Fibroblast growth factor 21: from pharmacology to physiology
Open accessAbstract
Fibroblast growth factor 21 (FGF21) is an atypical member of the FGF family that functions as an endocrine hormone. Pharmacologic studies show that FGF21 has broad metabolic actions in obese rodents and primates that include enhancing insulin sensitivity, decreasing triglyceride concentrations, and causing weight loss. In lean rodents, FGF21 expression is strongly induced in liver by prolonged fasting through a mechanism that involves the nuclear receptor peroxisome proliferator-activated receptor alpha. FGF21, in turn, induces the transcriptional coactivator protein peroxisome proliferator-activated receptor gamma coactivator protein 1alpha and stimulates hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis. FGF21 also blocks somatic growth and sensitizes mice to a hibernation-like state of torpor. Thus, FGF21 plays a key role in eliciting and coordinating the adaptive starvation response. Interestingly, FGF21 expression is induced in white adipose tissue by peroxisome proliferator-activated receptor gamma, which suggests that it also regulates metabolism in the fed state. This article highlights recent advances in our understanding of FGF21's pharmacologic and physiologic actions.
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
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?
The Steno 2 Study found that a multifactorial intervention lowered both cardiovascular and microvascular events, with the benefit persisting after the initial glucose, blood pressure, and lipid treatments were stopped.
“consistent with the multifactorial approach in the Steno 2 Study that demonstrated a reduction in both cardiovascular and microvascular events which was sustained even after cessation of the initial glucose, blood pressure and lipid lowering regimens132.”
From Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future (2014) · cites this paper as [132]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
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 · see citing works
Puigserver, P., & Spiegelman, B. M. (2003) · Endocrine Reviews · doi:10.1210/er.2002-0012 · Cited by 2,076 · see citing works
Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1
Yoon, J. C., Puigserver, P., Chen, G., Donovan, J., Wu, Z., Rhee, J., Adelmant, G., Stafford, J., Kahn, C. R., Granner, D. K., et al. (2001) · Nature · doi:10.1038/35093050 · Cited by 1,821 · see citing works
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 · see citing works
Self-citationBadman, 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 · see citing works
Xu, J., Lloyd, D. J., Hale, C., Stanislaus, S., Chen, M., Sivits, G., Vonderfecht, S., Hecht, R., Li, Y.-S., Lindberg, R. A., et al. (2009) · Diabetes · doi:10.2337/db08-0392 · Cited by 1,151 · see citing works
Fibroblast Growth Factor 21 Corrects Obesity in Mice
Coskun, T., Bina, H. A., Schneider, M. A., Dunbar, J. D., Hu, C. C., Chen, Y., Moller, D. E., & Kharitonenkov, A. (2008) · Endocrinology · doi:10.1210/en.2008-0816 · Cited by 1,031 · see citing works
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 · see citing works
Identification of a novel FGF, FGF-21, preferentially expressed in the liver
Nishimura, T., Nakatake, Y., Konishi, M., & Itoh, N. (2000) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(00)00067-1 · Cited by 847 · see citing works
Kurosu, H., Choi, M., Ogawa, Y., Dickson, A. S., Goetz, R., Eliseenkova, A. V., Mohammadi, M., Rosenblatt, K. P., Kliewer, S. A., & Kuro-o, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704165200 · Cited by 748 · see citing works
Self-citationThe metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21
Kharitonenkov, A., Wroblewski, V. J., Koester, A., Chen, Y.-F., Clutinger, C. K., Tigno, X. T., Hansen, B. C., Shanafelt, A. B., & Etgen, G. J. (2007) · Endocrinology · doi:10.1210/en.2006-1168 · Cited by 738 · see citing works
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 · see citing works
Self-citationβKlotho is required for metabolic activity of fibroblast growth factor 21
Ogawa, Y., Kurosu, H., Yamamoto, M., Nandi, A., Rosenblatt, K. P., Goetz, R., Eliseenkova, A. V., Mohammadi, M., & Kuro-o, M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701600104 · Cited by 617 · see citing works
Rhee, J., Inoue, Y., Yoon, J. C., Puigserver, P., Fan, M., Gonzalez, F. J., & Spiegelman, B. M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0730870100 · Cited by 564 · see citing works
Goetz, R., Beenken, A., Ibrahimi, O., Kalinina, J., Olsen, S., Eliseenkova, A. V., Xu, C.-F., Neubert, T., Zhang, F.-M., Linhardt, R., et al. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.02249-06 · Cited by 544 · see citing works
Self-citationGälman, 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 · see citing works
