PPARgamma is the master regulator of adipogenesis and the molecular target of the thiazolidinedione antidiabetic drugs. By screening for compounds that promote adipogenesis, we identified a small molecule that targets the PPARgamma 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 PPARgamma expression. Administration of harmine to diabetic mice mimics the effects of PPARgamma ligands on adipocyte gene expression and insulin sensitivity. Unlike thiazolidinediones, however, harmine does not cause significant weight gain or hepatic lipid accumulation. Molecular studies indicate that harmine controls PPARgamma 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 PPARgamma expression may represent a complementary approach to PPARgamma ligands in the treatment of insulin resistance.