Valine

Amino acid

Biology

Leucine

Catabolism

Endocrinology

Metabolism

Brown adipose tissue

Biochemistry

Branched-chain amino acid

Homeostasis

Thermogenesis

Insulin resistance

Energy metabolism

Energy homeostasis

Isoleucine

Internal medicine

Mitochondrion

Medicine

Chemistry

Obesity

Adipose tissue

Glucose homeostasis

Nature

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on 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, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health. The solute carrier transporter protein SLC25A44 regulates uptake of branched-chain amino acids in mitochondria of brown adipose tissue in which they are utilized for thermogenesis.

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44