BCAA catabolism in brown fat controls energy homeostasis through SLC25A44.

Authors:

Takeshi Yoneshiro 1,2,3,14, Qiang Wang 1,2,3,14, Kazuki Tajima 1,2,3, Mami Matsushita 4, Hiroko Maki 5, Kaori Igarashi 5, Zhipeng Dai 6, Phillip J. White 7, Robert W. McGarrah 7, Olga R. Ilkayeva 7, Yann Deleye 7, Yasuo Oguri 1,2,3, Mito Kuroda 1,2,3, Kenji Ikeda 1,2,3,8, Huixia Li 1,2,3, Ayano Ueno 5, Maki Ohishi 5, Takamasa Ishikawa 5, Kyeongkyu Kim 1,2,3, Yong Chen 1,2,3,Carlos Henrique Sponton 1,2,3, Rachana N. Pradhan 1,2,3, Homa Majd 2, Vanille Juliette Greiner 1,9, Momoko Yoneshiro 1,2,3, Zachary Brown 1,2,3, Maria Chondronikola 10, Haruya Takahashi 11, Tsuyoshi Goto 11, Teruo Kawada 11, Labros Sidossis 12,Francis C. Szoka 6, Michael T. McManus 1,9, Masayuki Saito 13, Tomoyoshi Soga 5 & Shingo Kajimura 1,2,3

Journal:

Nature.

Publication Date:

Wed, 2019-08-21

Institutions:

1UCSF Diabetes Center, San Francisco, CA, USA. 2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA. 3Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA. 4Department of Nutrition, Tenshi College, Sapporo, Japan. 5Institute for Advanced Biosciences, Keio University, Yamagata, Japan. 6Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA. 7Duke Molecular Physiology Institute, Duke University, Durham, NC, USA. 8Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan. 9Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. 10Center for Human Nutrition, Washington University in St Louis, St Louis, MO, USA. 11Laboratory of Molecular Function of Food, Graduate School of Agriculture, Kyoto University, Uji, Japan. 12Department of Kinesiology and Health, School of Arts and Sciences, Rutgers University, New Brunswick, NJ, USA. 13Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan. 14 These authors contributed equally: Takeshi Yoneshiro, Qiang Wang

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 dietinduced 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.