Fibroblast growth factor 21: a regulator of metabolic disease and health span
Open accessAbstract
Fibroblast growth factor 21 (FGF21) is a potent endocrine regulator with physiological effects on glucose and lipid metabolism and thus garners much attention for its translational potential for the management of obesity and related metabolic syndromes. FGF21 is mainly expressed in several metabolically active tissue organs, such as the liver, adipose tissue, skeletal muscle, and pancreas, with profound effects and therapeutic relevance. Emerging experimental and clinical data point to the demonstrated metabolic benefits of FGF21, which include, but are not limited to, weight loss, glucose and lipid metabolism, and insulin sensitivity. In addition, FGF21 also acts directly through its coreceptor β-klotho in the brain to alter light-dark cycle activity. In this review, we critically appraise current advances in understanding the physiological actions of FGF21 and its role as a biomarker of various metabolic diseases, especially type 2 diabetes mellitus. We also discuss the potentially exciting role of FGF21 in improving our health and prolonging our life span. This information will provide a fuller understanding for further research into FGF21, as well as providing a scientific basis for potentially establishing health care guidelines for this promising molecule.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Overexpression of FGF21 improves healthspan.
“Several findings demonstrate that the overexpression of FGF21 improves healthspan”
From Human Aging and Longevity Are Characterized by High Levels of Mitokines (2019) · cites this paper as [17]
Cites
Stevens, P. E., Levin, A., & for the Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members* (2013) · Annals of Internal Medicine · doi:10.7326/0003-4819-158-11-201306040-00007 · Cited by 3,607 · see citing works
Kenyon, C. J. (2010) · Nature · doi:10.1038/nature08980 · Cited by 2,739 · see citing works
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
Roles of PPARs in health and disease
Kersten, S., Desvergne, B., & Wahli, W. (2000) · Nature · doi:10.1038/35013000 · Cited by 1,956 · see citing works
Frederich, R. C., Hamann, A., Anderson, S., Löllmann, B., Lowell, B. B., & Flier, J. S. (1995) · Nature Medicine · doi:10.1038/nm1295-1311 · Cited by 1,660 · 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
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 · see citing works
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 · see citing works
The Endocrine Regulation of Aging by Insulin-like Signals
Tatar, M., Bartke, A., & Antebi, A. (2003) · Science · doi:10.1126/science.1081447 · Cited by 1,327 · 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
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
Obesity Is a Fibroblast Growth Factor 21 (FGF21)-Resistant State
Fisher, F. M., Chui, P. C., Antonellis, P. J., Bina, H. A., Kharitonenkov, A., Flier, J. S., & Maratos-Flier, E. (2010) · Diabetes · doi:10.2337/db10-0193 · Cited by 830 · see citing works
Cytotoxicity and genotoxicity of lipid-oxidation products
Esterbauer, H. (1993) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/57.5.779s · Cited by 817 · see citing works
Gospodarowicz, D. (1974) · Nature · doi:10.1038/249123a0 · Cited by 788 · see citing works
The 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
Functionally significant insulin-like growth factor I receptor mutations in centenarians
Suh, Y., Atzmon, G., Cho, M.-O., Hwang, D., Liu, B., Leahy, D. J., Barzilai, N., & Cohen, P. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705467105 · Cited by 703 · see citing works
Fon Tacer, K., Bookout, A. L., Ding, X., Kurosu, H., John, G. B., Wang, L., Goetz, R., Mohammadi, M., Kuro-o, M., Mangelsdorf, D. J., et al. (2010) · Molecular Endocrinology · doi:10.1210/me.2010-0142 · Cited by 700 · see citing works
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 · see citing works
Ripperger, J. A., & Schibler, U. (2006) · Nature Genetics · doi:10.1038/ng1738 · Cited by 593 · see citing works
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 · see citing works
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 · see citing works
Hu, M. C., Shiizaki, K., Kuro-o, M., & Moe, O. W. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183727 · Cited by 587 · see citing works
Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway
Chau, M. D. L., Gao, J., Yang, Q., Wu, Z., & Gromada, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006962107 · Cited by 548 · see citing works
FGF21 regulates metabolism and circadian behavior by acting on the nervous system
Bookout, A. L., de Groot, M. H. M., Owen, B. M., Lee, S., Gautron, L., Lawrence, H. L., Ding, X., Elmquist, J. K., Takahashi, J. S., Mangelsdorf, D. J., et al. (2013) · Nature Medicine · doi:10.1038/nm.3249 · Cited by 545 · see citing works
Thymic involution and immune reconstitution.
