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Molecular and Cellular Biology, June 2009, p. 3286-3296, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01742-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

All-trans-Retinoic Acid Represses Obesity and Insulin Resistance by Activating both Peroxisome Proliferation-Activated Receptor β/{delta} and Retinoic Acid Receptor{triangledown} ,{dagger}

Daniel C. Berry and Noa Noy*

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

Received 13 November 2008/ Returned for modification 15 January 2009/ Accepted 30 March 2009

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 peroxisome proliferation-activated receptor β/{delta} (PPARβ/{delta}). We show here that adipocyte differentiation is accompanied by a shift in RA signaling which, in mature adipocytes, allows RA to activate both RARs and PPARβ/{delta}, 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 downregulation of adipose PPARβ/{delta} expression and activity. RA treatment of obese mice induced expression of PPARβ/{delta} and RAR target genes involved in regulation of lipid homeostasis, leading to weight loss and improved insulin responsiveness. RA treatment also restored adipose PPARβ/{delta} expression. The data indicate that suppression of obesity and insulin resistance by RA is largely mediated by PPARβ/{delta} and is further enhanced by activation of RARs. By targeting two nuclear receptors, RA may be a uniquely efficacious agent in the therapy and prevention of the metabolic syndrome.

* Corresponding author. Mailing address: Department of Pharmacology, Case Western Reserve University, 10900 Euclid Ave., SOM W333, Cleveland, OH 44106. Phone: (216) 368-0302. Fax: (216) 368-1300. E-mail: nxn51{at}case.edu

{triangledown} Published ahead of print on 13 April 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2009, p. 3286-3296, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01742-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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