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)

Type 2 diabetes is characterized by decreased secretion of insulin and insulin resistance. Thiazolidinediones are drugs to ameliorate insulin resistance. At present, only pioglitazone is available in Japan. The first drug of this category, troglitazone, has been withdrawn from market because of its liver toxicity in a few patients. The decrease in fasting plasma glucose begins within 2 weeks and reaches the nadir in 8-12 weeks. Plasma insulin levels usually decrease together with plasma glucose. Thiazolidinedione drugs are effective in about 50% of type 2 diabetic patients. The efficacy is higher in patients with obesity, high insulin levels and in aged people and females. The mechanism is thought to be mediated by activation of a nuclear receptor, PPAR-gamma, which is most abundantly expressed in the adipose tissue. Current concept is that, when PPAR-gamma is activated by these drugs, the number of small adipocytes is increased to replace large adipocytes, thereby decreasing the release of TNF-alpha and FFA from adipose tissue. However, there seems to be a complex relationship between the activity of PPAR-gamma and insulin sensitivity. The effect of these new category drugs should be monitored carefully on a long-term basis.
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PMID:[Insulin sensitizer drugs, thiazolidinediones: current state and prospect]. 1171 93

Leptin-deficient ob/ob mice are protected from Con A-induced hepatitis. However, it is unclear whether leptin deficiency or obesity itself is responsible for this protection. To address this question, wild-type (WT) obese mice with high serum leptin levels were generated by injection of gold thioglucose (WT GTG). Both Con A-injected WT and WT GTG mice developed hepatitis, whereas no hepatic damage was observed in ob/ob mice. Moreover, TNF-alpha and IFN-gamma levels as well as expression of the activation marker CD69 were elevated in liver mononuclear cells of WT and WT GTG mice, but not in ob/ob mice following administration of Con A. The liver of WT and WT GTG mice had the same percentage of NK T cells, a lymphocyte population involved in Con A-induced hepatitis. This population decreased equally in both WT and WT GTG mice after Con A injection. In contrast, the liver of ob/ob mice contained 50% less NK T cells compared to WT and WT GTG mice. Furthermore, no decrease in NK T cells was observed in Con A-injected ob/ob mice. We conclude that leptin-deficiency, not obesity, is responsible for protection from Con A-induced hepatitis.
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PMID:Leptin deficiency, not obesity, protects mice from Con A-induced hepatitis. 1182 72

Insulin resistance and hyperinsulinemia have been observed in over 70% of the nonobese, nondiabetic subjects with essential hypertension (HT). Alpha-1 blockers, ACE-antagonists, long-acting Ca blockers including nifedipine CR, some form of beta-blockers, tilisolor, which is reported to increase blood flow, improve insulin sensitivity when blood pressure is better controlled. Decrease of serum potassium during insulin sensitivity test and intraplatelet free Ca2+ concentration is positively and negatively correlated with insulin sensitivity, respectively. Blood pressure is correlated with insulin resistance, which is also observed in secondary HT. The resistance is correlated with salt sensitivity as well as impaired nocturnal fall of blood pressure. These suggest the possible association of insulin resistance with altered intracellular cation metabolism. Insulin resistance and associated hyperinsulinemia have been observed in effort as well as vasospastic angina pectoris (VSAP), atherothrombotic cerebral infarction, and in ASO without obesity, HT, or diabetes, suggesting the resistance resulting from endothelial dysfunction. Insulin resistance has been observed in heart failure and is correlated with angiotensin II. Resistance is also observed in hypertrophic cardiomyopathy and is partially correlated with TNF-alpha. These results indicate that insulin resistance seem to be multifactorial. An effort to normalize insulin sensitivity is crucial to eliminate multiple risk factors as well as to prevent the progression of atherosclerotic vascular lesions.
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PMID:Multifactorial insulin resistance and clinical impact in hypertension and cardiovascular diseases. 1187 61

Insulin resistance is associated with hypertension, obesity, dyslipidemia, and type 2 diabetes. It is well known that tumor necrosis factor (TNF)-alpha is one of the factors linked to obesity-induced insulin resistance; however, there have been no reports on the role of TNF-alpha in insulin resistance in nonobese insulin-resistant hypertensives. We tested the hypothesis that TNF-alpha affects insulin resistance in nonobese insulin-resistant hypertensive fructose-fed rats (FFR) and that a TNF-alpha--converting enzyme (TACE) inhibitor that blocks TNF-alpha secretion improves insulin resistance in FFR. Six-week-old male Sprague-Dawley rats were fed either standard chow (control) or fructose-rich chow (FFR) for 6 weeks. For the last two weeks of a six-week period of either diet, the rats were treated with a vehicle (control or FFR) or a TACE inhibitor (100 mg/kg/d of KB-R7785; FFR+TACE-I) in peritoneal injection. At the age of 12 weeks, insulin sensitivity was assessed in all conscious rats by the euglycemic hyperinsulinemic glucose clamp technique. While FFR had higher blood pressure than the control rats (P<0.01), the TACE inhibitor did not change blood pressure. Insulin sensitivity (M-value) was reduced in FFR compared with that in the control rats (16.7 +/- 1.1 mg/kg per min and 10.3 +/- 0.6 mg/kg per min in the control rats and FFR, respectively, P<0.001), and the TACE inhibitor improved insulin sensitivity to the level of the control rats (14.3 +/- 1.2 mg/kg per min in FFR+TACE-I, P<0.01). These data indicate that TNF-alpha plays a major role in insulin resistance in nonobese insulin-resistant models and also suggest that TACE would be a good target for controlling insulin resistance not only in obese models but also in nonobese insulin-resistant models.
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PMID:Effect of TNF-alpha--converting enzyme inhibitor on insulin resistance in fructose-fed rats. 1188 11