Lynch, H. E., Goldberg, G. L., Chidgey, A., Van den Brink, M. R. M., Boyd, R., & Sempowski, G. D. (2009) · Trends in Immunology · doi:10.1016/j.it.2009.04.003 · Cited by 522 · see citing works
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 · see citing works
Haynes, B. F., Markert, M. L., Sempowski, G. D., Patel, D. D., & Hale, L. P. (2000) · Annual Review of Immunology · doi:10.1146/annurev.immunol.18.1.529 · Cited by 502 · 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
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
Genetic links between diet and lifespan: shared mechanisms from yeast to humans
Bishop, N. A., & Guarente, L. (2007) · Nature Reviews Genetics · doi:10.1038/nrg2188 · Cited by 421 · see citing works
The starvation hormone, fibroblast growth factor-21, extends lifespan in mice
Zhang, Y., Xie, Y., Berglund, E. D., Coate, K. C., He, T. T., Katafuchi, T., Xiao, G., Potthoff, M. J., Wei, W., Wan, Y., et al. (2012) · eLife · doi:10.7554/elife.00065 · Cited by 420 · see citing works
Insulin-Receptor Interaction in the Obese-Hyperglycemic Mouse
Kahn, C. R., Neville, D. M., & Roth, J. (1973) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)44468-2 · Cited by 410 · 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
Lundåsen, T., Gälman, C., Angelin, B., & Rudling, M. J. (2006) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2006.01731.x · Cited by 406 · see citing works
Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanismPreprint
Mitsui, S., Yamaguchi, S., Matsuo, T., Ishida, Y., & Okamura, H. (2001) · Genes & Development · doi:10.1101/gad.873501 · Cited by 403 · see citing works
Li, H., Fang, Q., Gao, F., Fan, J., Zhou, J., Wang, X., Zhang, H., Pan, X., Bao, Y., Xiang, K., et al. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.05.018 · Cited by 400 · see citing works
Insights into thymic aging and regeneration
Taub, D. D., & Longo, D. L. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00275.x · Cited by 393 · see citing works
Fibroblast growth factor 21 protects against cardiac hypertrophy in mice
Planavila, A., Redondo‐Angulo, I., Hondares, E., Vinciguerra, M., Munts, C., Iglesias, R., Gabrielli, L., Sitges, M., Giralt, M., van Bilsen, M., et al. (2013) · Nature Communications · doi:10.1038/ncomms3019 · Cited by 371 · see citing works
Endocrine regulation of ageing
Russell, S. J., & Kahn, C. R. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2234 · Cited by 356 · see citing works
FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver
von Holstein-Rathlou, S., BonDurant, L. D., Peltekian, L., Naber, M. C., Yin, T. C., Claflin, K. E., Urizar, A. I., Madsen, A. N., Ratner, C., Holst, B., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.003 · Cited by 347 · see citing works
FGF21 Regulates Sweet and Alcohol Preference
Talukdar, S., Owen, B. M., Song, P., Hernandez, G., Zhang, Y., Zhou, Y., Scott, W. T., Paratala, B., Turner, T., Smith, A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.008 · Cited by 342 · see citing works
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 · see citing works
Lemberger, T., Saladin, R., Vázquez‐Carrera, M., Assimacopoulos, F., Staels, B., Desvergne, B., Wahli, W., & Auwerx, J. H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.3.1764 · Cited by 329 · see citing works
Berglund, E. D., Li, C. Y., Bina, H. A., Lynes, S. E., Michael, M. D., Shanafelt, A. B., Kharitonenkov, A., & Wasserman, D. H. (2009) · Endocrinology · doi:10.1210/en.2009-0221 · Cited by 297 · see citing works
