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Published September 22, 2021 | Version v1
Journal article Open

Integration of feeding behavior by the liver circadian clock reveals network dependency of metabolic rhythms

  • 1. Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
  • 2. Bioinformatics Unit, Humanitas Clinical and Research Center–IRCCS, Rozzano 20089, Italy.
  • 3. Bioinformatics Unit, Humanitas Clinical and Research Center–IRCCS, Rozzano 20089, Italy
  • 4. Institute for Genomics and Bioinformatics, Department of Computer Science, UCI, Irvine, CA 92697, USA
  • 5. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain - Program in Cancer Research, Hospital del Mar Medical Research Institute (IMIM), Dr. Aiguader 88, Barcelona 08003, Spain.
  • 6. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain.
  • 7. Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona 08003, Spain
  • 8. German Center for Diabetes Research (DZD), Neuherberg, Germany - Computational Discovery Research, Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München, Neuherberg, Germany
  • 9. Institute for Genomics and Bioinformatics, Department of Computer Science, UCI, Irvine, CA 92697, USA.
  • 10. German Center for Diabetes Research (DZD), Neuherberg, Germany - Metabolic Physiology, Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.
  • 11. Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain - Spanish National Center on Cardiovascular Research (CNIC), Madrid 28029, Spain - Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain
  • 12. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain - Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain
  • 13. Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA

Description

Abstract

The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis. Clock function in peripheral tissues is required, but not sufficient, for this task. Because of the lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations. Here, we isolated the interaction between feeding and the liver clock by reconstituting Bmal1 exclusively in hepatocytes (Liver-RE), in otherwise clock-less mice, and controlling timing of food intake. We found that the cooperative action of BMAL1 and the transcription factor CEBPB regulates daily liver metabolic transcriptional programs.

Functionally, the liver clock and feeding rhythm are sufficient to drive temporal carbohydrate homeostasis. By contrast, liver rhythms tied to redox and lipid metabolism required communication with the skeletal muscle clock, demonstrating peripheral clock cross-talk. Our results highlight how the inner workings of the clock system rely on communicating signals to maintain daily metabolism.

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Additional details

Funding

UPGRADE – Unlocking Precision Gene Therapy 825825
European Commission