Cold-mediated regulation of systemic retinol transport controls adipose tissue browning

Browning of white fat reduces obesity in many preclinical models. Vitamin A metabolites (retinoids) have been linked to thermogenic programming of adipose tissue (AT), however the physiologic importance of systemic retinoid metabolism for AT browning is unknown. Here we show that cold stimulation in mice and humans increases circulating retinol and its plasma transporter, retinol binding protein (RBP). Cold exposure shifts retinol abundance from liver towards subcutaneous white AT which correlates with enhanced thermogenic gene transcription. Cold-mediated retinoid flux is abrogated in Rbp deficient (Rbp-/-) mice and AT browning is dramatically impaired, which renders Rbp-/- mice cold intolerant. Rbp deficiency attenuates cold-induced lipid clearance due to decreased oxidative capacity. In humans, cold-mediated retinol increase is associated with enhanced lipid utilization. Retinol stimulation in primary human adipocytes promotes thermogenic gene expression and mitochondrial respiration. In conclusion, coordinated retinol delivery is essential for cold-induced thermogenic programming of white fat.