AN ANTIDIABETIC THIAZOLIDINEDIONE IS A HIGH-AFFINITY LIGAND FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA(PPAR-GAMMA)

Thiazolidinedione derivatives are antidiabetic agents that increase th e insulin sensitivity of target tissues in animal models of non-insuli n dependent diabetes mellitus. In vitro, thiazolidinediones promote ad ipocyte differentiation of preadipocyte and mesenchymal stem cell line s; however, the molecular basis for this adipogenic effect has remaine d unclear. Here, we report that thiazolidinediones are potent and sele ctive activators of peroxisome proliferator activated receptor gamma ( PPAR gamma), a member of the nuclear receptor superfamily recently sho wn to function in adipogenesis. The most potent of these agents, BRL49 653, binds to PPAR gamma with a K-d of approximately 40 nM. Treatment of pluripotent C3H10T1/2 stem cells with BRL49653 results in efficient differentiation to adipocytes. These data are the first demonstration of a high affinity PPAR ligand and provide strong evidence that PPAR gamma is a molecular target for the adipogenic effects of thiazolidine diones. Furthermore, these data raise the intriguing possibility that PPAR gamma is a target for the therapeutic actions of this class of co mpounds.