BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

Nature. 2019 Aug;572(7771):614-619. doi: 10.1038/s41586-019-1503-x. Epub 2019 Aug 21.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / cytology
  • Adipose Tissue, Brown / metabolism*
  • Amino Acid Transport Systems / metabolism*
  • Amino Acids, Branched-Chain / metabolism*
  • Animals
  • Cold Temperature
  • Energy Metabolism*
  • Glucose Intolerance / metabolism
  • Homeostasis*
  • Humans
  • Male
  • Mice
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism*
  • Obesity / metabolism
  • Solute Carrier Proteins / metabolism*
  • Thermogenesis*

Substances

  • Amino Acid Transport Systems
  • Amino Acids, Branched-Chain
  • Mitochondrial Proteins
  • SLC25A44 protein, human
  • Solute Carrier Proteins