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Regulatory mechanism of glucose tolerance via mitochondrial BCAA transporter SLC25A44

Research Project

Project/Area Number 20K22647
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0702:Biology at cellular to organismal levels, and related fields
Research InstitutionTohoku University (2023)
The University of Tokyo (2020-2021)

Principal Investigator

Yoneshiro Takeshi  東北大学, 医学系研究科, 准教授 (40724167)

Project Period (FY) 2020-09-11 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsエネルギー消費量 / 褐色脂肪組織 / 分岐鎖アミノ酸 / インスリン抵抗性 / トランスポーター / エネルギー代謝 / インスリン感受性
Outline of Research at the Start

褐色脂肪組織(BAT)は糖や脂肪酸を代謝分解することで熱を産生する特殊な脂肪細胞である。最近、BATは新規ミトコンドリアトランスポーターSLC25A44を介して分岐鎖アミノ酸(BCAA)を積極的に代謝分解することが判明した。本研究では、このSLC25A44を介したBATにおけるBCAA代謝が体脂肪蓄積やインスリン抵抗性などの全身性エネルギー代謝に及ぼす影響とその分子機構を解明する。

Outline of Final Research Achievements

In this study, we examined the effects of the novel mitochondrial BCAA transporter SLC25A44 on brown adipose tissue (BAT) function and systemic glucose tolerance. Whole-body depletion of Slc25a44 in mice resulted in an elevated blood BCAA levels and impaired glucose tolerance despite no change in body weight. BAT-specific SLC25A44 KO mice exhibited impaired BAT thermogenesis. BCAA metabolic tracing revealed that BCAA-derived nitrogen is actively utilized in the synthesis of glutathione, which is known to be involved in the control of glucose tolerance and insulin sensitivity. Circulation glutathione levels in healthy participants was increased following cold exposure selectively in participants with high BAT activity while not in those without. These results suggest that mitochondrial catabolism of BCAAs regulates systemic glucose tolerance in an energy expenditure-dependent and -independent manner.

Academic Significance and Societal Importance of the Research Achievements

肥満や糖尿病患者では血中BCAA濃度が上昇することから、その因果関係が盛んに研究されているが、全容解明には至っていない。最近我々は、BATにおいてBCAAが活発に代謝分解されること、これを障害したマウスでは強いインスリン抵抗性が認められることを報告した(Nature 2019)。しかし、BATではグルコースや脂肪酸が主な基質となるため、BCAAの利用を止めるだけでなぜ顕著な耐糖能異常にまで至るのかは不明なままであった。本研究ではBCAAの代謝分解がエネルギーの消費につながるだけではなく、インスリン感受性を制御する代謝物の合成につながることを見出し、新規治療標的の可能性を提示した。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (36 results)

All 2024 2023 2022 2021 2020 Other

All Int'l Joint Research (1 results) Journal Article (21 results) (of which Int'l Joint Research: 12 results,  Peer Reviewed: 21 results,  Open Access: 10 results) Presentation (14 results) (of which Invited: 10 results)

  • [Int'l Joint Research] Harvard Medical School/Beth Israel Deaconess Medical Center(米国)

    • Related Report
      2020 Research-status Report
  • [Journal Article] Uncoupling metabolic health from thermogenesis via BCAA flux in brown fat.2024

    • Author(s)
      Verkerke ARP*, Wang D*, Yoshida N, Taxin ZH, Shi X, Zheng S, Li Y, Auger C, Oikawa S, Granath-Panelo M, He W, Zhang GF, Matsushita M, Saito M, Gerszten RE, Mills EL, Banks AS, Ishihama Y, White PJ**, McGarrah RW**, Yoneshiro T**, Kajimura S
    • Journal Title

