BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

Branched-chain amino acid (BCAA; valine, leucine, and isoleucine) supplementation is often beneficial to energy expenditure; however, paradoxically increased circulating BCAA levels are linked to obesity and diabetes. The mechanisms of the paradox remain elusive. Here we report that, upon cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation, and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, a previously uncharacterized mitochondrial transporter for BCAA. The present study suggests that BAT serves as a significant metabolic-filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.