ABSTRACT
Obese individuals with fat stored in visceral adipose tissue (VAT) generally suffer greater adverse metabolic consequences than those with fat stored predominantly in subcutaneous adipose tissue (SAT), but its molecular basis is not completely understood. We isolated paired samples of SAT and VAT from 15 lean and 15 obese subjects and systematically compared the transcription level of genes that may determine fat distribution and metabolic sequelae between SAT and VAT using quantitative real-time PCR. We found that, leptin levels were lower in VAT than SAT, for both lean and obese subjects. In lean subjects, tumor necrosis factor-alpha (TNF-alpha) was expressed equally in both fat depots, while toll-like receptor 4 (TLR4) and glucocorticoid receptor (GR) showed significantly lower expression in VAT than SAT. In obese subjects, TNF-alpha and TLR4 expression were significantly higher in VAT than SAT, yet GR expression did not differ in these areas. For all subjects, VAT 11beta-hydroxysteroid dehydrogenate type 1 (11beta-HSD1) level was significantly correlated with BMI. GR expression level was significantly correlated with TLR4 expression level. Cultured adipocytes showed higher TLR4 mRNA level after differentiation, and higher TNF-alpha level after treatment with free fatty acids. These results suggest that there are depot-specific differences in leptin, TNF-alpha, TLR4 and GR transcriptions in humans. TLR4 signaling and higher 11beta-HSD1 and GR levels in VAT may contribute predominantly to inflammatory factor production and subsequent metabolic sequelae in obese human.
Subject(s)
Intra-Abdominal Fat/metabolism , Subcutaneous Fat/metabolism , Transcription, Genetic , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adipocytes, White/metabolism , Adult , Aged , Asian People/genetics , Blood Glucose/analysis , Cells, Cultured , Female , Humans , Intra-Abdominal Fat/pathology , Male , Middle Aged , Obesity/genetics , Obesity/metabolism , Obesity/pathology , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Subcutaneous Fat/pathology , Thinness/genetics , Thinness/metabolism , Thinness/pathology , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Transcription, Genetic/physiology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
OBJECTIVE: To investigate the mechanism of BVT.2733 on insulin resistance, by using diet-induced obese (DIO) mice model. METHODS: After having been balanced for 3 days, the C57BL/6J mice were randomly divided into a normal diet group and a high-fat diet (HFD) group. After 20 weeks, the obese mice were further randomly divided into an obese control group, a BVT.2733 group and a pioglitazone (PGZ) group and they were orally administered with placebo, BVT.2733 and PGZ separately for two weeks. Adiponectin and leptin mRNA expression levels from adipose tissue were analyzed with real-time quantitative PCR. The levels of plasma glucose, serum insulin and adiponectin were measured with biochemical technology, radioimmunoassay and ELISA. Adipocyte sizes were observed with immunohistochemistry. RESULTS: The body weight, plasma glucose and serum insulin levels raised (P < 0.05) in the HFD group and the adipocyte sizes were bigger. Serum insulin levels significantly reduced (P < 0.05) and adipocyte sizes reduced, while plasma adiponectin level raised (P < 0.01) in the two treatment groups as compared with those in obese controls. Both the mRNA expressions of adiponectin and leptin upregulated (P < 0.05) in the PGZ group, but their expressions in the BVT.2733 group did not alter significantly. The body weight of the mice reduced significantly in the BVT.2733 group. CONCLUSION: BVT.2733 can reduce body weight significantly and improve insulin resistance, but cannot influence the expression of adipocytokines.
