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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Paradoxical Decrease of an Adipose-Specific Protein, Adiponectin, in Obesity
Arita, Y., Kihara, S., Ouchi, N., Takahashi, M., Maeda, K., Miyagawa, J.-I., Hotta, K., Shimomura, I., Nakamura, T., Miyaoka, K., et al. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0255 · Cited by 4,856
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
Inagaki, T., Dutchak, P., Zhao, G., Ding, X., Gautron, L., Parameswara, V., Li, Y., Goetz, R., Mohammadi, M., Esser, V., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.003 · Cited by 1,504
Badman, M. K., Pissios, P., Kennedy, A. R., Koukos, G., Flier, J. S., & Maratos-Flier, E. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.002 · Cited by 1,495
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
Cahill, G. F. (2006) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.26.061505.111258 · Cited by 1,360
Zhang, X., Yeung, D. C. Y., Karpisek, M., Stejskal, D., Zhou, Z.-G., Liu, F., Wong, R. L. C., Chow, W.-S., Tso, A. W. K., Lam, K. S. L., et al. (2008) · Diabetes · doi:10.2337/db07-1476 · Cited by 908
The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes
Gaich, G., Chien, J. Y., Fu, H., Glass, L. C., Deeg, M. A., Holland, W. L., Kharitonenkov, A., Bumol, T., Schilske, H. K., & Moller, D. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.005 · Cited by 885
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
Felig, P., Owen, O. E., Wahren, J., & Cahill, G. F. (1969) · Journal of Clinical Investigation · doi:10.1172/jci106017 · Cited by 729
Potthoff, M. J., Inagaki, T., Satapati, S., Ding, X., He, T., Goetz, R., Mohammadi, M., Finck, B. N., Mangelsdorf, D. J., Kliewer, S. A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904187106 · Cited by 704
Increased Fibroblast Growth Factor 21 in Obesity and Nonalcoholic Fatty Liver Disease
Dushay, J., Chui, P. C., Gopalakrishnan, G. S., Varela–Rey, M., Crawley, M., Fisher, F. M., Badman, M. K., Martinez–Chantar, M. L., & Maratos–Flier, E. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.04.054 · Cited by 607
FGF21 is an endocrine signal of protein restriction
Laeger, T., Henagan, T. M., Albarado, D. C., Redman, L. M., Bray, G. A., Noland, R. C., Münzberg, H., Hutson, S. M., Gettys, T. W., Schwartz, M. W., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74915 · Cited by 593 · cited 2×
“With regard to the potential therapeutic implications of this study, we cannot assume that any hypothesized functional roles of FGF21 in the starved state are relevant to supraphysiologic administration of FGF21 mimetics in patients with metabolic disease; however, this study underscores the emerging concept that the…”
BackgroundResultKratz (2004) · doi:10.1056/nejmcpc049016 · Cited by 593
Circulating FGF21 Is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding
Markan, K. R., Naber, M. C., Ameka, M. K., Anderegg, M. D., Mangelsdorf, D. J., Kliewer, S. A., Mohammadi, M., & Potthoff, M. J. (2014) · Diabetes · doi:10.2337/db14-0595 · Cited by 590
Oxidative damage to DNA: relation to species metabolic rate and life span.
