Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Intercellular adhesion molecule-1 (ICAM-1) is 1 of the possible factors linking obesity and diabetes with cardiovascular disease, however, the mechanism of the increase in ICAM-1 concentration in obesity remains unclear. Therefore, the aim of the present study was to assess plasma soluble ICAM-1 (sICAM-1) levels in obese subjects with normal glucose tolerance and to evaluate whether those levels may be related to insulin resistance and tumor necrosis factor-alpha (TNFalpha) system activity. The study was performed in 8 lean and 15 obese subjects. Anthropometric and biochemical parameters were measured, and insulin sensitivity was evaluated using the euglycemic hyperinsulinemic clamp technique (insulin infusion, 50 mU x kg(-1) x h(-1)). Obese subjects were markedly more hyperinsulinemic and insulin resistant and had higher plasma soluble TNF receptor 2 (sTNFR2) and sICAM-1 levels. sICAM-1 was related positively to body mass index (BMI), waist-to-hip ratio (WHR), percent of body fat, glycated hemoglobin (HbA(1c)), plasma insulin and triglycerides (TG), TNFalpha, and sTNFR2 and negatively to insulin sensitivity. Multiple regression analysis showed that only sTNFR2 and insulin sensitivity were independent predictors of sICAM-1 concentrations and were responsible for 66% of sICAM-1 variability. We conclude that an increase in plasma sICAM-1 concentration in obesity is related to TNFalpha system activation and insulin resistance.
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PMID:Elevated soluble intercellular adhesion molecule-1 levels in obesity: relationship to insulin resistance and tumor necrosis factor-alpha system activity. 1178 76

Inflammatory cytokines such as TNF alpha may play a role in the pathogenesis of common metabolic disorders, including hyperandrogenism and the polycystic ovary syndrome (PCOS). The TNF receptor 2 mediates most of the metabolic effects of TNF alpha. In the present study, we have evaluated serum soluble TNF receptor 2 levels, and several common polymorphisms in the TNF receptor 2 gene (TNFRSF1B), in women presenting with PCOS or hyperandrogenic disorders. Initial studies included 103 hyperandrogenic patients (42 presenting with PCOS) and 36 controls from Spain. The 196R alleles of the M196R (676 T-->G) variant in exon 6 of TNFRSF1B, which is in linkage disequilibrium with a CA-repeat microsatellite polymorphism in intron 4 of TNFRSF1B, tended to be more frequent in hyperandrogenic patients than in controls (P = 0.056), reaching statistical significance when the analysis was restricted to include only PCOS patients (P < 0.03). Extended analysis including another 11 hyperandrogenic patients from Spain and 64 patients and 29 controls from Italy confirmed the association between 196R alleles of the M196R variant and hyperandrogenic disorders (P < 0.05), which was maintained when restricting the analysis to PCOS patients (P < 0.02). On the contrary, the 3'-untranslated region (exon 10) variants 1663 G-->A, 1668 T-->G, and 1690 T-->C were not associated with hyperandrogenism. The soluble TNF receptor 2 levels were not different between patients and controls but were increased in obese subjects, compared with lean individuals, and were affected by the interaction between the 1663 G-->A and 1668 T-->G variants in the 3'-untranslated region of TNFRSF1B. The TNFRSF1B genotype did not influence any clinical or biochemical variable related to hyperandrogenism or insulin sensitivity and was not associated with obesity, both in hyperandrogenic patients and healthy controls considered separately. In conclusion, the M196R (676 T-->G) variant in exon 6 of TNFRSF1B is associated with hyperandrogenism and PCOS, further suggesting a role for inflammatory cytokines in the pathogenesis of these disorders.
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PMID:Comment: the methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. 1216 45

