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)

In adipose tissue from both obese mice and humans, plasminogen activator inhibitor 1 (PAI-1) expression has been reported to be upregulated to levels of increased plasma PAI-1. This elevated expression has been shown to be partly controlled by tumor necrosis factor (TNF)-alpha in mice. In humans, increased PAI-1 expression is associated with insulin resistance characterized by visceral fat accumulation. Therefore, the aim of this study was to investigate the expression pattern of PAI-1 and TNF-alpha (antigen and mRNA) in visceral human adipose fat in comparison with subcutaneous (SC) fat. Because transforming growth factor (TGF)-beta1 is a potent inducer of PAI-1 synthesis and has been shown to influence adipocyte metabolism, this work was extended to TGF-beta1 quantification. A total of 32 obese individuals (BMI 42 +/- 6.8 kg/m2) were investigated. Freshly collected visceral adipose tissue did not exhibit a higher content of PAI-1 or TGF-beta1 than did SC tissue. Although most of the TNF-alpha values were at the detection limit of the methods, TNF-alpha antigen was 3-fold higher and TNF-alpha mRNA was 1.2-fold higher in visceral fat. The levels of tissue TGF-beta1 antigen correlated well with those of PAI-1 antigen, regardless of the fat depot studied (SC tissue: n = 21, r = 0.72, P = 0.0006; visceral tissue: n = 20, r = 0.49, P < 0.03), and they were both significantly associated with BMI. Conversely, no relationship was observed between the levels of TNF-alpha and PAI-1 or TNF-alpha and BMI. Tissue PAI-1 levels were also significantly correlated with those of circulating PAI-1. These results describe, in severe obesity, a proportional increase in tissue PAI-1 and TGF-beta1 in visceral and SC tissues. This increased PAI-1 expression could be the result of tissue cytokine disturbances, such as elevated TGF-beta1 expression.
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PMID:Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity. 1092 40

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

To investigate the effect of oral nicotine administration on insulin resistance and insulin secretion in an animal model of obesity, Zucker fatty rats were administered nicotine tartrate dihydrate orally through tap water (4.6 mg/kg/d, N group). Plasma nicotine concentrations in N group were 33.67 +/- 10.49 ng/mL. The control (C) group consisted of pair-fed control rats. After 8 weeks of nicotine administration, both groups of rats were administered glucose (2 g/kg) orally in an anesthetized state, and blood was collected for glucose and plasma insulin measurements. The pancreases were isolated and perfused in vitro under pentobarbital anesthesia 1 week after glucose administration. The fat tissues were excised. The levels of tumor necrosis factor (TNF)-alpha protein were assessed using enzyme-linked immunosorbent assay (ELISA) or Western blot analysis. Serum leptin levels were measured using radioimmunoassay (RIA). Blood glucose levels in N group were significantly lower than in C group before and 120 minutes after glucose administration. The insulin secretion from the isolated perfused pancreases of N group appeared to be decreased compared with C group, but there was no significant difference. Histologic examination showed that the mean size of the pancreatic islets in N group was significantly smaller than in C group. The composition ratios of alpha and beta cell mass of the pancreatic islets and fibroelastic tissues were not altered by nicotine administration. Portal TNF-alpha levels were comparable to peripheral levels in both groups. There were no significant differences in peripheral serum levels of TNF-alpha, free fatty acids (FFA), or leptin levels between N and C group. The TNF-alpha levels in visceral fat tissues in N group were significantly lower than those in C group. These results suggest that oral nicotine administration reduces insulin resistance in obese diabetic rats by decreasing production of TNF-alpha in the visceral fat tissues. Decreased islet size may be a secondary phenomenon induced by ameliorated insulin resistance, because the cellularity and fibroelastic tissues were not affected by the nicotine.
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PMID:Oral nicotine administration decreases tumor necrosis factor-alpha expression in fat tissues in obese rats. 1117 79

Fatty acids, obesity and insulin resistance relationship are discussed. In the last decades fatty acids (FA) have been implicated in the etiology of insulin resistance. Initially, this process was related to FA inhibitory effects on glucose uptake mediated by the FA oxidation metabolites. This mechanism known as the Randle cycle has been presently discarded based on recent evidence for FA effects on glucose metabolism. Now is known that cytosolic lipid content and FA molecular structure determines higher or lower storage and oxidation capacity. Another factor is given by Tumor Necrosis Factor-alpha, which is overexpressed in animal and human obesity, producing insulin signaling and glucose uptake inhibition. This paper discuss the role played by FA and obesity on insulin resistance, mainly in relation to FA effects on glucose metabolism in the liver, muscle and adipose tissues. In the obesity condition adipose tissue releases higher levels of free FA which in turn stimulates hepatic glucose production. Adipose tissue also, increase TNF-alpha secretion impairing glucose utilization and insulin signaling. In muscle, cytosolic lipid content activate a Protein Kinase that inhibits the insulin signaling and reduce GLUT-4 translocation. The study of cellular and metabolic changes associated to weight gain and its relationship with insulin resistance etiology are encouraged.
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PMID:[Obesity and fatty acids in the etiology of insulin resistance]. 1122 45

