Pioglitazone reduces tumor necrosis factor-α serum concentration and mRNA expression of adipose tissue in hypercholesterolemic rabbits

BackgroundTumor necrosis factor-α (TNF-α) is an inflammatory cytokine involved in atherogenesis. Adipose tissue is an important source of endogenous TNF-α production. Pioglitazone, a member of the thiazolidinediones (TZDs), has anti-inflammatory and anti-atherogenic properties, while underlying mechanism has not been fully elucidated. The aim of this study was to evaluate the effect of pioglitazone on TNF-α serum concentration and mRNA expressions of subcutaneous adipose tissue in hypercholesterolemic rabbits.MethodsTen rabbits fed with high-cholesterol diet for 8 weeks were randomly divided into two groups: (1) high cholesterol group (n = 5): maintained high cholesterol diet for 4 weeks; (2) pioglitazone group (n = 5): the same cholesterol diet plus pioglitazone (3 mg/kg/day) for 4 weeks. Control group (n = 5) was fed with normal diet for 12 weeks. Subcutaneous adipose tissue was collected for RNA analysis. The direct effect of pioglitazone on TNF-α release was assayed in primary rabbit adipocytes. TNF-α levels in serum and adipocytes culture supernatant were measured by ELISA. RT-PCR was used to evaluate TNF-α mRNA expressions in adipose tissue and adipocytes.ResultsCompared with control group, rabbits fed with high cholesterol diet showed significantly higher levels of serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and TNF-α. Though having no effect on serum glucose level and lipid profile, pioglitazone administration significantly reduced circulating TNF-α concentrations, which were positively correlated with TNF-α mRNA expressions of adipose tissue (r = 0.53, P < 0.01). Pioglitazone dose-dependently inhibited lipopolysaccharide (LPS)-induced TNF-α secretion and mRNA expression in cultured adipocytes.ConclusionPioglitazone significantly reduced serum TNF-α level in hypercholesterolemic rabbits independent of its metabolic actions, which may at least partly be due to its direct inhibition of TNF-α expression and secretion of adipocytes. This may help to explain the mechanism by which pioglitazone exert anti-atherosclerotic effects.