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

• Authors: Daniel C Berry, Noa Noy
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 29 Issue 12 Pg. 3286-96 (Jun 2009) ISSN: 1098-5549 [Electronic] United States
• PMID: 19364826 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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