All-trans-Retinoic Acid Represses Obesity and Insulin Resistance by Activating both Peroxisome Proliferation-Activated Receptor β/δ and Retinoic Acid Receptor

Abstract

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/δ (PPARβ/δ). 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/δ, 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/δ expression and activity. RA treatment of obese mice induced expression of PPARβ/δ and RAR target genes involved in regulation of lipid homeostasis, leading to weight loss and improved insulin responsiveness. RA treatment also restored adipose PPARβ/δ expression. The data indicate that suppression of obesity and insulin resistance by RA is largely mediated by PPARβ/δ 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.

SUPPLEMENTAL MATERIAL

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ACKNOWLEDGMENTS

This study was supported by NIH grant R01 DK060684 and by ADVANCE grant 024505 for the ACES program of the Case Western Reserve University. The Mouse Metabolic Phenotyping Center of the Case Western Reserve University is supported by NIH grant DK59630.