Impact of Increased PPAR.GAMMA. Activity in Adipocytes in vivo on Adiposity, Insulin Sensitivity and the Effects of Rosiglitazone Treatment

Abstract

Peroxisome proliferator-activated receptor (PPAR)gamma, a transcription factor belonging to the nuclear receptor superfamily, is essential for adipogenesis. PPARgamma is recognized as a major target for the insulin-sensitizing effects of the thiazolidinediones. Previous studies have demonstrated that heterozygous PPARgamma-deficient mice are protected from high-fat diet (HFD)-induced adipocyte hypertrophy, obesity and insulin resistance, which suggests that PPARgamma may have a pivotal role in adipocyte hypertrophy, obesity and insulin resistance. In this study, we generated transgenic mice with the gain-of-function PPARgamma Ser112Ala mutation (S112A mice) using the aP2 promoter, to elucidate the impact of increased PPARgamma activity in mature adipocytes. Despite a 2-3-fold increase in the adipocyte PPARgamma2 gene expression and PPARgamma activity, the S112A mice showed comparable adiposity and insulin sensitivity to wild-type mice under both normal and HFD conditions. Although the expression levels of the PPARgamma target genes involved in lipid metabolism, such as aP2 and stearoyl-CoA desaturase 1, were upregulated in the white adipose tissue of the S112A mice, the serum levels of free fatty acid, triglyceride, adiponectin and leptin, as well as the oxygen consumption, were comparable between the wild-type and S112A mice under the HFD condition. Moreover, treatment with rosiglitazone ameliorated insulin resistance and glucose intolerance to a similar degree in the two genotypes under the HFD condition. In conclusion, whereas the 50% decrease in PPAR gamma activity showed protection from HFD-induced obesity and insulin resistance, in the present study, the 2-3-fold increase in PPARgamma2 expression and PPARgamma activity failed to show obesity and insulin resistance even under the HFD condition.