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

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