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BCAA catabolism in brown fat controls energy homeostasis through SLC25A44

Author

Listed:
  • Takeshi Yoneshiro

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • Qiang Wang

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • Kazuki Tajima

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • 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
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • Mito Kuroda

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • Kenji Ikeda

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco
    Tokyo Medical and Dental University)

  • Huixia Li

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • Ayano Ueno

    (Keio University)

  • Maki Ohishi

    (Keio University)

  • Takamasa Ishikawa

    (Keio University)

  • Kyeongkyu Kim

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • Yong Chen

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • Carlos Henrique Sponton

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • Rachana N. Pradhan

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • Homa Majd

    (Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research)

  • Vanille Juliette Greiner

    (UCSF Diabetes Center
    University of California, San Francisco)

  • Momoko Yoneshiro

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • Zachary Brown

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

  • 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
    University of California, San Francisco)

  • Masayuki Saito

    (Hokkaido University)

  • Tomoyoshi Soga

    (Keio University)

  • Shingo Kajimura

    (UCSF Diabetes Center
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
    University of California, San Francisco)

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.

Suggested Citation

  • 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 & M, 2019. "BCAA catabolism in brown fat controls energy homeostasis through SLC25A44," Nature, Nature, vol. 572(7771), pages 614-619, August.
    • Handle: RePEc:nat:nature:v:572:y:2019:i:7771:d:10.1038_s41586-019-1503-x
    DOI: 10.1038/s41586-019-1503-x
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    Cited by:

    1. Clément Pontoizeau & Marcelo Simon-Sola & Clovis Gaborit & Vincent Nguyen & Irina Rotaru & Nolan Tual & Pasqualina Colella & Muriel Girard & Maria-Grazia Biferi & Jean-Baptiste Arnoux & Agnès Rötig & , 2022. "Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Xiaofan Yu & Gabrielle Benitez & Peter Tszki Wei & Sofia V. Krylova & Ziyi Song & Li Liu & Meifan Zhang & Alus M. Xiaoli & Henna Wei & Fenfen Chen & Simone Sidoli & Fajun Yang & Kosaku Shinoda & Jeffr, 2024. "Involution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Donghua Hu & Min Tan & Dongliang Lu & Brian Kleiboeker & Xuejing Liu & Hongsuk Park & Alexxai V. Kravitz & Kooresh I. Shoghi & Yu-Hua Tseng & Babak Razani & Akihiro Ikeda & Irfan J. Lodhi, 2023. "TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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