The fasting polypeptide FGF21 can enter brain from blood
Hsuchou, H., Pan, W., & Kastin, A. J. (2007) · Peptides · doi:10.1016/j.peptides.2007.10.007 · Cited by 280 · see citing works
Mraz, M., Bartlova, M., Lacinova, Z., Michalsky, D., Kasalicky, M., Haluzikova, D., Matoulek, M., Dostalova, I., Humenanska, V., & Haluzik, M. (2009) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2008.03502.x · Cited by 279 · see citing works
Fibroblast growth factor 21 protects the heart from oxidative stress
Planavila, A., Redondo‐Angulo, I., Ribas‐Aulinas, F., Garrabou, G., Casademont, J., Giralt, M., & Villarroya, F. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvu263 · Cited by 265 · see citing works
Fisher, F. M., Chui, P. C., Nasser, I. A., Popov, Y., Cunniff, J. C., Lundasen, T., Kharitonenkov, A., Schuppan, D., Flier, J. S., & Maratos-Flier, E. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.07.044 · Cited by 263 · 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
Freidenberg, G. R., Henry, R. R., Klein, H. H., Reichart, D. R., & Olefsky, J. M. (1987) · Journal of Clinical Investigation · doi:10.1172/jci112789 · Cited by 234 · see citing works
Cellular Mechanisms by Which FGF21 Improves Insulin Sensitivity in Male Mice
Camporez, J. P., Jornayvaz, F. R., Petersen, M. C., Pesta, D. H., Guigni, B. A., Serr, J., Zhang, D., Kahn, M., Samuel, V. T., Jurczak, M. J., et al. (2013) · Endocrinology · doi:10.1210/en.2013-1191 · Cited by 226 · 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
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 222 · see citing works
FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans
Søberg, S., Sandholt, C. H., Jespersen, N. Z., Toft, U., Madsen, A. L., von Holstein-Rathlou, S., Grevengoed, T. J., Christensen, K. B., Bredie, W. L. P., Potthoff, M. J., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.009 · Cited by 216 · see citing works
Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework
Solon-Biet, S. M., Cogger, V. C., Pulpitel, T., Heblinski, M., Wahl, D., McMahon, A. C., Warren, A., Durrant-Whyte, J., Walters, K. A., Krycer, J. R., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.001 · Cited by 212 · see citing works
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 205 · see citing works
Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease
Yilmaz, Y. N., Eren, F., Yönal, O., Kurt, R., Aktaş, B., Çelikel, Ç., Özdogan, O. C., İmeryüz, N., Kalaycı, C., & Avşar, E. (2010) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.2010.02338.x · Cited by 196 · see citing works
Novel locus including FGF21 is associated with dietary macronutrient intake
Chu, A. Y., Workalemahu, T., Paynter, N. P., Rose, L. M., Giulianini, F., Tanaka, T., Ngwa, J. S., Qi, Q., Curhan, G. C., Rimm, E. B., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt032 · Cited by 195 · see citing works
Chow, W. S., Xu, A., Woo, Y. C., Tso, A. W. K., Cheung, S., Fong, C. H.-Y., Tse, H., Chau, M. T., Cheung, B. M. Y., & Lam, K. S. L. (2013) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.113.301599 · Cited by 193 · see citing works
Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes
Iizuka, K., Takeda, J., & Horikawa, Y. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.07.053 · Cited by 187 · 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
Lack of Overt FGF21 Resistance in Two Mouse Models of Obesity and Insulin Resistance
Hale, C., Chen, M. M., Stanislaus, S., Chinookoswong, N., Hager, T., Wang, M., Véniant, M. M., & Xu, J. (2012) · Endocrinology · doi:10.1210/en.2010-1262 · Cited by 185 · see citing works