      Cell

      Volume: -

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease2024

    • Author(s)
      Ito R, Xie S, Tumenjargal M, Sugahara Y, Yang C, Takahashi H, Arai M, Inoue SI, Uchida A, Nakano K, Choi H, Yang G, Zhao Y, Yamaguchi R, Jin H, Sagae H, Wada Y, Tanaka T, Kimura H, Kodama T, Aburatani H, Takeda K, Inagaki T, Osborne TF, Yoneshiro T, Matsumura Y, Sakai J.
    • Journal Title

      iScience

      Volume: 27(4) Issue: 4 Pages: 109398-109398

    • DOI

      10.1016/j.isci.2024.109398

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Brown fat thermogenesis and branched-chain amino acids in metabolic disease2024

    • Author(s)
      Brown Zachary、Yoneshiro Takeshi
    • Journal Title

      Endocrine Journal

      Volume: 71 Issue: 2 Pages: 89-100

    • DOI

      10.1507/endocrj.EJ23-0205

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 栄養・環境因子による褐色脂肪組織の代謝制御と肥満.2024

    • Author(s)
      米代武司
    • Journal Title

      体力科学

      Volume: 73 Pages: 46-46

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 交感神経系を介した褐色脂肪組織の熱産生と分岐鎖アミノ酸代謝.2024

    • Author(s)
      米代武司
    • Journal Title

      実験医学

      Volume: -

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 交感神経-エピゲノム酵素軸を介した脂肪細胞の機能調節と環境適応機構.2023

    • Author(s)
      伊藤亮, 高橋宙大, 荒井誠, 稲垣毅, 米代武司, 松村欣宏, 酒井寿郎
    • Journal Title

      実験医学

      Volume: 41 Pages: 29-37

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 食品成分によるTRPチャネル活性化と褐色脂肪組織を介した肥満予防.2023

    • Author(s)
      松下真美, 米代武司, 斉藤昌之.
    • Journal Title

      肥満研究

      Volume: 29 Pages: 24-30

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Melanin-concentrating hormone-producing neurons in the hypothalamus regulate brown adipose tissue and thus contribute to energy expenditure.2022

    • Author(s)
      Izawa S., Yoneshiro T., Kondoh K., Nakagiri S., Okamatsu-Ogura Y., Terao A., Minokoshi Y., Yamanaka A., and Kimura K.
    • Journal Title

      J. Physiol.

      Volume: 600 Issue: 4 Pages: 815-827

    • DOI

      10.1113/jp281241

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prolonged Treatment with Grains of Paradise (<i>Aframomum melegueta</i>) Extract Recruits Adaptive Thermogenesis and Reduces Body Fat in Humans with Low Brown Fat Activity2021

    • Author(s)
      YONESHIRO Takeshi、MATSUSHITA Mami、SUGITA Jun、AITA Sayuri、KAMEYA Toshimitsu、SUGIE Hiroki、SAITO Masayuki
    • Journal Title

      Journal of Nutritional Science and Vitaminology

      Volume: 67 Issue: 2 Pages: 99-104

    • DOI

      10.3177/jnsv.67.99

    • NAID

      130008031493

    • ISSN
      0301-4800, 1881-7742
    • Year and Date
      2021-04-30
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Spatiotemporal dynamics of SETD5-containing NCoR-HDAC3 complex determines enhancer activation for adipogenesis2021

    • Author(s)
      Matsumura Y, Ito R, Yajima A, Yamaguchi R, Tanaka T, Kawamura T, Magoori K, Abe Y, Uchida A, Yoneshiro T, Hirakawa H, Zhang J, Arai M, Yang C, Yang G, Takahashi H, Fujihashi H, Nakaki R, Yamamoto S, Ota S, Tsutsumi S, Inoue SI, Kimura H, Wada Y, Kodama T, Inagaki T, Osborne TF, Aburatani H, Node K, Sakai J.
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 7045-7045

    • DOI

      10.1038/s41467-021-27321-5

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bacteroides spp. promotes branched-chain amino acid catabolism in brown fat and inhibits obesity2021

