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The time is now: accounting for time-of-day effects to improve reproducibility and translation of metabolism research

Nature Metabolism volume 7, pages 454–468 (2025)Cite this article

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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.

Author information

Authors and Affiliations

  1. Salk Institute for Biological Studies, La Jolla, CA, USA

    Shaunak Deota & Satchidananda Panda

  2. Department of Biology, University of Kentucky, Lexington, KY, USA

    Julie S. Pendergast

  3. Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India

    Ullas Kolthur-Seetharam

  4. Tata Institute of Fundamental Research, Hyderabad, India

    Ullas Kolthur-Seetharam

  5. Department of Physiology and Aging, University of Florida, Gainesville, FL, USA

    Karyn A. Esser

  6. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Frédéric Gachon

  7. Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel

    Gad Asher

  8. Department of Surgery and Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Charna Dibner

  9. Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute for Science and Technology, Barcelona, Spain

    Salvador Aznar Benitah

  10. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain

    Salvador Aznar Benitah

  11. Departamento de Anatomía, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico

    Carolina Escobar

  12. Departments of Medicine and Pharmacology & Cancer Biology, Duke Molecular Physiology Institute, Durham, NC, USA

    Deborah M. Muoio

  13. National Institute of Biological Sciences, Beijing, China

    Eric Erquan Zhang

  14. Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Gökhan S. Hotamışlıgil

  15. Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Joseph Bass

  16. Department of Neuroscience, Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Joseph S. Takahashi

  17. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA

    Joshua D. Rabinowitz

  18. Department of Molecular and Cellular Biology and Department of Molecular Medicine, the Scripps Research Institute, La Jolla, CA, USA

    Katja A. Lamia

  19. Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA

    Rafael de Cabo

  20. Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA

    Shingo Kajimura

  21. Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA

    Valter D. Longo

  22. AIRC Institute of Molecular Oncology, Italian Foundation for Cancer Research Institute of Molecular Oncology, Milan, Italy

    Valter D. Longo

  23. CAM–SU Genomic Resource Center, Soochow University, Suzhou, China

    Ying Xu

  24. 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

  25. Buck Institute for Research on Aging, Novato, CA, USA

    Eric Verdin

  26. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    Juleen R. Zierath

  27. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

    Juleen R. Zierath

  28. Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Johan Auwerx

  29. 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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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 7, 454–468 (2025). https://doi.org/10.1038/s42255-025-01237-6

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