Lin, Z., Wu, Z., Yin, X., Liu, Y., Yan, X., Lin, S., Xiao, J., Wang, X., Feng, W., & Li, X. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015534 · Cited by 179 · see citing works
Evidence of preference for a high-concentration sucrose solution in alcoholic men
Kampov‐Polevoy, A. B., Garbutt, J. C., & Janowsky, D. S. (1997) · American Journal of Psychiatry · doi:10.1176/ajp.154.2.269 · Cited by 179 · see citing works
Klotho is a target gene of PPAR-γ
Zhang, H., Li, Y., Fan, Y., Wu, J., Zhao, B., Guan, Y., Chien, S., & Wang, N. (2008) · Kidney International · doi:10.1038/ki.2008.244 · Cited by 175 · see citing works
Differential Specificity of Endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in Complex with KLB
Yang, C., Jin, C., Li, X., Wang, F., McKeehan, W. L., & Luo, Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033870 · Cited by 173 · see citing works
Yu, H., Xia, F., Lam, K. S., Wang, Y., Bao, Y., Zhang, J., Gu, Y., Zhou, P., Lu, J., Jia, W., et al. (2011) · Clinical Chemistry · doi:10.1373/clinchem.2010.155184 · Cited by 170 · see citing works
Greenhalgh, C. J., Bertolino, P., Asa, S. L., Metcalf, D., Corbin, J. E., Adams, T. E., Davey, H. W., Nicola, N. A., Hilton, D. J., & Alexander, W. S. (2002) · Molecular Endocrinology · doi:10.1210/me.16.6.1394 · Cited by 166 · see citing works
FGF21-based pharmacotherapy – potential utility for metabolic disorders
Gimeno, R. E., & Moller, D. E. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2014.03.001 · Cited by 163 · see citing works
Disturbances in the normal regulation of SREBP-sensitive genes in PPARα-deficient mice
Patel, D. D., Knight, B. L., Wiggins, D. K., Humphreys, S. M., & Gibbons, G. F. (2001) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)31655-2 · Cited by 142 · see citing works
Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease
Shen, Y., Ma, X., Zhou, J., Pan, X., Hao, Y., Zhou, M., Lu, Z., Gao, M., Bao, Y., & Jia, W. (2013) · Cardiovascular Diabetology · doi:10.1186/1475-2840-12-124 · Cited by 135 · see citing works
Abramovitz, L., Rubinek, T., Ligumsky, H., Bose, S., Barshack, I., Avivi, C., Kaufman, B., & Wolf, I. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2749 · Cited by 134 · see citing works
Lin, Z., Zhou, Z., Liu, Y., Gong, Q., Yan, X., Xiao, J., Wang, X., Lin, S., Feng, W., & Li, X. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018398 · Cited by 129 · see citing works
Fibroblast Growth Factor 21 (FGF21) in Human Cerebrospinal Fluid
Tan, B. K., Hallschmid, M., Adya, R., Kern, W., Lehnert, H., & Randeva, H. S. (2011) · Diabetes · doi:10.2337/db11-0672 · Cited by 129 · see citing works
Youm, Y.-H., Horvath, T. L., Mangelsdorf, D. J., Kliewer, S. A., & Dixit, V. D. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1514511113 · Cited by 129 · see citing works
Huang, J., Ishino, T., Chen, G., Rolzin, P., Osothprarop, T. F., Retting, K., Li, L., Jin, P., Matin, M. J., Huyghe, B., et al. (2013) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.204420 · Cited by 121 · see citing works
Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress
Yang, C., Lu, W., Lin, T., You, P., Ye, M., Huang, Y., Jiang, X., Wang, C., Wang, F., Lee, M., et al. (2013) · BMC Gastroenterology · doi:10.1186/1471-230x-13-67 · Cited by 117 · see citing works
Zhang, C., Huang, Z., Gu, J., Yan, X., Lu, X., Zhou, S., Wang, S., Shao, M., Zhang, F., Cheng, P., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3630-8 · Cited by 113 · see citing works
FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action
Shin, D.-J., & Osborne, T. F. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808747200 · 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
So, W. Y., Cheng, Q., Chen, L., Evans‐Molina, C., Xu, A., Lam, K. S. L., & Leung, P. S. (2013) · Diabetes · doi:10.2337/db13-0645 · Cited by 109 · see citing works
Tong, X., Muchnik, M., Chen, Z., Patel, M., Wu, N., Joshi, S., Rui, L., Lazar, M. A., & Yin, L. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.172866 · Cited by 105 · see citing works
The paradox of the insulin/IGF-1 signaling pathway in longevity
(2004) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.03.006 · Cited by 102 · see citing works
Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease
Davis, R. L., Liang, C., Edema‐Hildebrand, F., Riley, C., Needham, M., & Sue, C. M. (2013) · Neurology · doi:10.1212/01.wnl.0000436068.43384.ef · Cited by 100 · see citing works
Uebanso, T., Taketani, Y., Yamamoto, H., Amo, K., Ominami, H., Arai, H., Takei, Y., Masuda, M., Tanimura, A., Harada, N., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022976 · Cited by 99 · see citing works
Circadian expression of FGF21 is induced by PPARα activation in the mouse liver
Oishi, K., Uchida, D., & Ishida, N. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.09.046 · Cited by 95 · see citing works
Fortuna, J. L. (2010) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2010.10400687 · Cited by 94 · see citing works
Wu, S., Levenson, A. E., Kharitonenkov, A., & Luca, F. D. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.343707 · Cited by 94 · see citing works
FGF21: a novel prospect for the treatment of metabolic diseases.
Kharitonenkov, A., & Shanafelt, A. B. (2009) · PubMed · Cited by 91 · see citing works
Lee, C., Hui, E. Y. L., Woo, Y. C., Yeung, C., Chow, W. S., Yuen, M. M. A., Fong, C. H.-Y., Xu, A., & Lam, K. S. L. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3465 · Cited by 84 · see citing works
Role of Fibroblast Growth Factor 21 (FGF21) in Undernutrition-Related Attenuation of Growth in Mice
Kubicky, R. A., Wu, S., Kharitonenkov, A., & Luca, F. D. (2012) · Endocrinology · doi:10.1210/en.2011-1909 · Cited by 81 · see citing works
So, W. Y., Cheng, Q., Xu, A., Lam, K. S. L., & Leung, P. S. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.80 · Cited by 78 · see citing works
Transcriptional regulation of metabolic processes: implications for cardiac metabolism
van Bilsen, M., Vusse, G. J., & Reneman, R. S. (1998) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s004240050739 · Cited by 77 · see citing works
Plasma 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 · see citing works
Minireview: Insights from Insulin-Like Growth Factor Binding Protein Transgenic Mice
Silha, J. V., & Murphy, L. J. (2002) · Endocrinology · doi:10.1210/en.2002-220116 · Cited by 68 · see citing works
FGF21 resistance is not mediated by downregulation of beta-klotho expression in white adipose tissue
Markan, K. R., Naber, M. C., Small, S. M., Peltekian, L., Kessler, R. L., & Potthoff, M. J. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.03.009 · Cited by 68 · see citing works
Weng, Y., Chabot, J., Bernardo, B. L., Yan, Q., Zhu, Y., Brenner, M. B., Vage, C., Logan, A., Calle, R. A., & Talukdar, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119104 · Cited by 67 · see citing works
Physiological and Pharmacological Roles of FGF21 in Cardiovascular Diseases
