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

Jakub Bunk, Mohammed F. Hussain, Maria Delgado-Martin, Bozena Samborska, Mina Ersin, Abhirup Shaw, Janane F. Rahbani and Lawrence Kazak ()
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Jakub Bunk: McGill University
Mohammed F. Hussain: McGill University
Maria Delgado-Martin: McGill University
Bozena Samborska: McGill University
Mina Ersin: McGill University
Abhirup Shaw: McGill University
Janane F. Rahbani: McGill University
Lawrence Kazak: McGill University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58294-4

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