The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.
FGF21 and the late adaptive response to starvation in humans
Open accessAbstract
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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“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]
In the citing paper
“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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Cites
Paradoxical Decrease of an Adipose-Specific Protein, Adiponectin, in Obesity
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FGF-21 as a novel metabolic regulator
Kharitonenkov, A., Shiyanova, T. L., Koester, A., Ford, A. M., Micanovic, R., Galbreath, E. J., Sandusky, G. E., Hammond, L. J., Moyers, J. S., Owens, R. A., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23606 · Cited by 2,125
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FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Fisher, F. M., Kleiner, S., Douris, N., Fox, E. C., Mepani, R. J., Verdeguer, F., Wu, J., Kharitonenkov, A., Flier, J. S., Maratos-Flier, E., et al. (2012) · Genes & Development · doi:10.1101/gad.177857.111 · Cited by 1,478
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The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes
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Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans
Lee, P., Linderman, J. D., Smith, S., Brychta, R. J., Wang, J., Idelson, C., Perron, R. M., Werner, C. D., Phan, G. Q., Kammula, U. S., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2013.12.017 · Cited by 802
Amino acid metabolism during prolonged starvation
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Cited by
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Peterson, M. N., Adair, K. E., & Funderburk, L. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.26.630421
Sex-specific metabolic responses to modulation of the glucagon-FGF21 axis in female micePreprint
Merrild, C., Johansen, V. B. I., Clemmensen, C., & Ranea‐Robles, P. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.09.647697
“FGF21 is a hormone with multifaceted roles in energy, lipid, and glucose homeostasis 14,16,17 .”
Epigenetically Mediated Health Effects of Intermittent Fasting
Işık, T. (2025) · İstanbul Gelişim Üniversitesi Sağlık Bilimleri Dergisi · doi:10.38079/igusabder.1529934
Treviño‐Alvarez, A. M., de Baca, T. C., Stinson, E. J., Fry, H. T., Gluck, M. E., Chang, D. C., Piaggi, P., & Krakoff, J. A. (2025) · Nutrients · doi:10.3390/nu17193160
“FGF21 concentrations change in humans facing nutritional challenges such as prolonged fasting [37,38], protein restriction [39], overeating [40], high glucose intake [41], and binge alcohol drinking [14].”
The value of fibroblast growth factor 21 in health and pathology
Akhverdyan, Y., Papichev, E., Zavodovsky, B. V., Polyakova, Y. V., Seewordova, L. E., & Сергеевна, Р. Е. (2025) · Сибирский журнал клинической и экспериментальной медицины · doi:10.29001/2073-8552-2025-40-3-28-35
Chen, Z., Xu, M., Chen, S., & Chen, L. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110977
“In both mice and humans, prolonged fasting robustly induces hepatic FGF21 expression (6).”
Vankrunkelsven, W., Thiessen, S., Derde, S., Vervoort, E., Derese, I., Pintelon, I., Matheussen, H., Jans, A., Goossens, C., Langouche, L., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26608503
Henderson, G. C. (2026) · The Journal of Physiology · doi:10.1113/jp290998
Rôle des aminoacides ramifiés dans le déterminisme génétique de la résistance à l’insuline
Haydar, S. (2018) · theses.fr (ABES) · doi:10.70675/5c14c2c4z469bz40fazb55cz985ea78d6c2a
Investigating fasting for metabolic health and longevity
Steinhauser, M. L., & Fazeli, P. K. (2026) · Biogerontology · doi:10.1007/s10522-026-10438-9
“…FGF21 does not appear to have the same dynamic functionality in mediating the acute transition from glucose to lipid metabolism in human fasting (Fazeli et al. 2015), the story of FGF21 can still be viewed as a successful example of what can be gained from such studies, given that various FGF21…”
Self-citationCytokines and insulin sensitivity
Khan, F., Akhtar, S., & Kumar, A. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-33590-7.00008-3
Increasing autophagy with fasting and diet: separating fact from fiction
Singh, S., & Sargeant, T. J. (2026) · Biochemical Society Transactions · doi:10.1042/bst20260632
“In contrast, FGF21 in humans does not peak until 10 days of fasting—7 days after the peak in serum ketones [101].”
Biological functions and emerging interplay of FGF21 and GDF15 in metabolic diseases and aging
Salmón‐Gómez, L., Keipert, S., Catalán, V., Rodrı́guez, A., Becerril, S., Frühbeck, G., & Gómez‐Ambrosi, J. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00627-w
“Refeeding suppresses the induction of FGF21 after fasting [209, 211, 212].”
Metadata
- 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 (medical) › 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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