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First published on February 8, 2007; DOI: 10.1124/mol.106.033662

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Received for publication December 21, 2006.
Revised February 7, 2007.
Accepted for publication February 8, 2007.

A Widely Used Retinoic Acid Receptor Antagonist Induces PPAR{gamma} Activity

Michael Schupp 1, Joshua C Curtin 1, Roy J Kim 1, Andrew N Billin 2, Mitchell A Lazar 1*

1 University of Pennsylvania 2 Department of High-throughput Biology, GlaxoSmithKline, Research Triangle Park, NC USA

* Address correspondence to: E-mail: lazar{at}mail.med.upenn.edu

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 (atRA), an activating ligand for Retinoic Acid Receptor {alpha} (RAR{alpha} ), is used to treat leukemia. Another RAR{alpha} ligand, RO 41-5253, is a potent antagonist that has been a useful and purportedly specific probe of RAR{alpha} function. Here we report that RO 41-5253 also activates the Peroxisome Proliferator-Activated Receptor{gamma} (PPAR{gamma}), 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 PPAR{gamma} target genes in mature adipocytes. Like the TZDs, RO 41-5253 also downregulated PPAR{gamma} protein expression in adipocytes. In addition, RO 41-5253 activated the PPAR{gamma}-ligand binding domain (LBD) in transiently transfected HEK293T cells. These effects were not prevented by a potent RAR{alpha} agonist nor by depleting cells of RAR{alpha}, indicating that PPAR{gamma} activation was not related to RAR{alpha} antagonism. Indeed, RO 41-5253 was able to compete with TZD ligands for binding to PPAR{gamma}, 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 PPAR{gamma} agonist as well as an RAR{alpha} antagonist, whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.


Key words: PPARs, Regulation of gene expression, Endocrine cells


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