Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P56851 (epididymal)
 11,273 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance is central to the pathogenesis of type 2 diabetes mellitus. Previous studies have demonstrated that compounds that cause adipogenesis and improve glucose uptake in 3T3-L1 cells are potential insulin sensitizers. Therefore, we evaluated one such compound, 18F9, for (1) adipogenesis in human subcutaneous preadipocyte (SQ) cells, (2) glucose uptake in human skeletal muscle myotubes and SQ cells, and (3) antidiabetic activity in db/db mice. We also investigated its effect on ex vivo glucose uptake in soleus muscle isolated from continuously treated db/db mice. Gene expression profiling in soleus muscle and epididymal fat of db/db mice was performed to understand its effect on glucose metabolism, lipid metabolism, and thermogenesis. 18F9 enhanced adipogenesis in SQ cells and increased glucose uptake in SQ and human skeletal muscle myotubes cells. In db/db mice, 18F9 exhibited dose-dependent reduction in plasma glucose and insulin level. Interestingly, 18F9 was as efficacious as rosiglitazone but did not cause body weight gain and hepatic adverse effects. In addition, 18F9 demonstrated no change in plasma volume in Wistar rats. Furthermore, it enhanced ex vivo glucose uptake in soleus muscles in these mice, which substantiates our in vitro findings. Human peroxisome proliferator activated receptor-gamma transactivation assay revealed a weak peroxisome proliferator activated receptor-gamma transactivation potential (44% of rosiglitazone at 10 mumol/L) of 18F9. Gene expression profiling indicated that 18F9 increased insulin sensitivity mainly through a phosphoinositide 3-kinase-dependent mechanism. 18F9 also up-regulated genes involved in lipid transport and synthesis at par with rosiglitazone. Unlike rosiglitazone, 18F9 elevated the expression of Pdk4. In addition, 18F9 elevated the expression of glycogen synthase and adiponectin significantly higher than rosiglitazone. Taken together, these observations suggest that 18F9 is a safer and potent insulin sensitizer that demonstrates promising antidiabetic activity and is worth further development.
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PMID:18F9 (4-(3,6-bis (ethoxycarbonyl)-4,5,6,7-tetrahydrothieno (2,3-c) pyridin-2-ylamino)-4-oxobutanoic acid) enhances insulin-mediated glucose uptake in vitro and exhibits antidiabetic activity in vivo in db/db mice. 1960 7

Cancer cachexia is a syndrome of unintentional weight loss that is characterized by wasting of both skeletal muscle and adipose tissue. Glucose intolerance and insulin resistance have been associated with cancer cachexia. However, it is unknown whether resistance to insulin has a role in the development of cachexia. In the present study, male CD2F1 mice with colon-26 adenocarcinoma tumors underwent an insulin tolerance test before the onset of weight loss. Compared to mice without tumors, mice with tumors had a profoundly blunted blood glucose response to insulin. Corroborating these findings, mice with tumors had decreased phosphorylation of Akt in quadriceps muscle and epididymal adipose tissue at the end of the study. Expression of Akt-regulated genes Atrogin-1, MuRF-1, and Bnip3 was increased in muscle, suggesting a role for decreased insulin signaling in the induction of both proteasomal proteolysis and autophagy in cachectic muscle. Rosiglitazone treatment increased serum adiponectin, insulin sensitivity, and body weight, and decreased Atrogin-1 and MuRF-1 expression in the skeletal muscle of tumor-bearing mice. In conclusion, insulin resistance is an early event in mice with cachexia induced by colon-26 tumors. Rosiglitazone improves insulin sensitivity and decreases early markers of cachexia. These data provide evidence that insulin resistance is not only present in cachexia, but also has a role in cachexia pathogenesis. Correction of insulin resistance may be a novel therapeutic target for the treatment of cancer cachexia.
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PMID:Evidence for the contribution of insulin resistance to the development of cachexia in tumor-bearing mice. 1963 37

