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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]
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“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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“In humans, however, ketogenic diet feeding and short-term fasting do not induce FGF21 (Dushay et al., 2010; G€alman et al., 2008), and 7–10 days without food are required for circulating FGF21 levels to rise (Fazeli et al., 2015; G€alman et al., 2008).”
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BackgroundDefining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework
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Albrechtsen, N. J. W., Pedersen, J., Galsgaard, K. D., Winther‐Sørensen, M., Suppli, M. P., Janah, L., Gromada, J., Vilstrup, H., Knop, F. K., & Holst, J. J. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00251 · Cited by 154
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“, 2014) and calorie restriction (Gälman et al., 2008; Fazeli et al., 2015), we found that moderate weight loss decreased basal FGF21 concentration and had no effect on plasma FGF21 concentration during the HECP in both the WL and WL-HP groups.”
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Glucose and Lipid Homeostasis and Inflammation in Humans Following an Isocaloric Ketogenic Diet
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Self-citationThe potential function and clinical application of FGF21 in metabolic diseases
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“In humans results have not been consistent, with FGF21 rising in only some studies of food restriction (43), including a prolonged 10-day fast (44), while not changing in other studies (31, 45, 103).”
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“In humans, circulating FGF21 is increased after a prolonged fast [38, 39], exercise [40], in type 2 diabetes [41], steatosis [42],”
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“Different from rodents, serum FGF21 has been shown not to increase upon acute fasting in human subjects [42], whereas KDs resulted in a decrease in FGF21 levels similar to that observed upon weight loss obtained with balanced hypocaloric diets [43–45].”
ResultCroon, M., Szczepanowska, K., Popović, M., Lienkamp, C., Senft, K., Brandscheid, C. P., Bock, T., Gnatzy-Feik, L., Ashurov, A., Acton, R., et al. (2022) · Science Advances · doi:10.1126/sciadv.abn7105 · Cited by 60
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Prolonged fasting drives a program of metabolic inflammation in human adipose tissue
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“We previously performed a 10-day zero-calorie fast in healthy volunteers [11].”
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“the same timeframe as the increase of serum FGF21 (90, 91), suggesting that FGF21 does not drive initial ketogenesis during starvation but rather may maintain ketogenesis and facilitate KB”
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“In mice, serum FGF21 concentrations in chow-fed mice range from 0.1 to 3,000 ng/ml (Badman et al., 2007; Fisher et al., 2010; Dutchak et al., 2012; Murata et al., 2013; Tezze et al., 2017; Jimenez et al., 2018).”
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“status (38) or circadian rhythm (177) that were not specified in these studies.”
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“The delayed increase of serum FGF21 levels correlates with the serum transaminase levels, suggesting that FGF21 contributes to the late adaptive response to fasting [189].”
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“reported in human fasting(14), but these changes were not reflected in the marrow sera (data not 304”
BackgroundResultInfluentialSelf-citationBone marrow adipose tissue in metabolic health
Pachón-Peña, G., & Bredella, M. A. (2022) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2022.03.003 · Cited by 52
Self-citationEnergy Restriction and Colorectal Cancer: A Call for Additional Research
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“Ketone bodies: Ketone bodies are generated in the liver from fatty acids when fasting, constituting the main energy source for many organs [133].”
BackgroundGosby, A. K., Lau, N. S., Tam, C. S., Iglesias, M. A., Morrison, C. D., Caterson, I. D., Brand-Miller, J., Conigrave, A. D., Raubenheimer, D., & Simpson, S. J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0161003 · Cited by 51
“In contrast, a delayed increase in serum FGF-21 level was observed after a 9 d fast in humans [34].”
BackgroundGliniak, C. M., Gordillo, R., Youm, Y., Lin, Q., Crewe, C., Zhang, Z., Field, B. C., Fujikawa, T., Virostek, M., Zhao, S., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.05.011 · Cited by 53
Mehdi, S. F., Qureshi, M., Pervaiz, S., Kumari, K., Saji, E., Shah, M., Abdullah, A., Zahoor, K., Qadeer, H., Katari, D. K., et al. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01074-z · Cited by 62
“Initial studies showed that FGF21 had many effects in rodent metabolism (especially diabetic and obese models) including decreasing blood glucose and triglycerides, inducing ketogenesis, gluconeogenesis, lipolysis, and lipid beta oxidation (Inagaki et al. 2008; Fazeli et al. 2015).”
Robinson, L., Law, J., Symonds, M. E., & Budge, H. (2016) · Experimental Physiology · doi:10.1113/ep085642 · Cited by 50
“For example, it has recently been shown that the 10-fold rise in plasma fibroblast growth factor 21 with prolonged fasting in humans is accompanied by reduced BAT function (Fazeli et al. 2015).”
