The metabolism of vitamin A and the diverse effects of its metabolites are tightly controlled by distinct retinoid-generating enzymes, retinoid-binding proteins and retinoid-activated nuclear receptors. Retinoic acid regulates differentiation and metabolism by activating the retinoic acid receptor and retinoid X receptor (RXR), indirectly influencing RXR heterodimeric partners. Retinoic acid is formed solely from retinaldehyde (Rald), which in turn is derived from vitamin A. Rald currently has no defined biologic role outside the eye. Here we show that Rald is present in rodent fat, binds retinol-binding proteins (CRBP1, RBP4), inhibits adipogenesis and suppresses peroxisome proliferator-activated receptor-c and RXR responses. In vivo, mice lacking the Rald-catabolizing enzyme retinaldehyde dehydrogenase 1 (Raldh1) resisted diet-induced obesity and insulin resistance and showed increased energy dissipation. In ob/ob mice, administrating Rald or a Raldh inhibitor reduced fat and increased insulin sensitivity. These results identify Rald as a distinct transcriptional regulator of the metabolic responses to a high-fat diet.Although vitamin A and its metabolite retinoic acid have therapeutic applications, frequent side effects limit their use 1-3 . In clinical trials involving β-carotene supplementation, worrisome increases in cardiovascular events and mortality have been noted, despite evidence suggesting possible beneficial vascular effects of this treatment 3 . These variable responses to retinoids probably derive from the fact that β-carotene and vitamin A (retinol) and their major metabolites-retinaldehyde (Rald) and retinoic acid-regulate diverse cellular responses, including development, immune function and vision 4,5 . The tight control of retinoid biology is evident in the elaborate system that governs the absorption, formation, transportation and action of these structurally and functionally distinct retinoid metabolites. Despite this, retinoids

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