All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta 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 (PPARbeta/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 PPARbeta/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 PPARbeta/delta expression and activity. RA treatment of obese mice induced expression of PPARbeta/delta and RAR target genes involved in regulation of lipid homeostasis, leading to weight loss and improved insulin responsiveness. RA treatment also restored adipose PPARbeta/delta expression. The data indicate that suppression of obesity and insulin resistance by RA is largely mediated by PPARbeta/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.
Department of Pharmacology, Case Western Reserve University, 10900 Euclid Ave., SOM W333, Cleveland, OH 44106, USA.
Daniel C
DC
Berry
Noa
N
Noy
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control*; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D009363:Neoplasm Proteins; D047494:PPAR delta; D048068:PPAR-beta; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin