FGF21 and the late adaptive response to starvation in humans
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In mice, FGF21 is rapidly induced by fasting, mediates critical aspects of the adaptive starvation response, and displays a number of positive metabolic properties when administered pharmacologically. In humans, however, fasting does not consistently increase FGF21, suggesting a possible evolutionary divergence in FGF21 function. Moreover, many key aspects of FGF21 function in mice have been identified in the context of transgenic overexpression or administration of supraphysiologic doses, rather than in a physiologic setting. Here, we explored the dynamics and function of FGF21 in human volunteers during a 10-day fast. Unlike mice, which show an increase in circulating FGF21 after only 6 hours, human subjects did not have a notable surge in FGF21 until 7 to 10 days of fasting. Moreover, we determined that FGF21 induction was associated with decreased thermogenesis and adiponectin, an observation that directly contrasts with previous reports based on supraphysiologic dosing. Additionally, FGF21 levels increased after ketone induction, demonstrating that endogenous FGF21 does not drive starvation-mediated ketogenesis in humans. Instead, a longitudinal analysis of biologically relevant variables identified serum transaminases--markers of tissue breakdown--as predictors of FGF21. These data establish FGF21 as a fasting-induced hormone in humans and indicate that FGF21 contributes to the late stages of adaptive starvation, when it may regulate the utilization of fuel derived from tissue breakdown.
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Starvation, high sugar intake, and dietary protein restriction all induce circulating FGF21 levels in humans.
“Starvation30,31, high sugar intake32,33 and dietary protein restriction26 all induce circulating FGF21 levels in humans.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [31]
Circulating FGF21 levels are induced in humans during prolonged fasting.
“Consistent with data from rodents, circulating levels of FGF21 are also induced in humans during prolonged fasting (33, 42).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [33]
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- Authors
- Fazeli, P. K., Lun, M., Kim, S. M., Bredella, M. A., Wright, S., Zhang, Y., Lee, H., Catana, C., Klibanski, A., Patwari, P., & Steinhauser, M. L.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Massachusetts General Hospital (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2015-11-03
- Volume
- 125
- Issue
- 12
- Pages
- 4601-4611
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4665770
- OpenAlex
- W2155047676
- Cited by
- 214
- References
- 47
- Citations by year
- 2026: 9 · 2025: 25 · 2024: 21 · 2023: 14 · 2022: 26 · 2021: 23 · 2020: 28 · 2019: 16 · 2018: 22 · 2017: 13 · 2016: 16 · 2015: 1
- FWCI
- 7.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000170, UL1TR001102)
- National Institute of Diabetes and Digestive and Kidney Diseases (K23DK094820, K08DK090147)
- National Institute of Biomedical Imaging and Bioengineering (P41EB015896)
- National Center for Research Resources (UL1RR025758)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- FGF21, fasting, starvation adaptation, human volunteers, thermogenesis, adiponectin, ketogenesis, transaminases, tissue breakdown, evolutionary divergence
- MeSH terms
- Adaptation, Physiological, Adult, Animals, Fasting, Female, Fibroblast Growth Factors, Humans, Male, Middle Aged, Starvation, Time Factors, Thermogenesis, Mice, Adiponectin
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