Modulation of PPARgamma activity with pharmaceutical agents: treatment of insulin resistance and atherosclerosis.

The anti-diabetic thiazolidinediones (TZDs) are a class of compounds with insulin-sensitizing activity that were originally discovered using in vivo pharmacological screens. In subsequent binding studies, TZDs were demonstrated to enhance insulin action by activating peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is a member of the ligand-activated nuclear receptor superfamily that promotes adipogenesis and enhances insulin sensitivity by controlling the expression of genes in glucose and lipid metabolism. Given the large size of the ligand binding pocket in PPARgamma, novel classes of both full and partial agonists that are structurally distinct from TZDs have been discovered. These compounds have been effective tools in differentiating adipogenic and insulin-sensitizing activities as well as tissue selectivity of PPARgamma activation. This information has led to the hypothesis that one ligand can activate or inactivate PPARs depending upon the tissue in which the PPAR resides. Thus particular compounds can be designated selective PPAR modulators or SPPARMs, a concept similar to that observed with the activation of estrogen receptor (ER) by SERMS. Additionally, both preclinical and clinical data suggest that PPARgamma activation is useful for the prevention of atherosclerosis. However, the effects of TZDs on plasma lipid profiles do not solely account for their anti-atherogenic effects. Recent studies with macrophage cells and animal models for atherosclerosis indicate that TZDs reduce the size and number of lesions formed in the vessel wall by modulating foam cell formation and inflammatory responses by macrophages. Thus in addition to the treatment of type II diabetes, PPARgamma agonists can be potentially employed for the treatment of atherosclerosis in general population.