title: The small molecule harmine is an antidiabetic cell-type-specific regulator of PPARgamma expression.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Hironori
authors.initials: H
authors.lastname: Waki
authors.forename: Kye Won
authors.initials: KW
authors.lastname: Park
authors.forename: Nico
authors.initials: N
authors.lastname: Mitro
authors.forename: Liming
authors.initials: L
authors.lastname: Pei
authors.forename: Robert
authors.initials: R
authors.lastname: Damoiseaux
authors.forename: Damien C
authors.initials: DC
authors.lastname: Wilpitz
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.forename: Enrique
authors.initials: E
authors.lastname: Saez
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002153:Calorimetry, Indirect; D002460:Cell Line; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D006247:Harmine / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008156:Luciferases; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D017931:DNA Primers; D047495:PPAR gamma; D006247:Harmine; D008156:Luciferases