Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that tumor necrosis factor (TNF)-alpha production from adipose tissue is elevated in rodent and human obesity and plays an important role in insulin resistance in experimental animal models. In this study, we examined the adipose expression of both TNF receptors (TNFR1 and TNFR2) in human obesity and demonstrated that obese female subjects express approximately twofold more TNFR2 mRNA in fat tissue and approximately sixfold more soluble TNFR2 in circulation relative to lean control subjects. In contrast, TNFR1 expression and protein levels were similar in these subjects. TNFR2 expression levels in adipose tissue were strongly correlated with BMI (r = 0.65, P < 0.001) and level of hyperinsulinemia (P < 0.001), an indirect measure of insulin resistance, as well as level of TNF-alpha mRNA expression in fat tissue (r = 0.56, P < 0.001). These results suggest that TNFR2 might play a role in human obesity by modulating the actions of TNF-alpha.
 ...
PMID:Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance. 903 2

Tumor necrosis factor-alpha (TNFalpha) and its soluble receptor 2 (TNFR2) are expressed in adipose tissue and are possibly involved in the pathogenesis of insulin resistance. Information about serum levels of TNFR2 in human obesity, especially the possible role of genetic factors and body fat distribution, is scanty. We measured serum TNFalpha and soluble TNFR2 concentrations in 23 identical twin pairs who had an average 18-kg intrapair difference in body weight. The mean TNFalpha concentration was 44.1 ng/L in obese and 34.2 ng/L in lean cotwins (P = 0.051). The respective values for TNFR2 were 1,989 and 1,840 ng/L (P = 0.004). The intrapair difference in TNFR2 level correlated positively (r-value always > or = 0.56; P < or = 0.01) with intrapair differences in body mass index, percent body fat, and abdominal sc fat area (assessed by magnetic resonance imaging), but not with differences in visceral fat area, glucose or insulin areas under the curve, or insulin sensitivity index in the oral glucose tolerance test. The intraclass correlation for TNFR2 was 0.67, and the genetic variation in circulating TNFR2 level was almost 6-fold higher than the variation due to obesity. We conclude that the soluble TNFR2 concentration is determined by both genetic factors and adiposity, especially sc fat. Measurement of circulating TNFR2 does not seem to be useful in identifying obese individuals who are insulin resistant.
 ...
PMID:Serum soluble tumor necrosis factor-alpha receptor 2 is elevated in obesity but is not related to insulin sensitivity: a study in identical twins discordant for obesity. 1094 72

The tumor necrosis factor system plays an important role in the pathogenesis of obesity and type 2 diabetes (DM), by a complex and only partially understood mechanism. In this study we analyze the mRNA expression levels of TNFalpha and its receptors (TNFR1 and TNFR2), in peripheral blood mononuclear cells (PBMC) from eleven, non-morbid, obese and 14, obese, type 2 DM women, by real-time quantitative PCR. We show an increase in the TNFR2 to TNFR1 ratio (mTNFR2/mTNFR1) in type 2 DM (r = 0.63; p = 0.021, after adjusting for age). Likewise, a positive correlation between mTNFR2/mTNFR1 and glucose was observed (r = 0.5; p = 0.029) in the whole group. We performed an oral glucose tolerance test with 75 g of glucose in obese, non-diabetic women in order to evaluate the effect of an acute glucose increase on the tumor necrosis factor system at 60 min and 120 min. We show that except for a positive association of mTNFR1 with body mass index at 60 min and of mTNFR2 with plasmatic triglycerids levels, no other significant differences were elicited by acute glucose in obese, non-diabetic women. These findings are in agreement with a functional role for the TNF system in obese women in obesity-linked, type 2 diabetes.
 ...
PMID:High expression of tumor necrosis factor alpha receptors in peripheral blood mononuclear cells of obese type 2 diabetic women. 1521 54

The gene encoding the human TNF alpha receptor (TNFR) 2 contains polymorphisms in the 3' untranslated region (UTR). Previous studies have shown that some variant alleles in this region are associated with obesity and insulin resistance. However, the effect of these polymorphisms on the expression of TNFR2 has not been studied to date. To examine the role played by different haplotypes in the control of TNFR2 expression (haplotypes A1-A5, referring to nucleotides 1663 G/A, 1668 T/G, and 1690 T/C), we introduced these sequences into the 3'-UTR of a heterologous reporter gene and expressed the corresponding constructs in a human T-cell line. We demonstrate that a 485-nt fragment of the TNFR2 3'-UTR that contains a U-rich region decreases reporter expression and that haplotypes A1-A4 exert a stronger effect than A5. Furthermore, time-course assays of mRNA stability using actinomycin D revealed that haplotypes A1-A4 destabilize the mRNA. The proximal TNFR2 3'-UTR, independently of haplotype differences, responded to T-cell activation by increasing mRNA decay. Electromobility shift analysis demonstrated that protein(s) found in T-cell extracts bind to the 485-nt fragment. We suggest that an increased rate of TNFR2 mRNA decay protects cells from unrestrained TNF alpha effects and that this protection is weakened in A5 subjects. These findings may explain the association of this haplotype with obesity and increased leptin levels.
 ...
PMID:A polymorphism in the 3' untranslated region of the gene for tumor necrosis factor receptor 2 modulates reporter gene expression. 1567 60

