resistant probands with coronarographically confirmed microvascular angina pectoris (n = 22) or IHD, mostly after a myocardial infarction (n = 43) with one or more significant stenoses on the epicardial coronary arteries in half the patients positive or elevated TNF-alpha was found and in 28% also IL-6. This increase did not correlate however with BMI, the percentage of body fat, IRI and C peptide levels nor with cortisol and leptin levels. Insulin resistant subjects had more frequently elevated homocysteine and Lp(a) values which are further two independent risk factors of atherothrombogenesis. Hyperhomocysteinaemia can be favourably influenced by vitamin fortification of the diet or by administration of folate and pyridoxine (1 tablet per day) involving negligible financial costs.
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PMID:[Relation between cytokines (TNF-alpha, IL-1 and 6) and homocysteine in android obesity and the phenomenon of insulin resistance syndromes]. 1042 20


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