MCB Accepts, published online ahead of print on 13 April 2009

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Mol. Cell. Biol. doi:10.1128/MCB.01742-08
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

All-trans-retinoic acid represses obesity and insulin resistance by activating both PPAR/ and RAR

Daniel C. Berry and Noa Noy^*

Department of Pharmacology and Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106

^* To whom correspondence should be addressed. Email: nxn51{at}case.edu.

Many biological activities of all-trans-retinoic acid (RA) are mediated by the ligand-activated transcription factors termed retinoic acid receptors (RARs) but this hormone can also activate the nuclear receptor PPAR/. We show here that adipocyte differentiation is accompanied by a shift in RA signalling which, in mature adipocytes, allows RA to activate both RARs and PPAR/, thereby enhancing lipolysis and depleting lipid stores. In vivo studies using a dietary-induced mouse model of obesity indicated that onset of obesity is accompanied by down-regulation of adipose PPAR/ expression and activity. RA treatment of obese mice induced expression of PPAR/ and RAR target genes involved in regulation of lipid homeostasis, leading to weight loss and improved insulin responsiveness. RA treatment also restored adipose PPAR/ expression. The data indicate that suppression of obesity and insulin resistance by RA is largely mediated by PPAR/ and is further enhanced by activation of RARs. By targeting two nuclear receptors, RA may be a uniquely efficacious agent in therapy and prevention of the metabolic syndrome.

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