The preferential channeling of different fuels to fat and changes in the transcription profile of adipose tissue and skeletal muscle are poorly understood processes involved in the pathogenesis of obesity and insulin resistance. Carbohydrate and lipid metabolism may play relevant roles in this context. Freely moving lean Zucker rats received 3- and 24-h infusions of Intralipid (Pharmacia and Upjohn, Milan, Italy) plus heparin, or saline plus heparin, to evaluate how an increase in free fatty acids (nonesterified fatty acid [NEFA]) modulates fat tissue and skeletal muscle gene expression and thus influences fuel partitioning. Glucose uptake was determined in various tissues at the end of the infusion period by means of the 2-deoxy-[1-3H]-D-glucose technique after a euglycemic-hyperinsulinemic clamp: high NEFA levels markedly decreased insulin-mediated glucose uptake in red fiber-type muscles but enhanced glucose utilization in visceral fat. Using reverse transcriptase-polymerase chain reaction and Northern blotting analyses, the mRNA expression of fatty acid translocase (FAT)/CD36, GLUT4, tumor necrosis factor (TNF)-alpha, peroxisome proliferator-activated receptor (PPAR)-gamma, leptin, uncoupling protein (UCP)-2, and UCP-3 was investigated in different fat depots and skeletal muscles before and after the study infusions. GLUT4 mRNA levels significantly decreased (by approximately 25%) in red fiber-type muscle (soleus) and increased (by approximately 45%) in visceral adipose tissue. Furthermore, there were marked increases in FAT/CD36, TNF-alpha, PPAR-gamma, leptin, UCP2, and UCP3 mRNA levels in the visceral fat and muscle of the treated animals in comparison with those measured in the saline-treated animals. These data suggest that the in vivo gene expression of FAT/CD36, GLUT4, TNF-alpha, PPAR-gamma, leptin, UCP2, and UCP3 in visceral fat and red fiber-type muscle are differently regulated by circulating lipids and that selective insulin resistance seems to favor, at least in part, a prevention of fat accumulation in tissues not primarily destined for fat storage, thus contributing to increased adiposity and the development of a prediabetic syndrome.
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PMID:Preferential channeling of energy fuels toward fat rather than muscle during high free fatty acid availability in rats. 1124 80

Tumor necrosis factor (TNF)-alpha is one of the candidate mediators of insulin resistance associated with obesity, a major risk factor for the development of type 2 diabetes. The insulin resistance induced by TNF-alpha is antagonized by thiazolidinediones (TZDs), a new class of insulin-sensitizing drugs. The aim of the current study was to dissect the mechanism whereby pioglitazone, one of the TZDs, ameliorates TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes. Pioglitazone restored insulin-stimulated 2-deoxyglucose (DOG) uptake, which was reduced by TNF-alpha, with concomitant restorations in tyrosine phosphorylation and protein levels of insulin receptor (IR) and insulin receptor substrate (IRS)-1, as well as association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 and PI 3-kinase activity. Adenovirus-mediated gene transfer of either wild-type human peroxisome proliferator-activated receptor (PPAR)-gamma2 or a mutant carrying a replacement at the consensus mitogen-activated protein kinase phosphorylation site (hPPAR-gamma2-S112A) promoted adipogenesis of 3T3-L1 fibroblasts and restored TNF-alpha-induced decrease of triglyceride in adipocytes as effectively as pioglitazone. Overexpression of the PPAR-gamma proteins in TNF-alpha-treated adipocytes restored protein levels of IR/IRS-1, but did not improve insulin-stimulated tyrosine phosphorylation of IR/IRS-1 or insulin-stimulated 2-DOG uptake. These results indicate that the ability of pioglitazone to restore insulin-stimulated tyrosine phosphorylation of IR/IRS-1, which is necessary for amelioration of TNF-alpha-induced insulin resistance, may be independent of the adipogenic activity of PPAR-gamma that regulates protein levels of IR/IRS-1.
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PMID:Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator--activated receptor-gamma. 1133 12