Adipose tissue dysfunction has been associated with diabetogenic effects. The effects of repeated Cd exposure on adipocytes remain largely unknown. We administered Cd at doses of 0, 5, 10, and 20 micromol/kgbw sc for 2 weeks (3.5 times/week) to mice and assessed the possible alteration of epididymal white adipose tissue (WAT), including histological difference, adipocyte differentiation and functional capacity. Whereas hepatic weight did not differ between the control and Cd-exposed groups, WAT weight, as well as adipose cell mass, significantly decreased in a dose-dependent manner in Cd-treated mice. The Cd concentration in WAT significantly increased in Cd-treated groups after 2 weeks of exposure. Next, we examined the effects of Cd on adipocyte differentiation and hypertrophy. Cd exposure significantly decreased the paternally expressed gene 1/Mesoderm-specific transcript mRNA expression levels. Both peroxisome proliferator-activated receptor gamma2 and CCAAT/enhancer-binding protein alpha mRNA expression levels in WAT tended to decrease in the Cd-treated groups. Next, we determined the effects of Cd exposure on the mRNA expression levels of adipose-derived hormones, such as adiponectin and resistin. The adiponectin mRNA expression level in WAT decreased after both 6h and 2 weeks of exposure to a high dose of Cd, and the reduction in resistin mRNA expression levels was observed after 2 weeks of exposure. These results suggest that Cd exposure causes abnormal adipocyte differentiation, expansion, and function, which might lead to development of insulin resistance, hypertension, and cardiovascular disease.
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PMID:Cadmium reduces adipocyte size and expression levels of adiponectin and Peg1/Mest in adipose tissue. 1966 79

This study investigated the anti-obesity effects of fucoxanthin in diet-induced obesity mice fed a high-fat diet (20% fat, wt/wt). The mice were supplemented with two doses of fucoxanthin (0.05 and 0.2%, wt/wt) for 6 wk. Fucoxanthin significantly lowered body weight and visceral fat-pads weights compared with the control group without altering food intake. In epididymal adipose tissue of fucoxanthin-fed mice, adipocyte sizes and mRNA expression of lipogenic and fatty acid beta-oxidation enzymes were significantly altered in a dose-dependent manner. Plasma leptin level was significantly lower in the fucoxanthin groups than in the control group, while the adiponectin level was elevated. Fucoxanthin significantly down-regulated various lipogenic enzyme activities in epididymal adipose tissue with a simultaneous decrease in fatty acid beta-oxidation activity. The 0.2% fucoxanthin supplement led to increase mRNA expression of uncoupling protein-1 (UCP-1) and UCP-3 in brown adipose tissue and that of UCP-2 in the epididymal white adipose tissue. However, the 0.05% fucoxanthin only elevated UCP-1 mRNA expression in epididymal white adipose tissue. These results suggest that the anti-obesity effect of fucoxanthin could be mediated by altering lipid-regulating enzymes and UCPs in the visceral fat tissues and plasma adipokine levels.
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PMID:Anti-obese property of fucoxanthin is partly mediated by altering lipid-regulating enzymes and uncoupling proteins of visceral adipose tissue in mice. 1984 4

Conjugated linoleic acid (CLA) has been reported as having body fat lowering properties and the ability to modulate the inflammatory system in several models. In the present study, the effects of CLA added to saturated fat diets, from vegetable and animal origins, on the serum adipokine profile of obese Zucker rats were assessed. In addition, the fatty acid composition of epididymal and retroperitoneal adipose tissues was determined and a principal component analysis (PCA) was used to assess possible relationships between fatty acids and serum metabolites. Atherogenic diets (2 % cholesterol) were formulated with palm oil and ovine fat and supplemented or not with 1 % of a mixture (1:1) of cis-9, trans-11 and trans-10, cis-12-CLA isomers. CLA-fed animals exhibited lower daily feed intake, final body and liver weights, and hepatic lipids content. Total and LDL-cholesterol levels were increased in CLA-supplemented groups. CLA also promoted higher adiponectin and lower plasminogen activator inhibitor-1 (PAI-1) serum concentrations. In contrast to palm oil diets, ovine fat increased insulin resistance and serum levels of leptin, TNF-alpha and IL-1beta. Epididymal and retroperitoneal adipose tissues had similar deposition of individual fatty acids. The PCA analysis showed that the trans-10, cis-12-CLA isomer was highly associated with adiponectin and PAI-1 levels. Summing up, CLA added to vegetable saturated enriched diets, relative to those from animal origin, seems to improve the serum profile of adipokines and inflammatory markers in obese Zucker rats due to a more favourable fatty acid composition.
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PMID:Serum adipokine profile and fatty acid composition of adipose tissues are affected by conjugated linoleic acid and saturated fat diets in obese Zucker rats. 1987 18

