The liver clock modulates circadian rhythms in white adipose tissue
Circadian rhythms are integral to maintaining metabolic health by temporally coordinating physiology across tissues. However, the mechanisms underlying circadian cross-tissue coordination remain poorly understood. In this study, we uncover a central role for the liver clock in regulating circadian rhythms in white adipose tissue (WAT). Using a hepatocyte-specific Bmal1 knockout mouse model, we show that hepatic circadian control modulates lipid metabolism in WAT. In addition, by utilizing a model where functional clocks are restricted to the hepatocytes, we demonstrate that the liver clock alone integrates feeding cues to modulate circadian gene expression in WAT, including Cebpa, a key regulator of adipogenesis. We show that the hepatocyte clock regulates adipocyte Cebpa rhythmicity through secreted proteins. Further investigation identified one of the contributing mediators to be the adaptor protein 14-3-3η (Ywhah). The clinical relevance of the liver clock for systemic metabolic function is supported by human cohort data, which revealed a gene regulatory network, consisting of several clock-controlled liver genes, linked to cardiometabolic risk. These findings provide evidence for how the hepatocyte clock coordinates WAT physiology and highlights the core clock system as a potential therapeutic target to improve cardiometabolic health.
Authors
- Oscar P. B. Wiklander (ORCID: https://orcid.org/0000-0003-1176-8114)
- Kevin B. Koronowski (ORCID: https://orcid.org/0000-0002-6808-1789)
- Gianluca Renzi
- Paul Petrus (ORCID: https://orcid.org/0000-0001-8297-3874)
- Doste R. Mamand
- Paolo Sassone‐Corsi (ORCID: https://orcid.org/0000-0001-7091-3954)
- Angela Ma
- Martin O. Bergö (ORCID: https://orcid.org/0000-0002-6915-7140)
- Jacob G. Smith (ORCID: https://orcid.org/0000-0001-5139-1054)
- Christopher Litwin (ORCID: https://orcid.org/0000-0001-6833-454X)
- Niklas Mejhert (ORCID: https://orcid.org/0000-0003-1785-833X)
- Johan Björkegren (ORCID: https://orcid.org/0000-0003-1945-7425)
- Christina Savva (ORCID: https://orcid.org/0000-0002-8019-1104)
- Leandro M. Vélez (ORCID: https://orcid.org/0000-0001-8371-2633)
- Carolina M. Greco (ORCID: https://orcid.org/0000-0002-9895-5635)
- Qing Zhang (ORCID: https://orcid.org/0000-0002-1160-2715)
- Marcus M Seldin (ORCID: https://orcid.org/0000-0002-8785-0766)
- Ivan Vlassakev
- Salvador Aznar Benitah (ORCID: https://orcid.org/0000-0002-9059-5049)
- Hema Saranya Ilamathi
- Pura Muñoz-Cánovez
Institutions
- Karolinska University Hospital (SE)
- Humanitas University (IT)
- Inserm (FR)
- The University of Texas at San Antonio Health Science Center (US)
- University of California, Irvine (US)
- Barcelona Biomedical Research Park (ES)
- Karolinska Institutet (SE)
- Institute for Research in Biomedicine (ES)
- IRCCS Humanitas Research Hospital (IT)
- Universitat de Barcelona (ES)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Molecular Metabolism
- Published
- 2025-09-12
- DOI
- https://doi.org/10.1016/j.molmet.2025.102249
- Citations
- 4
- Primary Topic
- Circadian rhythm and melatonin
- Type
- article
- Field-Weighted Citation Impact
- 3.66