Transformation of white into brown fat (“browning”) reduces obesity in many preclinical models and holds great promise as a therapeutic concept in metabolic disease. Vitamin A metabolites (retinoids) have been linked to thermogenic programming of adipose tissue; however, the physiologic importance of systemic retinoid transport for adipose tissue browning and adaptive thermogenesis is unknown.
We performed cold exposure studies in mice and humans and used a genetic model of defective vitamin A transport, the retinol binding protein deficient (Rbp−/-) mouse, to study the effects of cooling on systemic vitamin A and the relevance of intact retinoid transport on cold-induced adipose tissue browning.
We show that cold stimulation in mice and humans leads to an increase in circulating retinol and its plasma transporter, Rbp. In Rbp−/- mice, thermogenic programming of adipocytes and oxidative mitochondrial function are dramatically impaired in subcutaneous white fat, which renders Rbp−/- mice more cold-sensitive. In contrast, retinol stimulation in primary human adipocytes promotes thermogenic gene expression and mitochondrial respiration. In humans, cold-mediated retinol increase is associated with a shift in oxidative substrate metabolism suggestive of higher lipid utilisation.
Systemic vitamin A levels are regulated by cold exposure in mice and humans, and intact retinoid transport is essential for cold-induced adipose tissue browning and adaptive thermogenesis.