A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-γ activity

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 (RAR alpha), is used to treat leukemia. Another RAR alpha 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 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 down-regulated PPAR gamma protein expression in adipocytes. In addition, Ro 41-5253 activated the PPAR gamma-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RAR alpha agonist or 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.