BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

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

Takeshi Yoneshiro ¹ ² ³, Qiang Wang ¹ ² ³, 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 ¹⁴ ¹⁵ ¹⁶

Affiliations

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

PMID: 31435015 DOI: 10.1038/s41586-019-1503-x

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.

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