Adelman, R., Saul, R. L., & Ames, B. N. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.8.2706 · Cited by 580
An FGF21-Adiponectin-Ceramide Axis Controls Energy Expenditure and Insulin Action in Mice
Holland, W., Adams, A., Brozinick, J., Bui, H., Miyauchi, Y., Kusminski, C., Bauer, S., Wade, M., Singhal, E., Cheng, C. C., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.03.019 · Cited by 525
Gälman, C., Lundåsen, T., Kharitonenkov, A., Bina, H. A., Eriksson, M., Hafström, I., Dahlin, M., Åmark, P., Angelin, B., & Rudling, M. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.06.014 · Cited by 512
Inhibition of Growth Hormone Signaling by the Fasting-Induced Hormone FGF21
Inagaki, T., Lin, V. Y., Goetz, R., Mohammadi, M., Mangelsdorf, D. J., & Kliewer, S. A. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.05.006 · Cited by 409
Hondares, E., Rosell, M., Gonzalez, F. J., Giralt, M., Iglesias, R., & Villarroya, F. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.02.001 · Cited by 377
Hotta, Y., Nakamura, H., Konishi, M., Murata, Y., Takagi, H., Matsumura, S., Inoue, K., Fushiki, T., & Itoh, N. (2009) · Endocrinology · doi:10.1210/en.2009-0119 · Cited by 352
Xu, J., Stanislaus, S., Chinookoswong, N., Lau, Y. Y., Hager, T., Patel, J., Ge, H., Weiszmann, J., Lu, S.-C., Graham, M., et al. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00348.2009 · Cited by 340
Liang, Q., Zhong, L., Zhang, J., Wang, Y., Bornstein, S. R., Triggle, C. R., Ding, H., Lam, K. S. L., & Xu, A. (2014) · Diabetes · doi:10.2337/db14-0541 · Cited by 299
Cahill, G. F. (1976) · Clinics in Endocrinology and Metabolism · doi:10.1016/s0300-595x(76)80028-x · Cited by 278
The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue
Adams, A. C., Yang, C., Coskun, T., Cheng, C. C., Gimeno, R. E., Luo, Y., & Kharitonenkov, A. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2012.08.007 · Cited by 266
Portnay, G. I., O’Brian, J. T., Bush, J. E., Vagenakis, A. G., Azizi, F., Arky, R. A., Ingbar, S. H., & Braverman, L. E. (1974) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-39-1-191 · Cited by 252
Interplay between FGF21 and insulin action in the liver regulates metabolism
Emanuelli, B., Vienberg, S. G., Smyth, G., Cheng, C., Stanford, K. I., Arumugam, M., Michael, M. D., Adams, A. C., Kharitonenkov, A., & Kahn, C. R. (2014) · Journal of Clinical Investigation · doi:10.1172/jci67353 · Cited by 251
Fructose ingestion acutely stimulates circulating FGF21 levels in humans
Dushay, J. R., Toschi, E., Mitten, E. K., Fisher, F. M., Herman, M. A., & Maratos-Flier, E. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2014.09.008 · Cited by 233
Integrated Regulation of Hepatic Metabolism by Fibroblast Growth Factor 21 (FGF21) in Vivo
Fisher, F. M., Estall, J. L., Adams, A. C., Antonellis, P. J., Bina, H. A., Flier, J. S., Kharitonenkov, A., Spiegelman, B. M., & Maratos–Flier, E. (2011) · Endocrinology · doi:10.1210/en.2011-0281 · Cited by 231
FGF21 contributes to neuroendocrine control of female reproduction
Owen, B. M., Bookout, A. L., Ding, X., Lin, V. Y., Atkin, S. D., Gautron, L., Kliewer, S. A., & Mangelsdorf, D. J. (2013) · Nature Medicine · doi:10.1038/nm.3250 · Cited by 230
Precision and stability of dual-energy X-ray absorptiometry measurements
Johnson, J. L., & Dawson‐Hughes, B. (1991) · Calcified Tissue International · doi:10.1007/bf02556113 · Cited by 228
Mashili, F. L., Austin, R. L., Deshmukh, A. S., Fritz, T., Caidahl, K., Bergdahl, K., Zierath, J. R., Chibalin, A., Moller, D. E., Kharitonenkov, A., et al. (2011) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.1177 · Cited by 226
Functional thermogenic beige adipogenesis is inducible in human neck fat
Lee, P., Werner, C., Kebebew, E., & Celi, F. S. (2013) · International Journal of Obesity · doi:10.1038/ijo.2013.82 · Cited by 213
Foltz, I. N., Hu, S., King, C., Wu, X., Yang, C., Wang, W., Weiszmann, J., Stevens, J., Chen, J. S., Nuanmanee, N., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004690 · Cited by 211
Fu, T., Seok, S., Choi, S., Huang, Z., Suino-Powell, K. M., Xu, H. E., KEMPER, B. W., & Kemper, J. K. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00596-14 · Cited by 190
Christodoulides, C., Dyson, P., Sprecher, D., Tsintzas, K., & Karpe, F. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0111 · Cited by 153
Effects of rhIGF-I administration on bone turnover during short-term fasting.