It has been suggested that a low grade inflammatory state could predispose for developing insulin resistance and contribute to the development of obesity and type 2 diabetes. Corticosteroid-binding globulin (CBG), the main plasma protein transport for cortisol, has been shown to be negatively regulated by insulin and IL-6, at least in vitro, suggesting that insulin resistance and inflammation may both contribute to decreasing CBG levels. In the present study we measured CBG concentrations in a human healthy population and investigated the relationships of CBG with anthropometric and biochemical markers for inflammation and/or insulin resistance. The data showed that the mean serum CBG level was significantly lower in males (n = 151) than in females (n = 113; 32.5 +/- 9.1 vs. 39.2 +/- 13.9 mg/liter; P < 0.0001). In both sexes serum CBG levels were correlated negatively with age (r = -0.12; P = 0.04), body mass index (r = -0.31; P < 0.0001), waist to hip ratio (WHR; r = -0.39; P < 0.0001), systolic (r = -0.15; P < 0.01) and diastolic (r = -0.15; P = 0.01) blood pressures, and HOMA, an index of insulin resistance (r = -0.12; P = 0.04). In addition, the CBG concentration was negatively associated with serum IL-6 concentrations (r = -0.23; P = 0.017) and with the soluble fraction of TNFalpha receptors, soluble TNF receptor 1 (sTNFR1; r = -0.35; P < 0.0001), and sTNFR2 (r = -0.56; P < 0.0001) in women. A stepwise regression analysis using CBG as an independent variable showed that sex (P < 0.00001), body mass index (P = 0.0002), and HOMA (P = 0.0005), but not systolic blood pressure, diastolic blood pressure, IL-6, sTNFR1, or sTNFR2, constituted significant independent factors that explained 21% of the CBG variance (14%, 2%, and 5%, respectively). In a subsample of 120 men and 68 women, fasting serum free cortisol (calculated as the ratio fasting cortisol/CBG) was significantly associated with WHR (r = 0.24; P = 0.001), systolic (r = 0.18; P = 0.01) and diastolic (r = 0.19; P = 0.007) blood pressures, and HOMA value (r = 0.20; P = 0.005), but not with BMI or age. BMI (P < 0.0001), free cortisol (P = 0.003), and CBG (P = 0.009), but not WHR and age, contributed to 20%, 6%, and 8%, respectively, of HOMA variance in women in a multiple regression analysis. In this model only BMI (P < 0.0001) independently contributed to HOMA variance in men. These findings support the hypothesis that the CBG level is an interesting indicator for both insulin resistance and low grade inflammation. Whether the decrease in CBG levels is genetic by nature or directly associated to increased insulin and/or IL-6 merits further investigation. Nevertheless, because CBG has been shown to be expressed by the adipose tissue, decreased CBG could create locally increased cortisol disposal, with no change in circulating cortisol, and facilitate fat accumulation, insulin resistance, and type 2 diabetes.
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PMID:Serum corticosteroid-binding globulin concentration and insulin resistance syndrome: a population study. 1236 59

Adipose tissue expression of tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of obesity-linked insulin resistance and the dyslipoproteinemia of insulin resistance. This study has two aims: (1) to compare select inflammatory mediators in non-smoking, normoglycemic male subjects with and without the atherogenic dyslipoproteinemia (ADL), and (2) to determine the effects of statin therapy on select inflammatory mediators. ADL subjects had higher levels of insulin (16.7 +/- 7.5 versus 11.6 +/- 5.9 microIU/mL, P=0.008), soluble TNF receptor superfamily 1B (sTNFRSF1B) (3.3 +/- 0.7 versus 2.7 +/- 0.5 ng/mL, P=0.005), and interleukin-6 (IL-6) (2.6 +/- 2.2 versus 1.3 +/- 1.8 pg/mL, P=0.006) as compared to those of the non-ADL subjects. After adjustment for age, sTNFRSF1B (P=0.003) was more predictive of ADL than high-sensitivity C-reactive protein (hs-CRP) (P=0.047). Statin therapy did not change sTNFRSF1B, TNF-alpha, IL-6, hs-CRP, whereas soluble TNF receptor superfamily 1A (sTNFRSF1A) increased slightly (P=0.048). A high level of sTNFRSF1B is a strong marker of the pro-inflammatory state in this sample of male ADL subjects.
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PMID:Elevated soluble tumor necrosis factor receptor levels in non-obese adults with the atherogenic dyslipoproteinemia. 1548 68

Elevated plasma IL-18 is present in several conditions sharing insulin-resistance as common trait, but the association with insulin-resistance per se is not established. Plasma/serum IL-6, IL-18, TNF-alpha, soluble TNF receptor II (sTNFR2), and C-reactive protein (CRP) were measured in 97 patients with type 2 diabetes (DM) and 84 non-diabetic controls (CON). The association with insulin-resistance-estimated using the homeostasis model assessment (HOMA-IR)-was analyzed using multivariate linear and logistic regression. Compared to CON, DM demonstrated higher plasma levels of IL-18 (P = 0.001), IL-6 (P < 0.001), sTNFR2 (P = 0.005), and CRP (P < 0.001), while TNF-alpha was lower (P = 0.017). Plasma IL-18 increased across HOMA-IR quartiles in both DM and CON, both with and without adjustment for confounders (all P < 0.05). In contrast, neither IL-6, TNF-alpha, sTNFR2, nor CRP was associated with HOMA-IR in CON when adjusting for confounders. Accordingly, 50% increase of IL-18 corresponded to a marked increase of HOMA-IR in both DM and CON (DM: 26%, P = 0.014; CON: 25%, P = 0.003) after adjustment for confounders. Our results show that plasma IL-18 was associated with HOMA-IR independent of obesity and type 2 diabetes.
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PMID:Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans. 1611 17