    • Author(s)
      Yoshida Naofumi、Yamashita Tomoya、Osone Tatsunori、Shinohara Masakazu、Kitahama Seiichi、Sasaki Kengo、Sasaki Daisuke、Emoto Takuo、Saito Yoshihiro、Kitaura Yasuyuki、Shimomura Yoshiharu、Kondo Akihiko、Kajimura Shingo、Inagaki Takeshi、Yamada Takuji、Hirata Ken-ichi
    • Journal Title

      iScience

      Volume: 24 Issue: 11 Pages: 103342-103342

    • DOI

      10.1016/j.isci.2021.103342

    • NAID

      120007179184

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever2021

    • Author(s)
      Yoneshiro T, Kataoka N, Walejko JM, Ikeda K, Brown Z, Yoneshiro M, Crown SB, Osawa T, Sakai J, McGarrah RW, White PJ, Nakamura K, Kajimura S.
    • Journal Title

      Elife

      Volume: 10

    • DOI

      10.7554/elife.66865

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart2021

    • Author(s)
      Walejko JM, Christopher BA, Crown SB, Zhang GF, Pickar-Oliver A, Yoneshiro T, Foster MW, Page S, van Vliet S, Ilkayeva O, Muehlbauer MJ, Carson MW, Brozinick JT, Hammond CD, Gimeno RE, Moseley MA, Kajimura S, Gersbach CA, Newgard CB, White PJ, McGarrah RW
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 1680-1680

    • DOI

      10.1038/s41467-021-21962-2

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Kruppel‐like factor15 regulates fuel switching between glucose and fatty acids in brown adipocytes2021

    • Author(s)
      Nabatame Yuko、Hosooka Tetsuya、Aoki Chikako、Hosokawa Yusei、Imamori Makoto、Tamori Yoshikazu、Okamatsu‐Ogura Yuko、Yoneshiro Takeshi、Kajimura Shingo、Saito Masayuki、Ogawa Wataru
    • Journal Title

      Journal of Diabetes Investigation

      Volume: Online ahead of print Issue: 7 Pages: 1144-1151

    • DOI

      10.1111/jdi.13511

    • NAID

      120007098979

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 褐色脂肪細胞の新たな研究の展開2021

    • Author(s)
      米代武司, 田島一樹
    • Journal Title

      Medical Practice

      Volume: 38 Pages: 1059-1061

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] 褐色脂肪組織の個人差と肥満:BCAAの役割2021

    • Author(s)
      米代武司
    • Journal Title

      実験医学

      Volume: 39 Pages: 775-781

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] 褐色脂肪組織におけるアミノ酸代謝と糖尿病2021

    • Author(s)
      米代武司, 曽我朋義, 梶村真吾
    • Journal Title

      実験医学 別冊 メタボロミクス実践ガイド

      Volume: 1 Pages: 280-282

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Editorial: Current Challenges for Targeting Brown Fat Thermogenesis to Combat Obesity2020

    • Author(s)
      Yoneshiro Takeshi、Rodriguez-Rodriguez Rosalia、Betz Matthias Johannes、Rensen Patrick C. N.
    • Journal Title

      Frontiers in Endocrinology

      Volume: 11 Pages: 600341-600341

    • DOI

      10.3389/fendo.2020.600341

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Near-Infrared Time-Resolved Spectroscopy for Assessing Brown Adipose Tissue Density in Humans: A Review2020

    • Author(s)
      Hamaoka Takafumi、Nirengi Shinsuke、Fuse Sayuri、Amagasa Shiho、Kime Ryotaro、Kuroiwa Miyuki、Endo Tasuki、Sakane Naoki、Matsushita Mami、Saito Masayuki、Yoneshiro Takeshi、Kurosawa Yuko
    • Journal Title

      Frontiers in Endocrinology

      Volume: 11 Pages: 261-261

    • DOI

      10.3389/fendo.2020.00261

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Brown adipose tissue, diet-induced thermogenesis, and thermogenic food ingredients: from mice to men2020

