Thiazolidinediones (TZDs), agonists for PPARs, have been shown to block the inhibitory effects of TNF-alpha on insulin action using cultured cells. In order to clarify the in vivo effects of TZDs on the inhibition of insulin sensitivity by TNF-alpha on insulin action in muscles and adipose tissues was assessed in the TNF-alpha-overexpression mice model using transplantation of cells secreting the TNFalpha protein. After the pioglitazone treatment for 4 weeks, glucose uptake, insulin-induced IRS-1 phosphorylation, and lipoprotein lipase mRNA levels were analyzed. Pioglitazone did not ameliorate TNF-alpha-induced hyperinsulinemia in this model, as assessed by the OGTT. Glucose uptake and lipoprotein lipase mRNA levels were decreased by TNF-alpha in adipose tissues from the TNF-alpha-overexpressing mice, and pioglitazone blocked these inhibitions by TNF-alpha. On the other hand, in muscles, pioglitazone did not reverse the effects of TNF-alpha on insulin-induced phosphorylation of IRS-1, glucose uptake, and lipoprotein lipase mRNA levels. Present study revealed the different sensitivities of pioglitazone for the recovery of decreased insulin action in a TNF-alpha-overexpressing model using cell transplantation. These results suggest that the effect of TZDs is dependent on the fat distribution and accumulation in humans. (C) 2003 Elsevier Inc. All rights reserved.