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

Shaunak Deota¹, Julie S Pendergast², Ullas Kolthur-Seetharam^{3

4}, Karyn A Esser⁵, Frédéric Gachon⁶, Gad Asher⁷, Charna Dibner⁸, Salvador Aznar Benitah^{9

10}, Carolina Escobar¹¹, Deborah M Muoio¹², Eric Erquan Zhang¹³, Gökhan S Hotamışlıgil¹⁴, Joseph Bass¹⁵, Joseph S Takahashi¹⁶, Joshua D Rabinowitz¹⁷, Katja A Lamia¹⁸, Rafael de Cabo¹⁹, Shingo Kajimura²⁰, Valter D Longo^{21

22}, Ying Xu²³, Mitchell A Lazar²⁴, Eric Verdin²⁵, Juleen R Zierath^{26

27}, Johan Auwerx²⁸, Daniel J Drucker²⁹, Satchidananda Panda³⁰

Affiliations

¹ Salk Institute for Biological Studies, La Jolla, CA, USA.
² Department of Biology, University of Kentucky, Lexington, KY, USA.
³ Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
⁴ Tata Institute of Fundamental Research, Hyderabad, India.
⁵ Department of Physiology and Aging, University of Florida, Gainesville, FL, USA.
⁶ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁷ Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
⁸ Department of Surgery and Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁹ Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute for Science and Technology, Barcelona, Spain.
¹⁰ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
¹¹ Departamento de Anatomía, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
¹² Departments of Medicine and Pharmacology & Cancer Biology, Duke Molecular Physiology Institute, Durham, NC, USA.
¹³ National Institute of Biological Sciences, Beijing, China.
¹⁴ Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁵ Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁶ Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁷ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
¹⁸ Department of Molecular and Cellular Biology and Department of Molecular Medicine, the Scripps Research Institute, La Jolla, CA, USA.
¹⁹ Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
²⁰ Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA.
²¹ Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
²² AIRC Institute of Molecular Oncology, Italian Foundation for Cancer Research Institute of Molecular Oncology, Milan, Italy.
²³ CAM-SU Genomic Resource Center, Soochow University, Suzhou, China.
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.
²⁵ Buck Institute for Research on Aging, Novato, CA, USA.
²⁶ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
²⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
²⁸ Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
²⁹ The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
³⁰ Salk Institute for Biological Studies, La Jolla, CA, USA. satchin@salk.edu.

PMID: 40097742
DOI: 10.1038/s42255-025-01237-6

Review

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

Shaunak Deota et al. Nat Metab. 2025 Mar.

. 2025 Mar;7(3):454-468.

doi: 10.1038/s42255-025-01237-6. Epub 2025 Mar 17.

Authors

Affiliations

¹ Salk Institute for Biological Studies, La Jolla, CA, USA.
² Department of Biology, University of Kentucky, Lexington, KY, USA.
³ Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
⁴ Tata Institute of Fundamental Research, Hyderabad, India.
⁵ Department of Physiology and Aging, University of Florida, Gainesville, FL, USA.
⁶ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁷ Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
⁸ Department of Surgery and Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁹ Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute for Science and Technology, Barcelona, Spain.
¹⁰ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
¹¹ Departamento de Anatomía, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
¹² Departments of Medicine and Pharmacology & Cancer Biology, Duke Molecular Physiology Institute, Durham, NC, USA.
¹³ National Institute of Biological Sciences, Beijing, China.
¹⁴ Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁵ Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁶ Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁷ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
¹⁸ Department of Molecular and Cellular Biology and Department of Molecular Medicine, the Scripps Research Institute, La Jolla, CA, USA.
¹⁹ Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
²⁰ Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA.
²¹ Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
²² AIRC Institute of Molecular Oncology, Italian Foundation for Cancer Research Institute of Molecular Oncology, Milan, Italy.
²³ CAM-SU Genomic Resource Center, Soochow University, Suzhou, China.
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.
²⁵ Buck Institute for Research on Aging, Novato, CA, USA.
²⁶ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
²⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
²⁸ Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
²⁹ The Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
³⁰ Salk Institute for Biological Studies, La Jolla, CA, USA. satchin@salk.edu.

PMID: 40097742
DOI: 10.1038/s42255-025-01237-6

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.

PubMed Disclaimer

Conflict of interest statement

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.

References

1. Percie du Sert, N. et al. Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol. 18, e3000411 (2020). - PubMed - PMC - DOI
1. Nelson, R. J. et al. Time of day as a critical variable in biology. BMC Biol. 20, 142 (2022). - PubMed - PMC - DOI
1. la Fleur, S. E., Kalsbeek, A., Wortel, J., Fekkes, M. L. & Buijs, R. M. A daily rhythm in glucose tolerance: a role for the suprachiasmatic nucleus. Diabetes 50, 1237–1243 (2001). - PubMed - DOI
1. Zimmet, P. Z., Wall, J. R., Rome, R., Stimmler, L. & Jarrett, R. J. Diurnal variation in glucose tolerance: associated changes in plasma insulin, growth hormone, and non-esterified fatty acids. Br. Med. J. 1, 485–488 (1974). - PubMed - PMC - DOI
1. Klerman, E. B. et al. Keeping an eye on circadian time in clinical research and medicine. Clin. Transl. Med. 12, e1131 (2022). - PubMed - PMC - DOI

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

R01 DK127800/DK/NIDDK NIH HHS/United States

LinkOut - more resources

Full Text Sources
- Nature Publishing Group

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources