Retinoid metabolism and nuclear receptor responses: New insights into coordinated regulation of the PPAR–RXR complex

Retinoids, naturally‐occurring vitamin A derivatives, regulate metabolism by activating specific nuclear receptors, including the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). RXR, an obligate heterodimeric partner for other nuclear receptors, including peroxisome proliferator‐activated receptors (PPARs), helps coordinate energy balance. Recently, many groups have identified new connections between retinoid metabolism and PPAR responses. We found that retinaldehyde (Rald), a molecule that can yield RA through the action of retinaldehyde dehydrogenases (Raldh), is present in fat in vivo and can inhibit PPARγ‐induced adipogenesis. In vitro, Rald inhibits RXR and PPARγ activation. Raldh1‐deficient mice have increased Rald levels in fat, higher metabolic rates and body temperatures, and are protected against diet‐induced obesity and insulin resistance. Interestingly, one specific asymmetric β‐carotene cleavage product, apo‐14′‐carotenal, can also inhibit PPARγ and PPARα responses. These data highlight how pathways of β‐carotene metabolism and specific retinoid metabolites may have direct distinct metabolic effects.