Cheng, P., Zhang, F., Yu, L., Lin, X., He, L., Li, X., Lu, X., Yan, X., Tan, Y., & Zhang, C. (2016) · Journal of Diabetes Research · doi:10.1155/2016/1540267 · Cited by 67 · see citing works
Mottillo, E. P., Desjardins, E. M., Fritzen, A. M., Zou, V. Z., Crane, J. D., Yabut, J. M., Kiens, B., Erion, D. M., Lanba, A., Granneman, J. G., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.04.001 · Cited by 57 · see citing works
Wu, X., Qi, Y., Chang, J.-R., Lu, W., Zhang, J., Wang, S., Cheng, S., Zhang, M., Fan, Q., Lv, Y., et al. (2014) · Heart and Vessels · doi:10.1007/s00380-014-0557-9 · Cited by 51 · see citing works
Fgf21 is required for cardiac remodeling in pregnancy
Redondo‐Angulo, I., Mas‐Stachurska, A., Sitges, M., Tinahones, F. J., Giralt, M., Villarroya, F., & Planavila, A. (2017) · Cardiovascular Research · doi:10.1093/cvr/cvx088 · Cited by 48 · see citing works
Lowell, F. C. (1944) · Journal of Clinical Investigation · doi:10.1172/jci101485 · Cited by 47 · see citing works
Serum fibroblast growth factor 21 levels in polycystic ovary syndrome
Görar, S., Çulha, C., Üç, Z. A., Dellal, F. D., Serter, R., Aral, S., & Aral, Y. (2010) · Gynecological Endocrinology · doi:10.3109/09513590.2010.487587 · Cited by 43 · see citing works
Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia
Stepan, H., Kley, K., Hindricks, J., Kralisch, S., Jank, A., Schaarschmidt, W., Schrey-Petersen, S., Ebert, T., Lössner, U., Kratzsch, J., et al. (2013) · Cytokine · doi:10.1016/j.cyto.2013.02.019 · Cited by 40 · see citing works
Plasma Concentrations of Fibroblast Growth Factors 21 and 19 in Patients with Cushing's Syndrome
Ďurovcová, V., Marek, J., Hána, V., Matoulek, M., Zikán, V., Haluzíková, D., Kaválková, P., Lacinová, Z., Kršek, M., & Haluzı́k, M. (2010) · Physiological Research · doi:10.33549/physiolres.931801 · Cited by 33 · see citing works
Knott, M. E., & Minatta, J. N. (2016) · Journal of Molecular Biomarkers & Diagnosis · doi:10.4172/2155-9929.s2-015 · Cited by 32 · see citing works
Woolsey, S., Beaton, M. D., Mansell, S. E., Leon‐Ponte, M., Yu, J., Pin, C. L., Adams, P. C., Kim, R. B., & Tirona, R. G. (2016) · Molecular Pharmacology · doi:10.1124/mol.116.104687 · Cited by 32 · see citing works
Loss of FGF21 in diabetic mouse during hepatocellular carcinogenetic transformation.
Zhang, Q., Yan, L., Liang, T., Lu, X., Liu, X., Zhang, C., Jiang, X. M., Martin, R. C. G., Cheng, M., & Cai, L. (2015) · Europe PMC (PubMed Central) · Cited by 29 · see citing works
Fgf21 regulates T-cell development in the neonatal and juvenile thymus
Nakayama, Y., Masuda, Y., Ohta, H., Tanaka, T., Washida, M., Nabeshima, Y., Miyake, A., Itoh, N., & Konishi, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-00349-8 · Cited by 15 · see citing works
FGF21 and Pancreatic Islet Fatty Acid Metabolism
Sun, M. Y., Kilkenny, D. M., & Rocheleau, J. V. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2009.12.4039 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The Klotho proteins in health and disease
Kuro-o, M. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-018-0078-3 · Cited by 707 · see citing works
Human Aging and Longevity Are Characterized by High Levels of Mitokines
Conte, M., Ostan, R., Fabbri, C., Santoro, A., Guidarelli, G., Vitale, G., Mari, D., Sevini, F., Capri, M., Sandri, M., et al. (2019) · The Journals of Gerontology: Series A · doi:10.1093/gerona/gly153 · Cited by 219 · see citing works
“Higher levels of circulating FGF21 attenuate acute metabolic disorders and collaborate to extend life span (16,17).”
