All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor

Mol Cell Biol. 2009 Jun;29(12):3286-96. doi: 10.1128/MCB.01742-08. Epub 2009 Apr 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipogenesis / drug effects
  • Adipogenesis / physiology
  • Adiposity / drug effects
  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Diet / adverse effects
  • Disease Models, Animal
  • Fatty Acid-Binding Proteins / genetics
  • Fatty Acid-Binding Proteins / metabolism
  • Insulin Resistance*
  • Lipolysis / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Obesity / drug therapy
  • Obesity / metabolism*
  • Obesity / prevention & control*
  • PPAR delta / genetics
  • PPAR delta / metabolism*
  • PPAR-beta / genetics
  • PPAR-beta / metabolism*
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Signal Transduction / drug effects
  • Tretinoin / pharmacology*


  • Fabp5 protein, mouse
  • Fatty Acid-Binding Proteins
  • Neoplasm Proteins
  • PPAR delta
  • PPAR-beta
  • Receptors, Retinoic Acid
  • retinoic acid binding protein II, cellular
  • Tretinoin