The small molecule harmine is an antidiabetic cell-type-specific regulator of PPARγ expression

PPAR gamma is the master regulator of adipogenesis and the molecular target of the thiazolidine-dione antidiabetic drugs. By screening for compounds that promote adipogenesis, we identified a small molecule that targets the PPAR gamma pathway by a distinct mechanism. This molecule, harmine, is not a ligand for the receptor; rather, it acts as a cell-type-specific regulator of PPAR gamma expression. Administration of harmine to diabetic mice mimics the effects of PPAR gamma ligands on adipocyte gene expression and insulin sensitivity. Unlike thiazolidine-diones, however, harmine does not cause significant weight gain or hepatic lipid accumulation. Molecular studies indicate that harmine controls PPAR gamma expression through inhibition of the Wnt signaling pathway. This work validates phenotypic screening of adipocytes as a promising strategy for the identification of bioactive small molecules and suggests that regulators of PPAR gamma expression may represent a complementary approach to PPAR gamma ligands in the treatment of insulin resistance.