BackgroundIntestinal-derived FGF15 protects against deleterious effects of vertical sleeve gastrectomy in mice
Bozadjieva-Kramer, N., Shin, J. H., Shao, Y., Gutiérrez‐Aguilar, R., Li, Z., Heppner, K. M., Chiang, S., Vargo, S. G., Granger, K., Sandoval, D. A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24914-y · Cited by 49
FGF-based drug discovery: advances and challenges
Chen, G., Chen, L., Li, X., & Mohammadi, M. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01125-w · Cited by 51
“FGF21 serum levels are elevated in response to various stressors such as fasting, overfeeding, a ketogenic diet, alcohol consumption, a high carbohydrate diet, autophagy deficiency, as well as endoplasmic reticulum and mitochondrial stresses 74–77 .”
Santoso, P., Nakata, M., Shiizaki, K., Boyang, Z., Parmila, K., Otgon-Uul, Z., Hashimoto, K., Satoh, T., Mori, M., Kuro‐o, M., et al. (2017) · Scientific Reports · doi:10.1038/srep45819 · Cited by 45
Kim, E. R., Kim, S. R., Cho, W., Lee, S., Kim, S. H., Kim, J. H., Choi, E., Kim, J., Yu, J., Lee, B., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.843520 · Cited by 44
Self-citationKeihanian, A., Arazi, H., & Kargarfard, M. (2019) · Physiology International · doi:10.1556/2060.106.2019.01 · Cited by 42
“Very few resistance and aerobic-training studies that have investigated changes in hepatokines have also reported conflicting results (16, 22, 25, 27, 33, 36).”
BackgroundResultInfluentialGDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans
Plomgaard, P., Hansen, J. S., Townsend, L. K., Gudiksen, A., Secher, N. H., Clemmesen, J. O., Støving, R. K., Goetze, J. P., Wright, D. C., & Pilegaard, H. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1037948 · Cited by 43
“The fasting period for plasma FGF21 to increase in mice is 24 hour (42) and in humans 7 – 10 days (43, 44).”
BackgroundEffects of Short-Term Fasting and Different Overfeeding Diets on Thyroid Hormones in Healthy Humans
Basolo, A., Begaye, B., Hollstein, T., Vinales, K. L., Walter, M., Santini, F., Krakoff, J., & Piaggi, P. (2019) · Thyroid® · doi:10.1089/thy.2019.0237 · Cited by 37
Sommakia, S., Almaw, N. H., Lee, S. H., Ramadurai, D. K. A., Taleb, I., Kyriakopoulos, C. P., Stubben, C., Jing, L., Campbell, R. A., Alharethi, R. A., et al. (2021) · Circulation Heart Failure · doi:10.1161/circheartfailure.121.008910 · Cited by 38
Higgins, C. B., Zhang, Y., Mayer, A. L., Fujiwara, H., Stothard, A. I., Graham, M. J., Swarts, B. M., & DeBosch, B. J. (2018) · JCI Insight · doi:10.1172/jci.insight.120794 · Cited by 37
“The concept of the fasting and caloric restriction response as a therapeutic to be leveraged in longevity, healthspan, and metabolism from rodents to early primates to humans (1, 38–43) is gaining traction.”
Self-citationRegulation of thermogenic adipocytes during fasting and cold
Reinisch, I., Schreiber, R., & Prokesch, A. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.110869 · Cited by 36
Modulation of energy balance by fibroblast growth factor 21
Ramos, D. C., & Aguilar-Salinas, C. A. (2016) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2016-0023 · Cited by 36
“In one recent study, a notable surge in FGF21 occurred after 7–10 days of fasting, and did not drive starvation-mediated ketogenesis like in mice [46].”
BackgroundInfluentialYılmaz, Ü., Tekin, S., Demir, M. T., Çiğremiş, Y., & Sandal, S. (2018) · The Journal of Physiological Sciences · doi:10.1007/s12576-018-0595-7 · Cited by 30
“FGF21 and thyroid hormones are thought to interact since they regulate similar metabolisms, and are able to regulate each other’s circulating levels; however, such possible interactions are still not well understood due to controversial findings [18, 34, 37].”
Arndt, M. B., Cantera, J. L., Mercer, L. D., Kalnoky, M., White, H. N., Bizilj, G. T., Boyle, D. S., de Hostos, E. L., & Choy, R. K. M. (2020) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0008711 · Cited by 32
“FGF21 is an endocrine hormone suggestive of GH resistance attributable to reduced protein intake [16, 17].”
BackgroundThe paradox of marrow adipose tissue in anorexia nervosa
Fazeli, P. K., & Klibanski, A. (2018) · Bone · doi:10.1016/j.bone.2018.02.013 · Cited by 36
“In murine models, FGF21 is secreted early during starvation and is a regulator of ketogenesis, whereas in humans, FGF21 levels increase during late starvation (after 7-10 days of fasting) and circulating levels increase only after a peak in serum ketone levels [33-35].”
