Abstract 1556: Retinaldehyde Inhibits Adipogenesis Through RXR and PPAR-gamma Repression
Although visceral obesity is strongly associated with diabetes mellitus and atherosclerosis, mechanisms that determine visceral vs. subcutaneous fat accumulation remain obscure. We hypothesized that vitamin A metabolism may regulate the differentiation of specific fat depots through retinoic acid (RA) and its essential precursor retinaldehyde (Rald). RA regulates key metabolic and differentiation pathways as a natural ligand for two subfamilies of nuclear receptors: retinoic acid receptor and retinoid X receptor (RXR). RXR is activated only by the 9-cis RA isoform. Although Rald is essential for the visual cycle, an RA-independent role of Rald in adipogenesis is unknown. Using liquid chromatography-mass spectrometry analysis, we found Rald is present in rodent fat at 0.4–1.6 nmol/g. At similar concentrations, Rald blocked differentiation of 3T3-L1 preadipocytes, an effect that persisted even in the presence of the peroxisome proliferator-activated receptor γ (PPARγ) ligand rosiglitazone, a potent adipogenic stimulus. Although Rald also repressed expression of the PPARγ target genes adiponectin and aP2 in this system, transfection of RXRα/RXRβ siRNA minimized these effects. These results suggest that Rald can regulate activation of RXR and/or the heterodimeric PPARγ RXR complex. Consistent with this, in standard ligand binding domain (LBD)-GAL4 assays, Rald decreased RXRα LBD activation by 9-cis RA (IC50=200nM), inhibited PPAR response element activation (2.3-fold, 100nM), and suppressed induction of PPARγ RXR target genes. Given this opposing regulation of RXR by RA and Rald, we next tested the effects of vitamin A, RA, and Rald in vivo (all 500nM, daily intraperitoneal injection for 3 weeks) on peritoneal fat content in C57Bl6 mice using multi-slice MRI imaging. Mice receiving Rald had a significantly lower percentage of subcutaneous fat relative to total body fat vs. control (p<0.005), vitamin A (p<0.04), and RA groups (p<0.005). Fat distribution in RA and vitamin A groups was similar to controls. Our data identifies Rald as a biologically active vitamin A metabolite present in fat in vivo, where it can regulate adipogenesis and fat distribution, with divergent effects from the vitamin A/Rald metabolite RA.