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.
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PMID:An alternatively spliced soluble TNF-alpha receptor is associated with metabolic disorders: a replication study. 1697 82

Obesity is associated with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal production of proinflammatory cytokines such as TNF-alpha. Here we demonstrate that eNOS expression was reduced, with a concomitant reduction of mitochondrial biogenesis and function, in white and brown adipose tissue and in the soleus muscle of 3 different animal models of obesity. The genetic deletion of TNF receptor 1 in obese mice restored eNOS expression and mitochondrial biogenesis in fat and muscle; this was associated with less body weight gain than in obese wild-type controls. Furthermore, TNF-alpha downregulated eNOS expression and mitochondrial biogenesis in cultured white and brown adipocytes and muscle satellite cells of mice. The NO donors DETA-NO and SNAP prevented the reduction of mitochondrial biogenesis observed with TNF-alpha. Our findings demonstrate that TNF-alpha impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiological process that sustains obesity.
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PMID:TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. 1698 Oct 10

It is recognized that the path from physical inactivity and obesity to lifestyle-related diseases involves low-grade inflammation, indicated by elevated plasma levels of inflammatory markers. Interestingly, contracting skeletal muscle is a major source of circulating interleukin-6 (IL-6) in response to acute exercise, but with a markedly lower response in trained subjects. As C-reactive protein (CRP) is induced by IL-6, we hypothesized that basal levels of IL-6 and CRP reflect the degree of regular physical activity when compared with other markers of inflammation associated with lifestyle-related morbidity. Fasting plasma/serum levels of IL-6, IL-18, CRP, tumur necrosis factor-alpha (TNF-alpha), soluble TNF receptor II (sTNF-RII), and adiponectin were measured in healthy non-diabetic men and women (n=84). The amount of leisure-time physical activity (LTPA) was assessed by interview. Obesity was associated with elevated insulin, C-peptide, triglycerides, low-density lipoprotein, IL-6, CRP, and adiponectin (all P<0.05). Importantly, physical inactivity was associated with elevated C-peptide (P=0.036), IL-6 (P=0.014), and CRP (P=0.007) independent of obesity, age, gender, and smoking. Furthermore, the LTPA score was inversely associated with IL-6 (P=0.017) and CRP (P=0.005), but with neither of the other markers. The results indicate that low levels of IL-6 and CRP - not IL-18, TNF-alpha, sTNF-RII, or adiponectin - reflect regular physical activity.
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PMID:Plasma levels of interleukin-6 and C-reactive protein are associated with physical inactivity independent of obesity. 1707 27

Elevated levels of tumor necrosis factor (TNFalpha) are implicated in the development of insulin resistance, but the mechanisms mediating these chronic effects are not completely understood. We demonstrate that TNFalpha signaling through TNF receptor (TNFR) 1 suppresses AMPK activity via transcriptional upregulation of protein phosphatase 2C (PP2C). This in turn reduces ACC phosphorylation, suppressing fatty-acid oxidation, increasing intramuscular diacylglycerol accumulation, and causing insulin resistance in skeletal muscle, effects observed both in vitro and in vivo. Importantly even at pathologically elevated levels of TNFalpha observed in obesity, the suppressive effects of TNFalpha on AMPK signaling are reversed in mice null for both TNFR1 and 2 or following treatment with a TNFalpha neutralizing antibody. Our data demonstrate that AMPK is an important TNFalpha signaling target and is a contributing factor to the suppression of fatty-acid oxidation and the development of lipid-induced insulin resistance in obesity.
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PMID:Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. 1714 30

The tumor necrosis factor (TNF) pathway may be implicated in etiopathogenesis of PAI-1 overexpression during obesity. The aim of this study was to investigate the influence of polymorphism A36G of the TNF receptor 1 (TNFRSF1A +36A/G) on plasma concentrations of PAI-1 in 163 obese (31 with the metabolic syndrome, MetS) and 150 lean, healthy women. Genotypic and allele frequencies did not significantly differ between obese and lean subjects. TNFRSF1A genotypes were significantly associated with sTNFR1 plasma levels in obese women only (p < 0.01); TNFRSF1A +36G/G obese carriers exhibited higher sTNFR1 and PAI-1 levels than A carriers (p < 0.01 and p < 0.05, respectively). In obese women, the presence of the MetS significantly potentiated the elevation of sTNFR1 and PAI-1 levels observed in the TNFRSF1A + 36G/G carriers. Our results suggest that association between TNFRSF1A +36G/G genotype and the MetS renders obese women more prone to activation of the TNF pathway reflected by high circulating sTNFR1 and PAI-1 levels.
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PMID:Polymorphism A36G of the tumor necrosis factor receptor 1 gene is associated with PAI-1 levels in obese women. 1720 Jul 72


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