BackgroundSandireddy, R., Sakthivel, S., Gupta, P., Behari, J., Tripathi, M., & Singh, B. K. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1433857 · Cited by 229 · see citing works
The road ahead for health and lifespan interventions
Gonzalez-Freire, M., Diaz-Ruiz, A., Hauser, D., Martinez-Romero, J., Ferrucci, L., Bernier, M., & de Cabo, R. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101037 · Cited by 118 · see citing works
Inflammaging, hormesis and the rationale for anti-aging strategies
Santoro, A., Martucci, M., Conte, M., Capri, M., Franceschi, C., & Salvioli, S. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101142 · Cited by 114 · see citing works
Mitochondria, immunosenescence and inflammaging: a role for mitokines?
Conte, M., Martucci, M., Chiariello, A., Franceschi, C., & Salvioli, S. (2020) · Seminars in Immunopathology · doi:10.1007/s00281-020-00813-0 · Cited by 104 · see citing works
Ye, L., Wang, X. B., Cai, C., Zeng, S., Bai, J., Guo, K., Fang, M., HU, J. L., Liu, H., Zhu, L., et al. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.02.013 · Cited by 93 · see citing works
Gong, X.-M., Li, Y., Luo, J., Wang, J., Wei, J. N., Wang, J.-Q., Xiao, T., Xie, C., Hong, J., Ning, G., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0065-4 · Cited by 93 · see citing works
MECHANISMS IN ENDOCRINOLOGY: Anorexia nervosa and endocrinology: a clinical update
Støving, R. K. (2018) · European Journal of Endocrinology · doi:10.1530/eje-18-0596 · Cited by 72 · see citing works
Adipose‐derived exosomes: A novel adipokine in obesity‐associated diabetes
Zhang, B., Yang, Y., Xiang, L., Zhao, Z., & Ye, R. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28354 · Cited by 66 · see citing works
“Several previous studies reported that FGF21 possesses anti‐ obesogenic and antidiabetic potentials (Markan et al., 2014; T. Xie & Leung, 2017).”
BackgroundFGF21 attenuates pulmonary fibrogenesis through ameliorating oxidative stress in vivo and in vitro
Zhang, S., Yu, D., Wang, M., Huang, T., Wu, H., Zhang, Y., Zhang, T., Wang, W., Yin, J., Ren, G., et al. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.03.100 · Cited by 62 · see citing works
Endocrine complications of anorexia nervosa
Haines, M. S. (2023) · Journal of Eating Disorders · doi:10.1186/s40337-023-00744-9 · Cited by 57 · see citing works
“One potential mechanism for GH resistance may be elevated levels of fibroblast growth factor 21 (FGF-21), which inhibits GH’s intracellular effects, including the production of IGF-1 from the liver [43].”