We reported earlier that dietary cinnamon extract (CE) improves systemic insulin sensitivity and dyslipidemia by enhancing insulin signaling. In the present study, we have examined the effects of CE on several biomarkers including plasma levels of adipose-derived adipokines, and the potential molecular mechanisms of CE in epididymal adipose tissue (EAT). In Wistar rats fed a high-fructose diet (HFD) to induce insulin resistance, supplementation with a CE (Cinnulin PF, 50 mg/kg daily) for 8 weeks reduced blood glucose, plasma insulin, triglycerides, total cholesterol, chylomicron-apoB48, VLDL-apoB100, and soluble CD36. CE also inhibited plasma retinol binding protein 4 (RBP4) and fatty acid binding protein 4 (FABP4) levels. CE-induced increases in plasma adiponectin were not significant. CE did not affect food intake, bodyweight, and EAT weight. In EAT, there were increases in the insulin receptor ( IR) and IR substrate 2 ( IRS2) mRNA, but CE-induced increases in mRNA expression of IRS1, phosphoinositide-3-kinase, AKT1, glucose transporters 1 and 4 , and glycogen synthase 1 expression and decreased trends in mRNA expression of glycogen synthase kinase 3beta were not statistically significant. CE also enhanced the mRNA levels of ADIPOQ, and inhibited sterol regulatory element binding protein-1c mRNA levels. mRNA and protein levels of fatty acid synthase and FABP4 were inhibited by CE and RBP4, and CD36 protein levels were also decreased by CE. These results suggest that CE effectively ameliorates circulating levels of adipokines partially mediated via regulation of the expression of multiple genes involved in insulin sensitivity and lipogenesis in the EAT.
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PMID:Cinnamon extract regulates plasma levels of adipose-derived factors and expression of multiple genes related to carbohydrate metabolism and lipogenesis in adipose tissue of fructose-fed rats. 1993 69

Hepatic fat deposition with hepatocellular damage, a feature of non-alcoholic fatty liver disease, is mediated by several putative factors including prostaglandins. In the present study, we examined whether group IVA phospholipase A(2) (IVA-PLA(2)), which catalyzes the first step in prostanoid biosynthesis, is involved in the development of fatty liver, using IVA-PLA(2)-knockout mice. Male wild-type mice on high-fat diets (20% fat and 1.25% cholesterol) developed hepatocellular vacuolation and liver hypertrophy with an increase in the serum levels of liver damage marker aminotransferases when compared with wild-type mice fed normal diets. These high-fat diet-induced alterations were markedly decreased in IVA-PLA(2)-knockout mice. Hepatic triacylglycerol content was lower in IVA-PLA(2)-knockout mice than in wild-type mice under normal dietary conditions. Although high-fat diets increased hepatic triacylglycerol content in both genotypes, the degree was lower in IVA-PLA(2)-knockout mice than in wild-type mice. Under the high-fat dietary conditions, IVA-PLA(2)-knockout mice had lower epididymal fat pad weight and smaller adipocytes than wild-type mice. The serum level of prostaglandin E(2), which has a fat storage effect, was lower in IVA-PLA(2)-knockout mice than in wild-type mice, irrespective of the kind of diet. In both genotypes, high-fat diets increased serum leptin levels equally between the two groups, but did not affect the serum levels of adiponectin, resistin, free fatty acid, triacylglycerol, glucose, or insulin. Our findings suggest that a deficiency of IVA-PLA(2) alleviates fatty liver damage caused by high-fat diets, probably because of the lower generation of IVA-PLA(2) metabolites, such as prostaglandin E(2). IVA-PLA(2) could be a promising therapeutic target for obesity-related diseases including non-alcoholic fatty liver disease.
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PMID:Alleviation of high-fat diet-induced fatty liver damage in group IVA phospholipase A2-knockout mice. 1995 52

This study tests the hypothesis that a high-fat postnatal diet increases fat mass and reduces improved insulin sensitivity (IS) found in the low-protein model of maternal undernutrition. Offspring from Wistar dams fed either a 20% (control (CON)) or 8% (low protein (LP)) protein diet during gestation and lactation were randomly assigned to a control (con) or cafeteria (caf) diet at weaning (21 days) until 3 months of age at which point IS was measured (hyperinsulinemic-euglycemic clamp). Fat mass, growth, energy intake (EI) and expenditure (EE), fuel utilization, insulin secretion, and leptin and adiponectin levels were measured to identify a possible role in any changes in IS. IS was increased in LP-con in comparison to CON-con animals. Cafeteria feeding prevented this increase in LP animals but had no effect in CON animals (insulin-stimulated glucose infusion rates (GIRs; mg/min/kg); CON-con: 13.9 +/- 1.0, CON caf: 12.1 +/- 2.1, LP-con: 25.4 +/- 2.0, LP-caf: 13.7 +/- 3.7, P < 0.05). CON-caf animals had similar percent epididymal white adipose tissue (%EWAT; CON-con: 1.71 +/- 0.09 vs. CON-caf: 1.66 +/- 0.08) and adiponectin (microg/ml: CON-con: 4.61 +/- 0.34 vs. CON-caf: 3.67 +/- 0.18) except hyperinsulinemia and relative hyperleptinemia in comparison to CON-con. Differently, LP-caf animals had increased %EWAT (LP-con: 1.11 +/- 0.06 vs. LP-caf: 1.44 +/- 0.08, P < 0.05) and adiponectin (microg/ml: LP-con: 5.38 +/- 0.39 vs. LP-caf: 3.75 +/- 0.35, P < 0.05) but did not show cafeteria-induced hyperinsulinemia or relative hyperleptinemia. An increased propensity to store visceral fat in LP animals may prevent the elevated IS in LP offspring.
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PMID:Elevated insulin sensitivity in low-protein offspring rats is prevented by a high-fat diet and is associated with visceral fat. 2001 81

