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 ChenCarlos 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, Shingo Kajimura

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19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)614-619
Number of pages6
JournalNature
Volume572
Issue number7771
DOIs
Publication statusPublished - 2019 Aug 29

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Cite this

Yoneshiro, T., Wang, Q., Tajima, K., Matsushita, M., Maki, H., Igarashi, K., Dai, Z., White, P. J., McGarrah, R. W., Ilkayeva, O. R., Deleye, Y., Oguri, Y., Kuroda, M., Ikeda, K., Li, H., Ueno, A., Ohishi, M., Ishikawa, T., Kim, K., ... Kajimura, S. (2019). BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature, 572(7771), 614-619. https://doi.org/10.1038/s41586-019-1503-x