Growth hormone (GH) has an inhibitory effect on adipogenesis, and its effect is associated with insulin action in obesity. In this study, the relationship between GH effect on insulin sensitivity and adipocyte differentiation in vivo was investigated. Transgenic (TG) female mice expressing porcine GH had reduced body weights and weights of retroperitoneal and parametrial fat depots. Insulin treatment increased PPARgamma and GLUT4 expression in adipose tissue of WT mice but had no effect in TG mice. Content of transcription factors, PPARgamma and C/EBPalpha and beta, was higher in adipose tissue of WT mice, and for C/EBPalpha and PPARgamma, the difference occurred primarily in 24-, compared to 12-week-old, mice. Expression of preadipocyte factor-1 was higher in adipose tissue of TG mice, and expression of TNF-alpha and leptin was reduced in adipose tissue of 24-week-old TG mice. Our results suggest that increased expression of GH reduces adipogenesis by inducing adipocyte resistance to the adipogenic effect of insulin.
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PMID:Adipocyte insensitivity to insulin in growth hormone-transgenic mice. 1135 75

Adipose tissue is not only a passive storage organ for excessed energy intake, it is also able to produce and release several substances with local (autocrine) and systemic (endocrine) actions. An up-to-date review of our knowledge in this area is given here. Several of the compounds deriving from adipose tissue have been shown to play a role in obesity-related health complications. The production of cytokines (TNF-alpha, IL-6, IL-8) is implicated in the development of insulin resistance and atherosclerosis. All elements in the renin-angiotensin system are produced in adipose tissue, which is thus related to hypertension. The production of PAI-1 could be related to enhanced thrombogenesis. The release of the compounds described is generally higher from adipocytes in the visceral depot, which could explain the close association between this depot and health complications.
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PMID:[Fatty tissue as a secretory organ. Significance for obesity-related diseases]. 1140 68

To evaluate the role of TNF-alpha in the pathogenesis of hyperandrogenism, we have evaluated the serum TNF-alpha levels, as well as several polymorphisms in the promoter region of the TNF-alpha gene, in a group of 60 hyperandrogenic patients and 27 healthy controls matched for body mass index. Hyperandrogenic patients presented with mildly increased serum TNF-alpha levels as compared with controls (mean[median] +/- SD: 7.2[7.0] +/- 3.3 pg/ml vs. 5.6[4.4] +/- 4.0 pg/ml, P < 0.02). Although no differences in body mass index and insulin resistance indexes were observed between patients and controls, when subjects were classified by body weight, serum TNF-alpha was increased only in lean patients as compared with lean controls, but this difference was not statistically significant when comparing obese patients with obese controls. The TNF-alpha gene polymorphisms studied here (-1196C/T, -1125G/C, -1031T/C, -863C/A, -857C/T, -316G/A, -308G/A, -238G/A, and -163G/A) were equally distributed in hyperandrogenic patients and controls. However, carriers of the -308A variant presented with increased basal and leuprolide-stimulated serum androgens and 17-hydroxyprogesterone levels when considering patients and controls as a group. No differences were observed in serum TNF-alpha levels, body mass index, and insulin resistance indexes, depending on the presence or absence of these variants. In conclusion, our present results suggest that the TNF-alpha system might contribute to the pathogenesis of hyperandrogenism, independent of obesity and insulin resistance. However, elucidation of the precise mechanisms underlying the relationship between the TNF-alpha system and androgen excess is needed before considering TNF-alpha as a significant contributing factor to the development of hyperandrogenism.
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PMID:TNF-alpha and hyperandrogenism: a clinical, biochemical, and molecular genetic study. 1150 8

Leptin is capable of modulating the immune response. Proinflammatory cytokines induce leptin production, and we now demonstrate that leptin can directly activate the inflammatory response. RNA expression for the leptin receptor (Ob-R) was detectable in human PBMCs. Ob-R expression was examined at the protein level by whole blood flow cytometry using an anti-human Ob-R mAb 9F8. The percentage of cells expressing leptin receptor was 25 +/- 5% for monocytes, 12 +/- 4% for neutrophils, and 5 +/- 1% for lymphocytes (only B lymphocytes). Incubation of resting PBMCs with leptin induced rapid expression of TNF-alpha and IL-6 mRNA and a dose-dependent production of TNF-alpha and IL-6 by monocytes. Incubation of resting PBMCs with high-dose leptin (250 ng/ml, 3-5 days) induced proliferation of resting cultured PBMCs and their secretion of TNF-alpha (5-fold), IL-6 (19-fold), and IFN-gamma (2.5-fold), but had no effect on IL-4 secretion. The effect of leptin was distinct from, and additive to, that seen after exposure to endotoxin or activation by the mixed lymphocyte reaction. In conclusion, Ob-R is expressed on human circulating leukocytes, predominantly on monocytes. At high doses, leptin induces proinflammatory cytokine production by resting human PBMCs and augments the release of these cytokines from activated PBMCs in a pattern compatible with the induction of Th1 cytokines. These results demonstrate that leptin has a direct effect on the generation of an inflammatory response. This is of relevance when considering leptin therapy and may partly explain the relationship among leptin, proinflammatory cytokines, insulin resistance, and obesity.
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PMID:High-dose leptin activates human leukocytes via receptor expression on monocytes. 1159 88


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