    • Author(s)
      Saito M, Matsushita M, Yoneshiro T, Okamatsu-Ogura Y
    • Journal Title

      Front Endocrinol

      Volume: 11 Pages: 222-222

    • DOI

      10.3389/fendo.2020.00222

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The regulation of glucose and lipid homeostasis via PLTP as a mediator of BAT ?liver communication2020

    • Author(s)
      Sponton Carlos H、Hosono Takashi、Taura Junki、Jedrychowski Mark P、Yoneshiro Takeshi、Wang Qiang、Takahashi Makoto、Matsui Yumi、Ikeda Kenji、Oguri Yasuo、et al.
    • Journal Title

      EMBO reports

      Volume: 21 Issue: 9

    • DOI

      10.15252/embr.201949828

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] 栄養・環境因子による褐色脂肪組織の代謝制御と肥満.2023

    • Author(s)
      米代武司
    • Organizer
      日本体力医学会特別大会-2023東京シンポジウム
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Translational aspects of brown adipose tissue (BAT) activation by food ingredients.2023

    • Author(s)
      Takeshi Yoneshiro
    • Organizer
      Nutrition Society of Australia (NSA) Webinar
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 妊娠前の親の寒冷曝露が子の褐色脂肪組織の活性と肥満度に与える影響.2023

    • Author(s)
      米代武司, 松下真美,布施沙由理,黒岩美幸,黒澤裕子,山本恭子,山岡敏明, 飯田誠,隈健一,中村尚,浜岡隆文,酒井寿郎,斉藤昌之.
    • Organizer
      第77回日本栄養・食糧学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Translational aspects of brown fat activation by food-derived stimulants.2023

    • Author(s)
      Takeshi Yoneshiro
    • Organizer
      JSNFS, NST & KFN Joint Symposium
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 分岐差アミノ酸代謝を介したエネルギー恒常性の調節2021

    • Author(s)
      米代武司
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 褐色脂肪組織の分岐鎖アミノ酸クリアランス機能と糖尿病治療戦略2021

    • Author(s)
      米代武司
    • Organizer
      第94回日本生化学大会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 褐色脂肪組織の熱産生と体温調節2021

    • Author(s)
      米代武司
    • Organizer
      第74回日本自律神経学会総会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 褐色脂肪組織における基質選択性と酸素消費量への寄与2021

    • Author(s)
      米代武司, 松下真美, 斉藤昌之, 酒井寿郎
    • Organizer
      第27回医用近赤外線分光法研究会
    • Related Report
      2021 Research-status Report
  • [Presentation] 褐色脂肪組織の生理機能とアミノ酸代謝2021

    • Author(s)
      米代武司
    • Organizer
      第40回日本臨床運動療法学会学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 褐色脂肪は分岐鎖アミノ酸代謝フィルターとしてエネルギー代謝を制御する2021

    • Author(s)
      米代武司, 松下真美, 梶村真吾, 斉藤昌之
    • Organizer
      第75回日本栄養・食糧学会大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 褐色脂肪組織における分岐鎖アミノ酸代謝とエネルギー代謝調節2021

    • Author(s)
      米代武司
    • Organizer
      第41回日本肥満学会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 褐色脂肪組織における分岐鎖アミノ酸代謝とエネルギー代謝調節2021

    • Author(s)
      米代武司
    • Organizer
      第41回日本肥満学会・第38回日本肥満症治療学会学術集会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 褐色脂肪における分岐鎖アミノ酸代謝と寒冷適応2020

    • Author(s)
      米代武司
    • Organizer
      日本生理人類学会第81回大会
    • Related Report
      2020 Research-status Report
  • [Presentation] BCAA catabolism in brown adipose tissue and energy metabolism2020

    • Author(s)
      米代武司
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Research-status Report
    • Invited

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Published: 2020-09-29   Modified: 2025-01-30  

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