Grinspoon, S. K., Baum, H. B. A., Peterson, S., & Klibanski, A. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118137 · Cited by 112
Self-citationPlasma Concentrations of Fibroblast Growth Factors 19 and 21 in Patients with Anorexia Nervosa
Dostálová, I., Kaválková, P., Haluzíková, D., Lacinová, Z., Mráz, M., Papežová, H., & Haluzı́k, M. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0746 · Cited by 111
Glucocorticoids Regulate the Metabolic Hormone FGF21 in a Feed-Forward Loop
Patel, R., Bookout, A. L., Magomedova, L., Owen, B. M., Consiglio, G. P., Shimizu, M., Zhang, Y., Mangelsdorf, D. J., Kliewer, S. A., & Cummins, C. L. (2014) · Molecular Endocrinology · doi:10.1210/me.2014-1259 · Cited by 102
Self-citationPlasma FGF21 displays a circadian rhythm during a 72‐h fast in healthy female volunteers
Andersen, B., Beck‐Nielsen, H., & Højlund, K. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04084.x · Cited by 74
Fazeli, P. K., Faje, A. T., Cross, E. J., Lee, H., Rosen, C. J., Bouxsein, M., & Klibanski, A. (2015) · Bone · doi:10.1016/j.bone.2015.04.001 · Cited by 49
Self-citationSerum adiponectin concentrations during a 72-hour fast in over- and normal-weight humans
Merl, V., Peters, A., Oltmanns, K. M., Kern, W., Jan Born, A., Fehm, H., & Schultes, B. (2005) · International Journal of Obesity · doi:10.1038/sj.ijo.0802971 · Cited by 47
Hormonal Responses to Short Term Fasting in Postmenopausal Women*
Beitins, I. Z., Barkan, A. L., Klibanski, A., Kyung, N. H., Reppert, S. M., Badger, T. M., Veldhuis, J. D., & McArthur, J. W. (1985) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-60-6-1120 · Cited by 46
Self-citationDomouzoglou, E. M., Fisher, F. M., Astapova, I. I., Fox, E. C., Kharitonenkov, A., Flier, J. S., Hollenberg, A. N., & Maratos–Flier, E. (2014) · Endocrinology · doi:10.1210/en.2013-1902 · Cited by 41
Metabolic Aspects of Acute Starvation In Normal Humans: Performance and Cardiovascular Evaluation
Consolazio, C. F., Nelson, R. A., Johnson, H. L., MATOUSH, L. O., Krzywicki, H. J., & Isaac, G. J. (1967) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/20.7.684 · Cited by 37
Thyroid hormone receptor regulates most genes independently of fibroblast growth factor 21 in liver
Zhang, A., Sieglaff, D. H., York, J. P., Suh, J. H., Ayers, S. D., Winnier, G. E., Kharitonenkov, A., Pin, C. L., Zhang, P., Webb, P., et al. (2014) · Journal of Endocrinology · doi:10.1530/joe-14-0440 · Cited by 29
Protective effect of small amounts of glucose on abnormal liver function tests during starvation
Abraira, C., Virupannavar, C., & Nemchausky, B. M. (1980) · Metabolism · doi:10.1016/0026-0495(80)90037-2 · Cited by 10
Flagged first, then by citations
Cited by
Sorted by citations
Mechanisms of Insulin Action and Insulin Resistance
Petersen, M. C., & Shulman, G. I. (2018) · Physiological Reviews · doi:10.1152/physrev.00063.2017 · Cited by 3,028
The integrative biology of type 2 diabetes
Roden, M., & Shulman, G. I. (2019) · Nature · doi:10.1038/s41586-019-1797-8 · Cited by 1,167
Metabolites as regulators of insulin sensitivity and metabolism
Yang, Q., Vijayakumar, A., & Kahn, B. B. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0044-8 · Cited by 698
The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic
Geng, L., Lam, K. S. L., & Xu, A. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0386-0 · Cited by 607
The role of adipokines in chronic inflammation
Mancuso, P. (2016) · ImmunoTargets and Therapy · doi:10.2147/itt.s73223 · Cited by 405
“Unlike leptin, serum adiponectin levels remain stable after 3 days of fasting and decline slightly during a prolonged fast.(98,99) The decline of leptin in adaptation to starvation has been examined in murine models to determine the impact of leptin in thymic atrophy and pneumococcal pneumonia.”
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
