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

  • Nat Commun. 2025 Apr 4;16(1):3221. doi: 10.1038/s41467-025-58294-4.
Jakub Bunk  1  2 ,  Mohammed F Hussain  1  2 ,  Maria Delgado-Martin  1  2 ,  Bozena Samborska  1 ,  Mina Ersin  1  2 ,  Abhirup Shaw  1 ,  Janane F Rahbani  1 ,  Lawrence Kazak  3  4
Affiliations
  • 1. Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada.
  • 2. Department of Biochemistry, McGill University, Montreal, QC, Canada.
  • 3. Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada. [email protected].
  • 4. Department of Biochemistry, McGill University, Montreal, QC, Canada. [email protected].
PMID: 40185737 DOI: 10.1038/s41467-025-58294-4
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.

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