The one-two punch: Retinoic acid suppresses obesity both by promoting energy expenditure and by inhibiting adipogenesis

The vitamin A metabolite retinoic acid (RA) regulates gene transcription by activating the nuclear receptors RAR and PPARβ/δ and their cognate lipid binding proteins CRABP-II, which delivers RA to RAR, and FABP5, which shuttles the hormone to PPARβ/δ. In preadipocytes, RA signals predominantly through CRABP-II and the RAR isotype RARγ to induce the expression of hallmark markers of preadipocytes Pref-1, Sox9, and KLF2. RA thus maintains the preadipocyte phenotype and inhibits adipogenesis. In mature adipocytes, RA activates both of its receptors to upregulate expression of genes that enhance lipid oxidation, energy dissipation, and insulin responses. Consequently, RA potently protects mice from diet-induced obesity and insulin resistance by two distinct mechanisms: by counteracting adipogenesis, thereby moderating the formation of new fat cells, and by promoting energy expenditure, thereby preventing adipocyte hypertrophy.