TWEAK, a cytokine of the TNF family, has been found to be expressed under different inflammatory conditions but no data is available concerning the expression of this cytokine and its receptor (Fn14) in human obesity. In the present work we have evaluated the expression of many pro-inflammatory TNF system cytokines (TNF-alpha, TWEAK and their respective receptors, TNFR1, TNFR2 and Fn14) in human adipose tissue of 84 subjects some with different degree of obesity and type 2 diabetes, and its relation with inflammation by also measuring the expression of macrophage marker CD68. We detected expression of TWEAK and Fn14 in isolated mature adipocytes and in the stromovascular fraction. Additionally, we found that LPS upregulates the expression of both genes on THP-1 human monocytic cell line. TWEAK was expressed in adipose tissue of all studied subjects with no differences between obesity group, and was associated with Fn14 expression in morbid obese, mainly in women with type 2 diabetes. The data obtained here also showed that TNF-alpha and TNFR2 mRNAs were significantly more expressed in subcutaneous adipose tissue of subjects with morbid obesity compared to obese and non-obese subjects. In contrast, TNFR1 gene expression was negatively associated with BMI. Our results suggest that the expression of TNF-derived pro-inflammatory cytokines are increased in severe obesity, where macrophage infiltrate could modulate the inflammatory environment through activation of its receptors.
 ...
PMID:Expression of TWEAK and its receptor Fn14 in human subcutaneous adipose tissue. Relationship with other inflammatory cytokines in obesity. 1650 47

Tumour necrosis factor (TNF)alpha is implicated in the relationship between obesity and insulin resistance/ type 2 diabetes. In an effort to understand this association better we (i) profiled gene expression patterns of TNF, TNFR1 and TNFR2 and (ii) investigated the effects of TNF on glucose uptake in isolated adipocytes and adipose tissue explants from omental and subcutaneous depots from lean, overweight and obese individuals. TNF expression correlated with expression of TNFR2, but not TNFR1, and TNF and TNFR2 expression increased in obesity. TNFR1 expression was higher in omental than in subcutaneous adipocytes. Expression levels of TNF or either receptor did not differ between adipocytes from individuals with central and peripheral obesity. TNF only suppressed glucose uptake in insulin-stimulated subcutaneous tissue and this suppression was only observed in tissue from lean subjects. These data support a relationship between the TNF system and body mass index (BMI), but not fat distribution, and suggest depot specificity of the TNF effect on glucose uptake. Furthermore, adipose tissue from obese subjects already appears insulin 'resistant' and this may be a result of the increased TNF levels.
 ...
PMID:TNF and TNF receptor expression and insulin sensitivity in human omental and subcutaneous adipose tissue--influence of BMI and adipose distribution. 1678 78

In a previous study, we identified a biologically active form of tumor necrosis factor-alpha receptor 2 (sTNFR2) produced by differential splicing (DS-TNFR2) which antagonized TNF-alpha biological activity. Obesity, insulin resistance and type 2 diabetes are linked to increased TNF-alpha action. We hypothesized that subjects with detectable DS-TNFR2 would be protected from developing obesity and related metabolic disorders. Thus, we investigated if circulating DS-TNFR2 concentration was associated with components of the so-called metabolic syndrome among 269 consecutive subjects from the general population. DS-TNFR2 was measured using a monoclonal antibody against an epitope present in TNFR2 (first 14 residues of the juxtamembrane region) but predicted to be absent in soluble proteolytic cleavage-produced TNFR2. Plasma DS-TNFR2 concentration was significantly decreased among patients with glucose intolerance or type 2 diabetes mellitus (p=0.026). DS-TNFR2 tended to be associated with fasting and post-load glucose (both r=-0.11, p=0.054), and with diastolic blood pressure in men (r=-0.16, p=0.07). Serum DS-TNFR2 concentration was significantly associated with LDL cholesterol (r=-0.28, p=0.002), uric acid (r=-0.13, p=0.04) and with blood glycated hemoglobin (r=-0.13, p=0.04). DS-TNFR2 declined with increased number of components of the metabolic syndrome (p=0.03). Those subjects with 2 or more components had significantly decreased circulating DS-TNFR2 levels (0.96+/-2.2 versus 1.7+/-3.2, p=0.033). In summary, the circulating concentration of DS-TNFR2 seems to be inversely linked to metabolic disorders, hinting at a possible anti-inflammatory role.
 ...
PMID:An alternatively spliced soluble TNF-alpha receptor is associated with metabolic disorders: a replication study. 1697 82

