Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator-activated receptor-gamma

Tumor necrosis factor (TNF)-alpha is one of the candidate mediators of insu lin resistance associated with obesity, a major risk factor for the develop ment of type 2 diabetes. The insulin resistance induced by TNF-alpha is ant agonized by thiazolidinediones (TZDs), a new class of insulin-sensitizing d rugs. The aim of the current study was to dissect the mechanism whereby pio glitazone, one of the TZDs, ameliorates TNF-alpha -induced insulin resistan ce in 3T3-L1 adipocytes. Pioglitazone restored insulin-stimulated 2-deoxygl ucose (DOG) uptake, which was reduced by TNF-alpha, with concomitant restor ations in tyrosine phosphorylation and protein levels of insulin receptor ( IR) and insulin receptor substrate (IRS)-1, as well as association of the p 85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 and PI 3-kinase activity. Adenovirus-mediated gene transfer of either wild-type human peroxisome proliferator-activated receptor (PPAR)-gamma2 or a mutant carrying a replacement at the consensus mitogen-activated protein kinase p hosphorylation site (hPPAR-gamma2-S112A) promoted adipogenesis of 3T3-L1 fi broblasts and restored TNF-alpha -induced decrease of triglyceride in adipo cytes as effectively as pioglitazone, Overexpression of the PPAR-gamma prot eins in TNF-alpha -treated adipocytes restored protein levels of IR/IRS-1, but did not improve insulin-stimulated tyrosine phosphorylation of IR/IRS-1 or insulin-stimulated 2-DOG uptake. These results indicate that the abilit y of pioglitazone to restore insulin-stimulated tyrosine phosphorylation of IR/IRS-1, which is necessary for amelioration of TNF-alpha -induced insuli n resistance, may be independent of the adipogenic activity of PPAR-gamma t hat regulates protein levels of IR/IRS-1.