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.