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 α (RARα), is used to treat leukemia. Another RARα 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 RARα function. Here, we report that Ro 41-5253 also activates the peroxisome proliferator-activated receptor γ (PPARγ), 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 PPARγ target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPARγ protein expression in adipocytes. In addition, Ro 41-5253 activated the PPARγ-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RARα agonist or by depleting cells of RARα, indicating that PPARγ activation was not related to RARα antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPARγ, 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 PPARγ agonist as well as an RARα antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.
Footnotes
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This work was supported by National Institutes of Health grant R01-DK49780 (to M.A.L). M.S. was supported by Mentored Fellowship award from the American Diabetes Association, and J.C.C was supported by National Institute of Diabetes and Digestive and Kidney Diseases training grants 5-F32-DK070405-03 and 5-R01-DK045780-12.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.106.033662.
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ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; RAR, retinoic acid receptor; TZD, thiazolidinedione; RXR, retinoid X receptor; NR, nuclear receptors; atRA, all-trans retinoid acid; Ro 41-5253, (E)-S,S-dioxide-4-(2-(7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)-1-propenyl)-benzoic acid; IBMX, 3-isobutyl-1-methylxanthine; SGBS, Simpson Golabi Behmel Syndrome; LBD, ligand binding domain; aP2, adipose protein 2; GW2433, 2-(4-{3-[1-[2-(2-chloro-6-fluoro-phenyl)-ethyl]-3-(2,3-dichloro-phenyl)-ureido]-propyl}-phenoxy)-2-methyl-propionic acid; PPRE, peroxisome proliferator-activated receptor response element; AM-580, 4-[(5,5,8,8-tetramethyl6,7-dihydronaphthalene-2-carbonyl)amino]benzoic acid.
- Received December 19, 2006.
- Accepted February 8, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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