Abstract
The constant expansion of the field of metabolic research has led to more nuanced and sophisticated understanding of the complex mechanisms that underlie metabolic functions and diseases. Collaborations with scientists of various fields such as neuroscience, immunology and drug discovery have further enhanced the ability to probe the role of metabolism in physiological processes. However, many behaviours, endocrine and biochemical processes, and the expression of genes, proteins and metabolites have daily ~24-h biological rhythms and thus peak only at specific times of the day. This daily variation can lead to incorrect interpretations, lack of reproducibility across laboratories and challenges in translating preclinical studies to humans. In this Review, we discuss the biological, environmental and experimental factors affecting circadian rhythms in rodents, which can in turn alter their metabolic pathways and the outcomes of experiments. We recommend that these variables be duly considered and suggest best practices for designing, analysing and reporting metabolic experiments in a circadian context.
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Fig. 1: Daily biological rhythms at various organizational levels.
Fig. 2: Schematic representation of the peaks of various hormones in the serum in diurnal humans and nocturnal rodents.
Fig. 3: Factors affecting circadian rhythms and metabolic outcomes.
Fig. 4: Various scenarios demonstrating how the timing of experiments or sample collection can affect conclusions.
Fig. 5: Examples of how ignoring the reporting of sample collection time (or using single-time point measurements) can lead to incorrect experimental conclusions.
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Acknowledgements
F.G. receives funding from the Australian National Health and Medical Research Council (Synergy Grant 2019260), the National Institutes of Health (R01AG078241) and the Novo Nordisk Foundation (Hallas-Møller Ascending Investigator grant 0087882). Research in S.P.’s laboratory is supported by NIH grants AG068550 and CA258221, the Wu Tsai Human Performance Alliance and the Joe and Clara Tsai Foundation.
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Authors and Affiliations
Salk Institute for Biological Studies, La Jolla, CA, USA
Shaunak Deota & Satchidananda Panda
Department of Biology, University of Kentucky, Lexington, KY, USA
Julie S. Pendergast
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
Ullas Kolthur-Seetharam
Tata Institute of Fundamental Research, Hyderabad, India
Ullas Kolthur-Seetharam
Department of Physiology and Aging, University of Florida, Gainesville, FL, USA
Karyn A. Esser
Department of Biomedicine, Aarhus University, Aarhus, Denmark
Frédéric Gachon
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
Gad Asher
Department of Surgery and Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
Charna Dibner
Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute for Science and Technology, Barcelona, Spain
Salvador Aznar Benitah
Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
Salvador Aznar Benitah
Departamento de Anatomía, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
Carolina Escobar
Departments of Medicine and Pharmacology & Cancer Biology, Duke Molecular Physiology Institute, Durham, NC, USA
Deborah M. Muoio
National Institute of Biological Sciences, Beijing, China
Eric Erquan Zhang
Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Gökhan S. Hotamışlıgil
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Joseph Bass
Department of Neuroscience, Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
Joseph S. Takahashi
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
Joshua D. Rabinowitz
Department of Molecular and Cellular Biology and Department of Molecular Medicine, the Scripps Research Institute, La Jolla, CA, USA
Katja A. Lamia
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
Rafael de Cabo
Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA
Shingo Kajimura
Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
Valter D. Longo
AIRC Institute of Molecular Oncology, Italian Foundation for Cancer Research Institute of Molecular Oncology, Milan, Italy
Valter D. Longo
CAM–SU Genomic Resource Center, Soochow University, Suzhou, China
Ying Xu
Institute for Diabetes, Obesity and Metabolism and Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Mitchell A. Lazar
Buck Institute for Research on Aging, Novato, CA, USA
Eric Verdin
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Juleen R. Zierath
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Juleen R. Zierath
Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Johan Auwerx
The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Daniel J. Drucker
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Shaunak Deota
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Contributions
S.D. and S.P. wrote the initial draft of the manuscript and led the revisions. All authors contributed to the content and organization of this Review; contributed to writing, editing and/or revising the manuscript; and approved the final version.
Corresponding author
Correspondence to Satchidananda Panda.
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Competing interests
S.A.B. is a cofounder and scientific advisor of Ona Therapeutics. G.S.H. is a scientific advisory board member of Crescenta Biosciences. J.S.T. is a founder and scientific advisory board member of Synchronicity Pharma. J.D.R. is a paid adviser and/or stockholder in Colorado Research Partners, L.E.A.F. Pharmaceuticals, Faeth Therapeutics and Empress Therapeutics; a paid consultant of Pfizer; a founder and stockholder in Marea Therapeutics; and a founder, director and stockholder of Farber Partners, Raze Therapeutics and Sofro Pharmaceuticals. S.K. serves as a scientific advisory board member of Moonwalk Biosciences. V.D.L. has equity interest in L-Nutra, a company making medical food, and has filed patents related to fasting-mimicking diets and their medical use. M.A.L. is on the advisory board of Pfizer and serves on the advisory board and is a cofounder of Flare Therapeutics. E.V. is a scientific cofounder of Napa Therapeutics and BHB Therapeutics and serves on the scientific advisory board of Seneque. J.A. is a board member of NOV Metapharma, a founder and/or consultant for Vandria and Amprenta Therapeutics and consults for OrsoBio, MetroBiotech and Amazentis (now Timeline); none of these companies develop products regulating circadian activity. D.J.D. has served as a consultant or speaker within the past 12 months for Amgen, AstraZeneca, Boehringer Ingelheim, Kallyope, Novo Nordisk and Pfizer. S.P. is the author of the books the Circadian Code and the Circadian Diabetes Code and is a scientific advisor to Hooke London, Avadel and WndrHlth. Other authors have no conflict of interests to declare.
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Nature Metabolism thanks Kevin Koronowski, Annie Curtis and Min-Dian Li for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt, in collaboration with the Nature Metabolism editorial team.
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Deota, S., Pendergast, J.S., Kolthur-Seetharam, U. et al. The time is now: accounting for time-of-day effects to improve reproducibility and translation of metabolism research. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01237-6
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Received:21 July 2024
Accepted:07 February 2025
Published:17 March 2025
DOI:https://doi.org/10.1038/s42255-025-01237-6
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