Wente, W., Efanov, A. M., Brenner, M. B., Kharitonenkov, A., Koster, A. M., Sandusky, G. E., Sewing, S., Treinies, I., Zitzer, H., & Gromada, J. (2006) · Diabetes · doi:10.2337/db05-1435 · Cited by 497 · see citing works
Adiponectin in insulin resistance: lessons from translational research
Ziemke, F., & Mantzoros, C. S. (2009) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2009.28449c · Cited by 422 · see citing works
Functional evolutionary history of the mouse Fgf gene family
Itoh, N., & Ornitz, D. M. (2007) · Developmental Dynamics · doi:10.1002/dvdy.21388 · Cited by 409 · see citing works
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 · see citing works
Self-citationPPARα is a key regulator of hepatic FGF21
Lundåsen, T., Hunt, M., Nilsson, L.-M., Sanyal, S., Angelin, B., Alexson, S., & Rudling, M. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.06.068 · Cited by 361 · see citing works
Suzuki, M., Uehara, Y., Motomura-Matsuzaka, K., Oki, J., Koyama, Y., Kimura, M., Asada, M., Komi-Kuramochi, A., Oka, S., & Toru, T. (2008) · Molecular Endocrinology · doi:10.1210/me.2007-0313 · Cited by 345 · see citing works
FGF‐21/FGF‐21 receptor interaction and activation is determined by βKlotho
Kharitonenkov, A., Dunbar, J. D., Bina, H. A., Bright, S. W., Moyers, J. S., Zhang, C., Ding, L., Micanovic, R., Mehrbod, S. F., Knierman, M. D., et al. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21357 · Cited by 329 · see citing works
Ito, S., Kinoshita, S., Shiraishi, N., Nakagawa, S., Sekine, S., Fujimori, T., & Nabeshima, Y. (2000) · Mechanisms of Development · doi:10.1016/s0925-4773(00)00439-1 · Cited by 312 · see citing works
Muise, E. S., Azzolina, B., Kuo, D. W., El-Sherbeini, M., Tan, Y., Yuan, X., Mu, J., Thompson, J. R., Berger, J. P., & Wong, K. K. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.044826 · Cited by 294 · see citing works
FGF21 attenuates lipolysis in human adipocytes – A possible link to improved insulin sensitivity
Arner, P., Pettersson, A., Mitchell, P. J., Dunbar, J. D., Kharitonenkov, A., & Rydén, M. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.04.038 · Cited by 234 · see citing works
Constant darkness is a circadian metabolic signal in mammals
Zhang, J., Kaasik, K., Blackburn, M. R., & Lee, C. C. (2006) · Nature · doi:10.1038/nature04368 · Cited by 225 · see citing works
The Klotho gene family as a regulator of endocrine fibroblast growth factors.
Kurosu, H., & Kuro-o, M. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.10.052 · Cited by 196 · see citing works
Chen, W.-W., Li, L., Yang, G.-Y., Li, K., Qi, X.-Y., Zhu, W., Tang, Y., Liu, H., & Boden, G. (2007) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/s-2007-985148 · Cited by 186 · see citing works
Wang, H., Qiang, L., & Farmer, S. R. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00992-07 · Cited by 181 · see citing works
Higgins, L. S., & DePaoli, A. M. (2009) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2009.28449e · Cited by 166 · see citing works
Andrews, M. T., Squire, T. L., Bowen, C. M., & Rollins, M. B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.8392 · Cited by 165 · see citing works
Regulation of Insulin-like Growth Factor-I in Starvation and Injury
Thissen, J., Underwood, L. E., & Ketelslegers, J. (2009) · Nutrition Reviews · doi:10.1111/j.1753-4887.1999.tb06939.x · Cited by 157 · see citing works
Actions and Mode of Actions of FGF19 Subfamily Members
Fukumoto, S. (2008) · Endocrine Journal · doi:10.1507/endocrj.kr07e-002 · Cited by 125 · see citing works
Burgess, S. C., Leone, T. C., Wende, A. R., Croce, M. A., Chen, Z., Sherry, A. D., Malloy, C. R., & Finck, B. N. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600050200 · Cited by 111 · see citing works
Plasma 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 · see citing works
Li, H., Bao, Y., Xu, A., Pan, X., Lu, J., Wu, H., Lu, H., Xiang, K., & Jia, W. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-2331 · Cited by 108 · see citing works
Plasma FGF-21 levels in type 2 diabetic patients with ketosis
Li, L., Yang, G., Ning, H., Yang, M., Liu, H., & Chen, W. (2008) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2008.07.012 · Cited by 55 · see citing works
Peroxisome proliferator-activated receptor translational research and clinical experience
Cheatham, W. W. (2009) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2009.28449d · Cited by 42 · see citing works
Blackburn, G. L. (2009) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2009.28449a · Cited by 18 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The Fibroblast Growth Factor signaling pathway
Ornitz, D. M., & Itoh, N. (2015) · WIREs Developmental Biology · doi:10.1002/wdev.176 · Cited by 2,050 · see citing works
PPARγ signaling and metabolism: the good, the bad and the future
Ahmadian, M., Suh, J. M., Hah, N., Liddle, C., Atkins, A. R., Downes, M., & Evans, R. M. (2013) · Nature Medicine · doi:10.1038/nm.3159 · Cited by 2,016 · see citing works
Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future
Kahn, S. E., Cooper, M. E., & Del Prato, S. (2014) · The Lancet · doi:10.1016/s0140-6736(13)62154-6 · Cited by 1,743 · see citing works
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 · see citing works
AMP-Activated Protein Kinase (AMPK) Controls the Aging Process via an Integrated Signaling Network
Salminen, A., & Kaarniranta, K. (2012) · Ageing Research Reviews · doi:10.1016/j.arr.2011.12.005 · Cited by 860 · see citing works
Targeting adipose tissue in the treatment of obesity-associated diabetes
Kusminski, C. M., Bickel, P. E., & Scherer, P. E. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.75 · Cited by 678 · see citing works
Talukdar, S., Zhou, Y., Li, D., Rossulek, M., Dong, J., Somayaji, V., Weng, Y., Clark, R., Lanba, A., Owen, B. M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.02.001 · Cited by 496 · see citing works
Tanaka, T., Ngwa, J. S., van Rooij, F. J., Zillikens, M. C., Wojczynski, M. K., Frazier-Wood, A. C., Houston, D. K., Kanoni, S., Lemaitre, R. N., Luan, J., et al. (2013) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.112.052183 · Cited by 226 · see citing works
Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment
Van Gaal, L., & Scheen, A. (2015) · Diabetes Care · doi:10.2337/dc14-1630 · Cited by 221 · see citing works
Ye, D., Wang, Y., Li, H., Jia, W., Man, K., Lo, C. M., Wang, Y., Lam, K. S. L., & Xu, A. (2014) · Hepatology · doi:10.1002/hep.27060 · Cited by 184 · see citing works
FGF21 Requires βklotho to Act In Vivo
Adams, A. C., Cheng, C. C., Coskun, T., & Kharitonenkov, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049977 · Cited by 181 · see citing works
Exercise increases serum fibroblast growth factor 21 (FGF21) levels
Cuevas-Ramos, D., Almeda-Valdés, P., Meza-Arana, C. E., Brito-Córdova, G., Gómez-Pérez, F. J., Mehta, R., Oseguera-Moguel, J., & Aguilar-Salinas, C. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038022 · Cited by 178 · see citing works
LY2405319, an engineered FGF21 variant, improves the metabolic status of diabetic monkeys
Adams, A. C., Halstead, C. A., Hansen, B. C., Irizarry, A. R., Martin, J. A., Myers, S. R., Reynolds, V. L., Smith, H. W., Wroblewski, V. J., & Kharitonenkov, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065763 · Cited by 169 · see citing works
Huang, Z., Zhong, L., Lee, J. T. H., Zhang, J., Wu, D., Geng, L., Wang, Y., Wong, C.-M., & Xu, A. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.003 · Cited by 147 · see citing works
Arai, H., Yamashita, S., Yokote, K., Araki, E., Suganami, H., & Ishibashi, S. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.03.032 · Cited by 124 · see citing works
Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15
Zhou, M., Luo, J., Chen, M., Yang, H., Learned, R. M., DePaoli, A. M., Tian, H., & Ling, L. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.01.027 · Cited by 102 · see citing works
Cuevas-Ramos, D., Almeda-Valdes, P., Gómez-Pérez, F. J., Meza-Arana, C. E., Cruz-Bautista, I., Arellano-Campos, O., Navarrete-López, M., & Aguilar-Salinas, C. A. (2010) · European Journal of Endocrinology · doi:10.1530/eje-10-0454 · Cited by 58 · see citing works
Epidemiology of Obesity and Pharmacologic Treatment Options
Shettar, V., Patel, S., & Kidambi, S. (2017) · Nutrition in Clinical Practice · doi:10.1177/0884533617713189 · Cited by 26 · see citing works
The role of FGF21 in the metabolic adjustments required for exercise capacity
Abe, L., & Dantzer, R. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123940 · Cited by 5 · see citing works
- Authors
- Kliewer, S. A., & Mangelsdorf, D. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Kliewer, Steven A
- Venue
- The American Journal of Clinical Nutrition
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 91
- Issue
- 1
- Pages
- 254S-257S
- ISSN
- 0002-9165 (ISSN-L)
- PMC
- PMC2793111
- OpenAlex
- W1966887410
- Cited by
- 219
- References
- 40
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 9 · 2023: 7 · 2022: 3 · 2021: 5 · 2020: 8 · 2019: 6 · 2018: 14 · 2017: 16 · 2016: 14 · 2015: 20 · 2014: 21 · 2013: 25 · 2012: 21
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal of Clinical Nutrition (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (RL1GM084436)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- FGF21, obesity, insulin sensitivity, fasting, PPARα, PPARγ coactivator-1α, hepatic gluconeogenesis, fatty acid oxidation, ketogenesis, hibernation, torpor, white adipose tissue, metabolic regulation
- MeSH terms
- Adipose Tissue, Animals, Diabetes Mellitus, Diabetes Mellitus, Experimental, Fibroblast Growth Factors, Glucagon, Growth Substances, Humans, Insulin, Liver, Obesity, Pancreas, Primates, Rodentia, Starvation, Triglycerides, Weight Loss, Mice
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