The onset of insulin resistance, the sites of action, and the mechanisms through which tumor necrosis factor-alpha (TNF-alpha) exacerbates the increase in adiposity and the development of insulin resistance in mice fed high-fat (HF) diet remain unclear. Here we investigated the effect of TNF-alpha deficiency on adiposity and insulin resistance during the initial 1 to 4 weeks of HF feeding. We examined body weight; the distribution of white adipose tissue (WAT); homeostasis model assessment; and levels of leptin, resistin, and adiponectin in the initial 4 weeks of HF feeding in TNF-alpha knockout (KO) mice and wild-type (WT) controls. Through 4 weeks of HF feeding, KO mice, unlike WT mice, maintained normal insulin sensitivity. Although WT-HF and KO-HF mice had similar levels of WAT at this time, KO-HF mice had more subcutaneous and less epididymal fat than WT-HF mice. The KO-HF mice also had less liver fat than the WT-HF mice. Finally, KO-HF mice had lower plasma levels of resistin than WT-HF mice. These data demonstrate that genetic lack of TNF-alpha protects insulin sensitivity during the early phase of HF feeding in the absence of altered total WAT. The data also suggest that the mechanism maintaining insulin sensitivity in the absence of TNF-alpha may involve redirection of the fat deposition to the metabolically more inert subcutaneous depot or decreases in circulating resistin and resultant decrease in liver fat deposition. The efficacy of therapeutic measures designed to counteract the effects of TNF-alpha may be increased during the early stages of obesity and insulin resistance.
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PMID:Diet-genotype interactions in the early development of obesity and insulin resistance in mice with a genetic deficiency in tumor necrosis factor-alpha. 2004 54

The importance of hypertension treatment has expanded beyond blood pressure management to include additional risk factors, mainly diabetes. It was considered of interest to test the effect of telmisartan, an angiotensin receptor 1 antagonist and peroxisome proliferator activator receptor-gamma partial agonist, on Cohen-Rosenthal diabetic hypertensive nonobese (CRDH) rats, a unique model combining both pathologies. Its effect was examined on fat-derived and inflammatory agents in CRDH. To determine the extent of the drug's peroxisome proliferator activator receptor-gamma modulating beneficial metabolic actions, results were compared with those obtained with valsartan and rosiglitazone in CRDH and Cohen diabetic rat (CDR). Telmisartan and valsartan were given in drinking water at 3 and 12 mg/kg/d, whereas rosiglitazone (3 mg/kg/d) was given as food admixture for a period of 5 months. Blood pressure, glucose, insulin, adiponectin, leptin, and tumor necrosis factor alpha were examined. Telmisartan and valsartan significantly (P < .01) reduced blood pressure, whereas telmisartan and rosiglitazone considerably reduced blood glucose levels to normoglycemic levels (P < .01) in these 2 strains. Insulin levels were not affected by telmisartan and valsartan but were slightly reduced by rosiglitazone in CDR. In contrast to valsartan, adiponectin was significantly (60%, P < .01) increased by telmisartan in both CDR and CRDH, whereas rosiglitazone induced a 60% and 180% increase in CRDH and CDR animals, respectively, on day 30 of treatment. Co-treatment with GW9662 averted telmisartan-induced rise of adiponectin. Tumor necrosis factor alpha declined in telmisartan-treated rats, less so with rosiglitazone, but not valsartan. Telmisartan also induced downsizing of epididymal adipocytes compared with valsartan. Leptin levels were significantly increased by valsartan (P < .05) but reduced by telmisartan and rosiglitazone. The telmisartan-induced increase in adiponectin was most probably associated with a decrease in glucose and tumor necrosis factor alpha levels. Therefore, in addition to its hypotensive effect, telmisartan demonstrated beneficial thiazolidinedione-like effects.
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PMID:Telmisartan ameliorates hyperglycemia and metabolic profile in nonobese Cohen-Rosenthal diabetic hypertensive rats via peroxisome proliferator activator receptor-gamma activation. 2007 Sep 92


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