BackgroundSelf-citationHigher serum levels of fibroblast growth factor 21 in old patients with cachexia
Franz, K., Ost, M., Otten, L., Herpich, C., Coleman, V., Endres, A., Klaus, S., Müller‐Werdan, U., & Norman, K. (2018) · Nutrition · doi:10.1016/j.nut.2018.11.004 · Cited by 31
Relation of diet-induced thermogenesis to brown adipose tissue activity in healthy men
Loeliger, R. C., Maushart, C. I., Gashi, G., Senn, J. R., Felder, M., Becker, A. S., Müller, J., Baláž, M., Wolfrum, C., Burger, I. A., et al. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00237.2020 · Cited by 31
Fatty acids homeostasis during fasting predicts protection from chemotherapy toxicity
Barradas, M., Plaza, A., Colmenarejo, G., Lázaro, I., Costa‐Machado, L. F., Martín‐Hernández, R., Micó, V., López-Aceituno, J. L., Herránz, J., Pantoja, C., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33352-3 · Cited by 34
Gene pathway development in human epicardial adipose tissue during early life
Ojha, S., Fainberg, H. P., Wilson, V., Pelella, G., Castellanos, M., May, S. T., Lotto, A. A., Sacks, H. S., Symonds, M. E., & Budge, H. (2016) · JCI Insight · doi:10.1172/jci.insight.87460 · Cited by 28
Liao, Y., Wang, Y.-H., Wu, C.-Y., Hsu, F.-Y., Chien, C.-Y., & Lee, Y.-C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062934 · Cited by 29
Neuroendocrine adaptations to starvation
Amorim, T., Khiyami, A. M., Latif, T., & Fazeli, P. K. (2023) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2023.106365 · Cited by 33
Self-citationModerate-Intensity Continuous Training Improves FGF21 and KLB Expression in Obese Mice
Xiong, Y., Chen, Y., Liu, Y., & Zhang, B. (2020) · Biochemistry (Moscow) · doi:10.1134/s000629792008009x · Cited by 26
Recharacterizing the Metabolic State of Energy Balance in Thrifty and Spendthrift Phenotypes
Hollstein, T., Basolo, A., Ando, T., Votruba, S. B., Walter, M. F., Krakoff, J. A., & Piaggi, P. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa098 · Cited by 25
Fibroblast Growth Factor 21 Facilitates the Homeostatic Control of Feeding Behavior
Wu, C.-T., CHAFFIN, A. T. B., & Ryan, K. K. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11030580 · Cited by 24
Low Bone Mineral Density in Anorexia Nervosa: Treatments and Challenges
Fazeli, P. K. (2019) · Clinical Reviews in Bone and Mineral Metabolism · doi:10.1007/s12018-019-09260-4 · Cited by 26
Self-citationExercise and Metabolic Health: The Emerging Roles of Novel Exerkines
Yazgan, B., Türkel, İ., Özerkliğ, B., ATAKAN, M. M., Aktitiz, S., & Koşar, Ş. N. (2022) · Current Protein and Peptide Science · doi:10.2174/1389203723666220629163524 · Cited by 25
Pérez‐Martí, A., Sandoval, V., Marrero, P. F., Haro, D., & Relat, J. (2016) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2016-0034 · Cited by 24
“These data establish FGF21 as a fasting-induced hormone in humans and indicate that it contributes to the late stages of adaptation to starvation, when it may regulate the utilization of fuel derived from tissue breakdown [151].”
BackgroundNygaard, E. B., Ørskov, C., Almdal, T., Vestergaard, H., & Andersen, B. (2018) · Journal of Endocrinology · doi:10.1530/joe-18-0002 · Cited by 24
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“Indeed, FGF21 is increased in the liver in response to starvation 70,71 , which potentially involves nutrient sensing pathways 72 .”
Advances in Biological Functions and Clinical Studies of FGF21
Lin, W. J., Zhang, T., Zhou, Y., Zheng, J., & Lin, Z. (2021) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s317096 · Cited by 24
Andriessen, C., Doligkeit, D., Moonen‐Kornips, E., Mensink, M., Hesselink, M. K. C., Joris Hoeks, J., & Schrauwen, P. (2023) · Clinical Nutrition · doi:10.1016/j.clnu.2023.10.010 · Cited by 23
Admin, A., Hollstein, T., Heinitz, S., Ando, T., Rodzevik, T. L., Basolo, A., Walter, M., Chang, D. C., Krakoff, J., & Piaggi, P. (2020) · Diabetes · doi:10.2337/db20-0153 · Cited by 23
“While in humans the decrease in FGF21 during short-term fasting has been described previously (17), changes in FGF21 during COLD are inconclusive.”
BackgroundHutin, D., Long, A. S., Sugamori, K. S., Shao, P., Singh, S. K., Rasmussen, M., Olafsen, N. E., Pettersen, S., Grimaldi, G., Grant, D. M., et al. (2021) · Toxicological Sciences · doi:10.1093/toxsci/kfab075 · Cited by 21
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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