BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

Takeshi Yoneshiro, Qiang Wang, Kazuki Tajima, Mami Matsushita, Hiroko Maki, Kaori Igarashi, Zhipeng Dai, Phillip J. White, Robert W. McGarrah, Olga R. Ilkayeva, Yann Deleye, Yasuo Oguri, Mito Kuroda, Kenji Ikeda, Huixia Li, Ayano Ueno, Maki Ohishi, Takamasa Ishikawa, Kyeongkyu Kim, Yong Chen, Carlos Henrique Sponton, Rachana N. Pradhan, Homa Majd, Vanille Juliette Greiner, Momoko Yoneshiro, Zachary Brown, Maria Chondronikola, Haruya Takahashi, Tsuyoshi Goto, Teruo Kawada, Labros Sidossis, Francis C. Szoka, Michael T. McManus, Masayuki Saito, Tomoyoshi Soga and Shingo Kajimura ()
Additional contact information
Takeshi Yoneshiro: UCSF Diabetes Center
Qiang Wang: UCSF Diabetes Center
Kazuki Tajima: UCSF Diabetes Center
Mami Matsushita: Tenshi College
Hiroko Maki: Keio University
Kaori Igarashi: Keio University
Zhipeng Dai: University of California, San Francisco
Phillip J. White: Duke University
Robert W. McGarrah: Duke University
Olga R. Ilkayeva: Duke University
Yann Deleye: Duke University
Yasuo Oguri: UCSF Diabetes Center
Mito Kuroda: UCSF Diabetes Center
Kenji Ikeda: UCSF Diabetes Center
Huixia Li: UCSF Diabetes Center
Ayano Ueno: Keio University
Maki Ohishi: Keio University
Takamasa Ishikawa: Keio University
Kyeongkyu Kim: UCSF Diabetes Center
Yong Chen: UCSF Diabetes Center
Carlos Henrique Sponton: UCSF Diabetes Center
Rachana N. Pradhan: UCSF Diabetes Center
Homa Majd: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
Vanille Juliette Greiner: UCSF Diabetes Center
Momoko Yoneshiro: UCSF Diabetes Center
Zachary Brown: UCSF Diabetes Center
Maria Chondronikola: Washington University in St Louis
Haruya Takahashi: Kyoto University
Tsuyoshi Goto: Kyoto University
Teruo Kawada: Kyoto University
Labros Sidossis: Rutgers University
Francis C. Szoka: University of California, San Francisco
Michael T. McManus: UCSF Diabetes Center
Masayuki Saito: Hokkaido University
Tomoyoshi Soga: Keio University
Shingo Kajimura: UCSF Diabetes Center

Nature, 2019, vol. 572, issue 7771, 614-619

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1503-x

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