The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58294-4 |
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| author | Jakub Bunk Mohammed F. Hussain Maria Delgado-Martin Bozena Samborska Mina Ersin Abhirup Shaw Janane F. Rahbani Lawrence Kazak |
| author_facet | Jakub Bunk Mohammed F. Hussain Maria Delgado-Martin Bozena Samborska Mina Ersin Abhirup Shaw Janane F. Rahbani Lawrence Kazak |
| author_sort | Jakub Bunk |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ca6ddcbb8e784295983f7ffd2c373c55 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ca6ddcbb8e784295983f7ffd2c373c552025-08-20T03:07:43ZengNature PortfolioNature Communications2041-17232025-04-0116111410.1038/s41467-025-58294-4The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BATJakub Bunk0Mohammed F. Hussain1Maria Delgado-Martin2Bozena Samborska3Mina Ersin4Abhirup Shaw5Janane F. Rahbani6Lawrence Kazak7Rosalind & Morris Goodman Cancer Institute, McGill UniversityRosalind & Morris Goodman Cancer Institute, McGill UniversityRosalind & Morris Goodman Cancer Institute, McGill UniversityRosalind & Morris Goodman Cancer Institute, McGill UniversityRosalind & Morris Goodman Cancer Institute, McGill UniversityRosalind & Morris Goodman Cancer Institute, McGill UniversityRosalind & Morris Goodman Cancer Institute, McGill UniversityRosalind & Morris Goodman Cancer Institute, McGill UniversityAbstract 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.https://doi.org/10.1038/s41467-025-58294-4 |
| spellingShingle | Jakub Bunk Mohammed F. Hussain Maria Delgado-Martin Bozena Samborska Mina Ersin Abhirup Shaw Janane F. Rahbani Lawrence Kazak The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT Nature Communications |
| title | The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT |
| title_full | The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT |
| title_fullStr | The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT |
| title_full_unstemmed | The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT |
| title_short | The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT |
| title_sort | futile creatine cycle powers ucp1 independent thermogenesis in classical bat |
| url | https://doi.org/10.1038/s41467-025-58294-4 |
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