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; Shingo Kajimura

doi:https://doi.org/10.1038/s41586-019-1503-x

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

School of Arts and Sciences, Kinesiology & Health

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

84 Scopus citations

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 language	American English
Pages (from-to)	614-619
Number of pages	6
Journal	Nature
Volume	572
Issue number	7771
DOIs	https://doi.org/10.1038/s41586-019-1503-x
State	Published - Aug 29 2019

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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

@article{81cf6e4b63194c4680018301c8cce3d8,

title = "BCAA catabolism in brown fat controls energy homeostasis through SLC25A44",

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.",

author = "Takeshi Yoneshiro and Qiang Wang and Kazuki Tajima and Mami Matsushita and Hiroko Maki and Kaori Igarashi and Zhipeng Dai and White, {Phillip J.} and McGarrah, {Robert W.} and Ilkayeva, {Olga R.} and Yann Deleye and Yasuo Oguri and Mito Kuroda and Kenji Ikeda and Huixia Li and Ayano Ueno and Maki Ohishi and Takamasa Ishikawa and Kyeongkyu Kim and Yong Chen and Sponton, {Carlos Henrique} and Pradhan, {Rachana N.} and Homa Majd and Greiner, {Vanille Juliette} and Momoko Yoneshiro and Zachary Brown and Maria Chondronikola and Haruya Takahashi and Tsuyoshi Goto and Teruo Kawada and Labros Sidossis and Szoka, {Francis C.} and McManus, {Michael T.} and Masayuki Saito and Tomoyoshi Soga and Shingo Kajimura",

note = "Funding Information: Acknowledgements We thank C. B. Newgard for the initial metabolomics analysis, E. Kunji for liposome study, Y. Seo and T. Huynh for the PET–CT scan, Y. Cheng and E. Green for HEK293S cells, E. T. Chouchani and E. Mills for cell respiration studies, and X. Lu and K. Shinoda for technical help. This work was supported by the NIH (DK97441 and DK112268) and the Edward Mallinckrodt Jr. Foundation to S.K., the American Diabetes Association Pathways Award (1-16-INI-17) to P.J.W., the AMED–CREST from the Japan Agency for Medical Research and Development to T.S., and the NIH (U19CA179513 and P30 DK063720) to M.T.M. T.Y. and M.K. are supported by the JSPS Fellowships. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = aug,

day = "29",

doi = "https://doi.org/10.1038/s41586-019-1503-x",

language = "American English",

volume = "572",

pages = "614--619",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7771",

}

Yoneshiro, T, Wang, Q, Tajima, K, Matsushita, M, Maki, H, Igarashi, K, Dai, Z, White, PJ, McGarrah, RW, Ilkayeva, OR, Deleye, Y, Oguri, Y, Kuroda, M, Ikeda, K, Li, H, Ueno, A, Ohishi, M, Ishikawa, T, Kim, K, Chen, Y, Sponton, CH, Pradhan, RN, Majd, H, Greiner, VJ, Yoneshiro, M, Brown, Z, Chondronikola, M, Takahashi, H, Goto, T, Kawada, T, Sidossis, L, Szoka, FC, McManus, MT, Saito, M, Soga, T & Kajimura, S 2019, 'BCAA catabolism in brown fat controls energy homeostasis through SLC25A44', Nature, vol. 572, no. 7771, pp. 614-619. https://doi.org/10.1038/s41586-019-1503-x

TY - JOUR

T1 - BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

AU - Yoneshiro, Takeshi

AU - Wang, Qiang

AU - Tajima, Kazuki

AU - Matsushita, Mami

AU - Maki, Hiroko

AU - Igarashi, Kaori

AU - Dai, Zhipeng

AU - White, Phillip J.

AU - McGarrah, Robert W.

AU - Ilkayeva, Olga R.

AU - Deleye, Yann

AU - Oguri, Yasuo

AU - Kuroda, Mito

AU - Ikeda, Kenji

AU - Li, Huixia

AU - Ueno, Ayano

AU - Ohishi, Maki

AU - Ishikawa, Takamasa

AU - Kim, Kyeongkyu

AU - Chen, Yong

AU - Sponton, Carlos Henrique

AU - Pradhan, Rachana N.

AU - Majd, Homa

AU - Greiner, Vanille Juliette

AU - Yoneshiro, Momoko

AU - Brown, Zachary

AU - Chondronikola, Maria

AU - Takahashi, Haruya

AU - Goto, Tsuyoshi

AU - Kawada, Teruo

AU - Sidossis, Labros

AU - Szoka, Francis C.

AU - McManus, Michael T.

AU - Saito, Masayuki

AU - Soga, Tomoyoshi

AU - Kajimura, Shingo

N1 - Funding Information: Acknowledgements We thank C. B. Newgard for the initial metabolomics analysis, E. Kunji for liposome study, Y. Seo and T. Huynh for the PET–CT scan, Y. Cheng and E. Green for HEK293S cells, E. T. Chouchani and E. Mills for cell respiration studies, and X. Lu and K. Shinoda for technical help. This work was supported by the NIH (DK97441 and DK112268) and the Edward Mallinckrodt Jr. Foundation to S.K., the American Diabetes Association Pathways Award (1-16-INI-17) to P.J.W., the AMED–CREST from the Japan Agency for Medical Research and Development to T.S., and the NIH (U19CA179513 and P30 DK063720) to M.T.M. T.Y. and M.K. are supported by the JSPS Fellowships. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2019/8/29

Y1 - 2019/8/29

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85070951094&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070951094&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/s41586-019-1503-x

DO - https://doi.org/10.1038/s41586-019-1503-x

M3 - Article

C2 - 31435015

SN - 0028-0836

VL - 572

SP - 614

EP - 619

JO - Nature

JF - Nature

IS - 7771

ER -

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

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