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A Widely Used Retinoic Acid Receptor Antagonist Induces Peroxisome Proliferator-Activated Receptor- Activity

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and Department of Genetics, and the Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (M.S., J.C.C., R.J.K., A.N.B., M.A.L); Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (R.J.K.); and Department of High-Throughput Biology, GlaxoSmithKline, Research Triangle Park, North Carolina (A.N.B.)

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 (RAR), is used to treat leukemia. Another RAR 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 RAR function. Here, we report that Ro 41-5253 also activates the peroxisome proliferator-activated receptor (PPAR), 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 target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPAR protein expression in adipocytes. In addition, Ro 41-5253 activated the PPAR-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RAR agonist or by depleting cells of RAR, indicating that PPAR activation was not related to RAR antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPAR, 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 agonist as well as an RAR antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.

Address correspondence to: Dr. Mitchell A. Lazar, Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, 611 CRB, 415 Ci Blvd., Philadelphia, PA 19104-6149. E-mail: lazar{at}mail.med.upenn.edu

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