The major risk factor for the development of insulin resistance and type 2 diabetes is obesity. A key role is the new understanding of adipocytes as an endocrine system. Adipocytes secrete numerous substances that contribute to peripheral insulin resistance, including adiponectin, resistin, TNF-alpha and interleukin 6. There is also a role of free fatty acids by blocking directly intracellular metabolism of glucose and by their lipotoxicity. The pre-receptor metabolism of cortisol may be enhanced in visceral adipose tissue by activation of 11 beta-hydroxysteroid dehydrogenase type 1. The new class of thiazolidinediones (glitazones), binding to the peroxisome proliferator activated receptor (PPAR-gamma) lowers the levels of resistin and increases adiponectin, resulting in an improvement of glucose homeostasis. However, the first step to avoid insulin resistance should be an attempt to reduce body weight and to increase physical activity. These are successful means to avoid the development of type 2 diabetes from prediabetic states, as shown recently in 3 independent intervention trials.
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PMID:[From obesity to diabetes]. 1223 30

Obesity is associated with the increased risk of cardiovascular disease; however, mechanisms responsible for such an increase are not fully understood. IL-8 is a cytokine that might have atherogenic properties. Recent in vitro studies revealed that IL-8 is produced and secreted by human adipocytes. The aim of the present study was to evaluate plasma IL-8 concentrations in obese subjects and the relationships between circulating IL-8 and anthropometric and biochemical parameters and TNF-alpha system. A total of 75 subjects with normal glucose tolerance, 35 lean and 40 obese, were recruited for this study. Plasma IL-8 levels were measured in fasting state, after an oral glucose tolerance test and after the euglycemic hyperinsulinemic clamp. A significant increase in plasma IL-8 was observed in the obese group. In simple regression analysis, performed for the initial evaluation of relationships, plasma IL-8 was related to body mass index, percentage of body fat, fat mass (FM), and soluble TNF-alpha receptor 2 (sTNFR2) in both groups and with waist-to-hip ratio and sTNFR1 in the obese. In multiple regression analysis, FM, waist-to-hip ratio, gender, sTNFR2, and low density lipoprotein cholesterol were responsible for 44% of IL-8 variability. During oral glucose tolerance testing, mean plasma IL-8 concentrations increased in both groups, whereas clamp resulted in a significant increase in plasma IL-8 only in the obese. We conclude that plasma IL-8 levels are increased in obese subjects, and are related to FM and TNF-alpha system. Increase in circulating IL-8 might be one of the factors linking obesity with greater cardiovascular risk.
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PMID:Plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-alpha system. 1236 41

Abnormalities in coagulation and haemostasis represent a well-known link between obesity and thrombosis (both arterial and venous). Several studies have shown that obese patients have higher plasma concentrations of all pro-thrombotic factors (fibrinogen, vonWillebrand factor (vWF), and factor VII), as compared to non-obese controls, with a positive association with central fat. Similarly, plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be higher in obese patients as compared to non-obese controls and to be directly correlated with visceral fat. Furthermore, obesity is characterized by higher plasma concentrations of anti-thrombotic factors, such as tissue-type plasminogen activator (t-PA) and protein C, as compared to non-obese controls, the increase in these factors being likely to represent a protective response partly counteracting the increase in pro-thrombotic factors. The issue of whether adipose tissue contributes directly to plasma PAI-1, its products stimulating other cells to produce PAI-1, or whether it primarily contributes indirectly has not yet been resolved. It has been proposed that the secretion of interleukin-6 (IL-6) by adipose tissue, combined with the actions of adipose tissue-expressed TNF-alpha in obesity, could underlie the association of insulin resistance with endothelial dysfunction, coagulopathy, and coronary heart disease. The role of leptin in impairing haemostasis and promoting thrombosis has been recently reported. Finally, some hormonal abnormalities (androgen, F, catecholamines) associated with the accumulation of body fat may contribute to the impairment of coagulative pathway in obesity. As to intervention strategies, dietary (i.e., low-fat high-fiber diet) and lifestyle (i.e., physical activity) measures have been demonstrated to be effective in improving the obesity-associated pro-thrombotic risk profile.
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PMID:Coagulation and fibrinolysis abnormalities in obesity. 1250 53