The aim of this study was to analyze LPIN1 adipose tissue gene expression levels in 3 clinical insulin-resistant conditions-obesity, type 2 diabetes mellitus, and human immunodeficiency virus (HIV)-associated lipodystrophy-and its relationship with adipogenic and inflammatory markers. Subcutaneous adipose tissue samples were obtained from 2 cohorts: 98 subjects with different degrees of adiposity and with or without the presence of type 2 diabetes mellitus and 37 HIV-infected patients. Real-time polymerase chain reaction was used to measure gene expression of LPIN1 and adipogenic (PPARgamma, SREBP1c) and inflammatory markers (IL6, TNFalpha, TNFR1, and TNFR2). LPIN1 messenger RNA expression levels were significantly lower in the obese group (P = .002), were similar in type 2 diabetes mellitus patients and control subjects (P = .211), and were significantly higher in HIV-infected patients (P < .001). LPIN1 messenger RNA levels positively correlated with insulin sensitivity in all subjects. Moreover, an inverse correlation with proinflammatory cytokines was observed.
 ...
PMID:Human subcutaneous adipose tissue LPIN1 expression in obesity, type 2 diabetes mellitus, and human immunodeficiency virus--associated lipodystrophy syndrome. 1795 Jan 3

Obesity with insulin resistance and alcohol are the most frequent causes of steatohepatitis. This work investigates the contribution of bioactive TNF and Th1 type cytokines in a mouse model of steatohepatitis induced by FAT alone or FAT+EtOH and endotoxin. The extent of liver injury and cytokine activation induced by endotoxin in chronic FAT-fed mice, FAT+EtOH-fed mice, or mice fed standard chow were analyzed. Endotoxin administration to either FAT-fed or FAT+EtOH-fed mice increased serum ALT and AST compared to standard chow mice. Immunoreactive TNF was strongly activated by LPS in FAT-fed and FAT+EtOH-fed mice which presented the highest levels, but low levels were found in standard chow mice. In contrast, bioactive TNF was only present in serum of FAT-fed and in particular the highest levels were found in FAT+EtOH-fed mice. Moreover, soluble TNFR2 but not TNFR1 was found in lower amounts in serum of FAT+EtOH-fed mice compared to FAT-fed mice. Steatohepatitis was associated with increased IL-6, IFN-gamma, and iNOS mRNA and proteins. Data show that a moderately FAT diet and low-dose EtOH concur to generate steatohepatitis and TNF liver expression after LPS. In this model, changes in the regulation of TNF are associated with increased expression of IL-6, IFN-gamma, and iNOS.
 ...
PMID:Fat diet and alcohol-induced steatohepatitis after LPS challenge in mice: role of bioactive TNF and Th1 type cytokines. 1872 87

TNF-alpha signals through two receptors, TNFR1 and TNFR2. Our goals were: 1) determine the role of TNFRs in obesity and metabolic disease and 2) investigate whether TNFRs contribute to the link between obesity and adipose tissue macrophage infiltration and polarization. R1(-/-)R2(-/-) (RKO) and wild-type (WT) mice were fed standard chow or a high-fat/high-sucrose diet (HFHS) over 14 wk. Body composition, food intake, and energy expenditure were measured. Oral glucose tolerance and insulin sensitivity tests assessed glucose homeostasis. Adipose tissue and systemic inflammatory status were evaluated by quantifying plasma adipokine levels and macrophage-specific gene expression in fat. RKO mice were heavier (10%) and fatter (18%) than WT controls at 4 wk of age and were 26% heavier and 50% fatter than WT after 14 wk of HFHS diet feeding. Age- and diet-adjusted 24-h oxygen consumption, activity, and respiratory exchange ratio were significantly reduced in RKO mice. Obese RKO mice were markedly insulin resistant, suggesting that intact TNFR signaling is not required for the effect of obesity to impair glucose metabolism. Adipose tissue from HFHS-fed RKO mice exhibited increased macrophage infiltration, but compared with WT mice, macrophage phenotypic markers featured a predominance of antiinflammatory M2 over proinflammatory M1 cells. TNFRs play a physiological role to limit body weight and adiposity by modestly increasing metabolic rate and fatty acid oxidation, and they are required for obesity-induced activation of adipose tissue macrophages. Despite these effects, TNFRs are not required for obesity-induced insulin resistance.
 ...
PMID:Receptors for tumor necrosis factor-alpha play a protective role against obesity and alter adipose tissue macrophage status. 1947 37


1 2 Next >>