title: A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity.
abstract: Nuclear receptors (NRs) are transcription factors whose activity is regulated by the binding of small lipophilic ligands, including hormones, vitamins, and metabolites. Pharmacological NR ligands serve as important therapeutic agents; for example, all-trans retinoic acid, an activating ligand for retinoic acid receptor alpha (RARalpha), is used to treat leukemia. Another RARalpha ligand, (E)-S,S-dioxide-4-(2-(7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)-1-propenyl)-benzoic acid (Ro 41-5253), is a potent antagonist that has been a useful and purportedly specific probe of RARalpha function. Here, we report that Ro 41-5253 also activates the peroxisome proliferator-activated receptor gamma (PPARgamma), a master regulator of adipocyte differentiation and target of widely prescribed antidiabetic thiazolidinediones (TZDs). Ro 41-5253 enhanced differentiation of mouse and human preadipocytes and activated PPARgamma target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPARgamma protein expression in adipocytes. In addition, Ro 41-5253 activated the PPARgamma-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RARalpha agonist or by depleting cells of RARalpha, indicating that PPARgamma activation was not related to RARalpha antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPARgamma, suggesting that Ro 41-5253 directly affects PPAR activity. These results vividly demonstrate that pharmacological NR ligands may have "off-target" effects on other NRs. Ro 41-5253 is a PPARgamma agonist as well as an RARalpha antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6149, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Schupp
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Curtin
authors.forename: Roy J
authors.initials: RJ
authors.lastname: Kim
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Billin
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D047494:PPAR delta / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors*; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D001565:Benzoates; D002839:Chromans; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D047494:PPAR delta; D047495:PPAR gamma; D048068:PPAR-beta; D020033:Protein Isoforms; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes; C068073:Am 580; C084904:Ro 41-5253