Aging is associated with low-grade increases in circulating levels of TNF-alpha and IL-6. A wide range of factors, including smoking, obesity, infections, the decline in sex hormones, and the genotype, induce and modify this age-related inflammatory activity, which on the other hand may cause age-related pathology. Several classical risk factors are indeed controlled by TNF-alpha and IL-6. TNF-alpha induces insulin resistance and endothelial dysfunction, IL-6 promotes procoagulant changes and both cytokines cause dyslipidaemia. Moreover, systemic low-grade elevations in both cytokines have been related to cardiovascular diseases and TNF-alpha has been associated with Alzheimer's disease and type 2 diabetes mellitus. TNF-alpha and IL-6 are also differently and independently of each other associated with mortality in elderly populations, indicating points of distinction in the biological effects of the two cytokines. Moreover, the association between cytokines and mortality is independent of co-morbidity, suggesting that low-grade increases in circulating cytokines are strong, independent risk factors of morbidity and mortality in old populations, although life style factors and co-morbidity may modulate levels.
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PMID:Effects of tumor necrosis factor-alpha and interleukin-6 in elderly populations. 1251 24

Aging is associated with chronic low-grade increases in circulating levels of inflammatory markers. A wide range of environmental factors, including smoking, infections, and obesity, genetic factors, and the declining function of sex hormones may contribute to systemic low-grade inflammatory activity in older individuals. Age-associated disease may exacerbate this phenomenon. The multifunctional cytokines TNF-alpha and IL-6 have been associated with morbidity and mortality in the elderly. Evidence supports the direct role of TNF-alpha in the pathogeneses of atherosclerosis, type 2 DM, and AD in older individuals. Age-related increases in systemic levels of TNF-alpha could provide a unifying basis for these disorders. Furthermore, TNF-alpha induces a catabolic state that causes frailty. Circulating levels of IL-6 seem to be a strong risk factor for frailty in the elderly, which could reflect its association with increased production of TNF-alpha. IL-6 also may be a risk factor for thromboembolic complications. In healthy, elderly populations, high circulating levels of TNF-alpha and IL-6 predict mortality, independent of comorbidity, indicating that TNF-alpha and IL-6 cause morbidity and mortality. In cohorts of frail, older individuals, TNF-alpha and IL-6 also act as disease markers. Circulating levels of TNF-alpha seem to be the best predictor of mortality in frail, elderly populations with a high mortality rate, whereas IL-6 seems to be the strongest risk marker in healthy, elderly populations. This finding could reflect that in relatively healthy old populations the increase in circulating levels of IL-6 represent a systemic response to local proinflammatory activities; however, when age-related inflammatory diseases progress, levels of TNF-alpha increase in the circulation and become gradually a stronger risk marker than IL-6. In conclusion low-grade elevations in levels of circulating cytokines are strong independent risk factors of morbidity and mortality in the elderly, and lifestyle factors and comorbidities may modulate these levels. Exercise and dietary interventions may be possible strategies to decrease inflammatory activity and improve the health status of the elderly.
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PMID:Age-related inflammatory cytokines and disease. 1264 76

Previous linkage and association studies have suggested that a region of human chromosome 6 containing the tumor necrosis factor (TNF)-alpha gene is involved in the pathogenesis of obesity and obesity-associated hypertension. The aim of the present investigation was to establish whether a segment of rat chromosome 20 (RNO20), which also contains the TNF-alpha gene, determines diet-induced changes in adiposity and blood pressure (BP). The results showed that a transfer of the RNO20 segment from the normotensive Brown Norway (BN) rat onto the background of the spontaneously hypertensive rat (SHR) is associated with a significantly greater increase in adiposity, glucose intolerance, circulating leptin levels, and BP during 12-week, high-fat-diet feeding. In contrast, the transfer is not associated with significant changes in these variables during 12-week, normal-diet feeding. In addition, sequencing of the TNF-alpha gene revealed differences between SHR and BN in the 5'- and 3'-regulatory regions of the gene. Subsequent analyses of TNF-alpha gene expression in fat, muscle, and liver, however, did not provide support for the functional involvement of these differences. In summary, the investigated RNO20 segment contains 1 or more gene variants that affect adiposity, glucose tolerance, serum leptin levels, and BP, but only when the animals are exposed to a particular environment, ie, high-fat-diet feeding. Further studies are needed to identify genes mediating these effects. Considering current changes in our lifestyle involving an increased calorie and fat intake, we believe that gene-environment interactions, such as those described here, play an important role in the current epidemic of obesity and obesity-associated hypertension.
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PMID:Segment of rat chromosome 20 regulates diet-induced augmentations in adiposity, glucose intolerance, and blood pressure. 1265 11


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