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The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT

Author

Listed:
  • Jakub Bunk

    (McGill University
    McGill University)

  • Mohammed F. Hussain

    (McGill University
    McGill University)

  • Maria Delgado-Martin

    (McGill University
    McGill University)

  • Bozena Samborska

    (McGill University)

  • Mina Ersin

    (McGill University
    McGill University)

  • Abhirup Shaw

    (McGill University)

  • Janane F. Rahbani

    (McGill University)

  • Lawrence Kazak

    (McGill University
    McGill University)

Abstract

Classical brown adipose tissue (BAT) is traditionally viewed as relying exclusively on uncoupling protein 1 (UCP1) for thermogenesis via inducible proton leak. However, the physiological significance of UCP1-independent mechanisms linking substrate oxidation to ATP turnover in classical BAT has remained unclear. Here, we identify the Futile Creatine Cycle (FCC), a mitochondrial-localized energy-wasting pathway involving creatine phosphorylation by creatine kinase b (CKB) and phosphocreatine hydrolysis by tissue-nonspecific alkaline phosphatase (TNAP), as a key UCP1-independent thermogenic mechanism in classical BAT. Reintroducing mitochondrial-targeted CKB exclusively into interscapular brown adipocytes in vivo restores thermogenesis and cold tolerance in mice lacking native UCP1 and CKB, in a TNAP-dependent manner. Furthermore, mice with inducible adipocyte-specific co-deletion of TNAP and UCP1 exhibit severe cold-intolerance. These findings challenge the view that BAT thermogenesis depends solely on UCP1 because of insufficient ATP synthase activity and establishes the FCC as a physiologically relevant thermogenic pathway in classical BAT.

Suggested Citation

  • Jakub Bunk & Mohammed F. Hussain & Maria Delgado-Martin & Bozena Samborska & Mina Ersin & Abhirup Shaw & Janane F. Rahbani & Lawrence Kazak, 2025. "The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58294-4
    DOI: 10.1038/s41467-025-58294-4
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    References listed on IDEAS

    as
    1. Sven Enerbäck & Anders Jacobsson & Elizabeth M. Simpson & Carmen Guerra & Hitoshi Yamashita & Mary-Ellen Harper & Leslie P. Kozak, 1997. "Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese," Nature, Nature, vol. 387(6628), pages 90-94, May.
    2. Yizhi Sun & Janane F. Rahbani & Mark P. Jedrychowski & Christopher L. Riley & Sara Vidoni & Dina Bogoslavski & Bo Hu & Phillip A. Dumesic & Xing Zeng & Alex B. Wang & Nelson H. Knudsen & Caroline R. K, 2021. "Mitochondrial TNAP controls thermogenesis by hydrolysis of phosphocreatine," Nature, Nature, vol. 593(7860), pages 580-585, May.
    3. Janane F. Rahbani & Anna Roesler & Mohammed F. Hussain & Bozena Samborska & Christien B. Dykstra & Linus Tsai & Mark P. Jedrychowski & Laurent Vergnes & Karen Reue & Bruce M. Spiegelman & Lawrence Kaz, 2021. "Creatine kinase B controls futile creatine cycling in thermogenic fat," Nature, Nature, vol. 590(7846), pages 480-485, February.
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