Retinol, the major form of the fat-soluble vitamin A, is converted into various metabolites. Retinoic acid (RA), the chief metabolite, acts through the retinoic acid and retinoid X receptors (RAR and RXR) to regulate the transcription of target genes; no direct role outside the retina has been identified for the intermediate metabolite retinaldehyde (see Desvergne). Using reduction to retinaldehyde oximes to measure the unstable retinaldehyde, Ziouzenkova et al. identified retinaldehyde in rodent fat and determined that it was present at a lower concentration in fat from obese mice than it was in fat from lean mice. Retinaldehyde inhibited the expression of mRNA encoding adipogenic genes in 3T3-L1 mouse preadipocytes. Its effects were distinct from those of retinoic acid: Whereas retinaldehyde and 9-cis and all-trans isomers of retinoic acid all inhibited expression of the gene encoding adiponectin (Adipoq) when added early in adipogenesis, only retinaldehyde inhibited Adipoq later in this process. Retinaldehyde inhibited adipogenesis in response to stimulation of peroxisome proliferator-activated receptor-γ (PPAR-γ, which heterodimerizes RXR) and agonist-dependent activation of a gene reporter containing the PPAR response element. Experiments using siRNA directed against RXR-α and RXR-β, however, suggested that inhibition of adipogenesis by retinaldehyde involved both RXR-dependent and RXR-independent effects. Adipocytes from mice lacking retinaldehyde dehydrogenase-1 (Raldh1), which catabolizes retinaldehyde to RA, were smaller than those from wild-type mice, and in vitro adipogenesis of fibroblasts from Raldh1–/– mice was reduced. Intriguingly, Raldh1–/– mice gained less weight in response to a high-fat diet than did wild-type mice, showed decreased body fat, increased metabolism, and were less susceptible to developing insulin resistance. Moreover, retinaldehyde (or an Raldh1 inhibitor) decreased body fat and increased glucose tolerance in transgenic mice that become obese on a normal diet. Thus, the authors conclude that retinaldehyde plays a distinct role in inhibiting adipogenesis and in mediating the metabolic response to diet.
O. Ziouzenkova, G. Orasanu, M. Sharlach, T. E. Akiyama, J. P. Berger, J. Viereck, J. A. Hamilton, G. Tang, G. G. Dolnikowski, S. Vogel, G. Duester, J. Plutzky, Retinaldehyde represses adipogenesis and diet-induced obesity. Nat. Med. 13, 695-702 (2007). [PubMed]
B. Desvergne, Retinaldehyde: More than meets the eye. Nat. Med. 13, 671-673 (2007). [PubMed]