Thiazolidinediones (PPARγ agonists) but not PPAR α agonists increase IRS‐2 gene expression in 3T3‐L1 and human adipocytes ¹

Thiazolidinediones (TZD) improve insulin sensitivity in human as well as in different animal models of insulin resistance and Type 2 diabetes. However, no clear link to the insulin signaling events has been identified. Using differentiated 3T3‐L1 adipocytes, we found that TZD rapidly and markedly increased IRS‐2 gene expression. This effect was specific for PPARγ agonists and was not seen with PPAR α agonists. It was rapidly induced (within 4 h) and maintained throughout the observation period of 48 h. It was also concentration dependent (EC 50 ~50 nM) and not inhibited by cycloheximide, suggesting a direct effect on the IRS‐2 promoter. There was no evidence that TZD altered IRS‐2 mRNA stability, supporting that the increased mRNA levels were due to an increased gene transcription. IRS‐2 protein expression was increased ~30% after 48 h and ~50% after 96 h. No effects of TZD were seen on IRS‐1, PKB/Akt, or GLUT4 gene expression. TZD also increased IRS‐2 mRNA levels in cultured human adipose tissue. These data show the first direct link between TZD and a critical molecule in insulin's signaling cascade in both 3T3‐L1 and human adipocytes, and indicate a novel mode of action of these compounds.—Smith, U., Gogg, S., Johansson, A., Olausson, T., Rotter, V., Svalstedt, B. Thiazolidinediones (PPARγ agonists) but not PPARa agonists increase IRS‐2 gene expression in 3T3‐L1 and human adipocytes. FASEB J. 15, 215–220 (2001)