BackgroundXie, T., So, W. Y., Li, X. Y., & Leung, P. S. (2019) · Clinical Science · doi:10.1042/cs20190093 · Cited by 55 · see citing works
Avogaro, A., Fadini, G. P., & Prato, S. D. (2019) · Diabetes Care · doi:10.2337/dc19-1410 · Cited by 50 · see citing works
Independent links between plasma xanthine oxidoreductase activity and levels of adipokines
Furuhashi, M., Matsumoto, M., Murase, T., Nakamura, T., Higashiura, Y., Koyama, M., Tanaka, M., Moniwa, N., Ohnishi, H., Saitoh, S., et al. (2018) · Journal of Diabetes Investigation · doi:10.1111/jdi.12982 · Cited by 49 · see citing works
Torre-Villalvazo, I., Alemán, G., Valle‐Rios, R., & Noriega, L. G. (2019) · Nutrition Research · doi:10.1016/j.nutres.2019.06.006 · Cited by 44 · see citing works
Packer, M. (2020) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2020.107647 · Cited by 40 · see citing works
Yamakage, H., Tanaka, M., Inoue, T., Odori, S., Kusakabe, T., & Satoh‐Asahara, N. (2019) · Journal of Diabetes Investigation · doi:10.1111/jdi.13179 · Cited by 39 · see citing works
FGF21 and autophagy coordinately counteract kidney disease progression during aging and obesity
Minami, S., Sakai, S., Yamamoto, T., Takabatake, Y., Namba‐Hamano, T., Takahashi, A., Matsuda, J., Yonishi, H., Nakamura, J., Maeda, S., et al. (2023) · Autophagy · doi:10.1080/15548627.2023.2259282 · Cited by 39 · see citing works
“FGF21 is mainly expressed in several metabolically active tissue organs, such as the liver, adipose tissue, and pancreas [17].”
BackgroundRebollo‐Hernanz, M., Aguilera, Y., Martin-Cabrejas, M. A., & de Mejı́a, E. G. (2022) · Antioxidants · doi:10.3390/antiox11010136 · Cited by 37 · see citing works
Novel targets for delaying aging: The importance of the liver and advances in drug delivery
Hunt, N. J., McCourt, P., Couteur, D. G. L., & Cogger, V. C. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.09.006 · Cited by 36 · see citing works
Xu, T., Zhu, Q., Huang, Q., Gu, Q., Zhu, Y., Tang, M., Tian, S., Wang, L., Yan, F., Ge, J., et al. (2023) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.110753 · Cited by 35 · see citing works
“FGF21 has no adverse effects in treating diseases [31] and does not influence cell differentiation and tumor formation [32].”
Circulating mast cell progenitors correlate with reduced lung function in allergic asthma
Salomonsson, M., Malinovschi, A., Kalm‐Stephens, P., Dahlin, J. S., Janson, C., Alving, K., & Hallgren, J. (2019) · Clinical & Experimental Allergy · doi:10.1111/cea.13388 · Cited by 33 · see citing works
Klotho Protein and Cardio-Vascular System
Tyurenkov, I. N., Perfilova, V. N., Нестерова, А. А., & Glinka, Y. (2021) · Biochemistry (Moscow) · doi:10.1134/s0006297921020024 · Cited by 34 · see citing works
Stutz, H. (2022) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2022.115089 · Cited by 33 · see citing works
“FGF21 is a 19 kDa hormone that modulates glucose and lipid metabolism, thus representing a promising target for pharmaceuticals directed against type 2 diabetes and metabolic syndrome [32,343,344].”
BackgroundQi, J., Wu, Y., Guo, Z., Zhu, S., Xiong, J., Hu, F., Liang, X., & Ye, X. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.132896 · Cited by 32 · see citing works
Takahashi, A., Abe, K., Fujita, M., Hayashi, M., Okai, K., & Ohira, H. (2020) · Medicine · doi:10.1097/md.0000000000020399 · Cited by 32 · see citing works
“FGF21 is produced by not only hepatocytes but also muscle cells, and it regulates glucose and lipid metabolism.([18,19]) FGF21 levels are elevated in NAFLD and in obesity, metabolic syndrome, and type 2 diabetes.”
BackgroundSporadic Inclusion Body Myositis: An Acquired Mitochondrial Disease with Extras
Paepe, B. D. (2019) · Biomolecules · doi:10.3390/biom9010015 · Cited by 31 · see citing works
Fibroblast growth factor 21 as a potential master regulator in metabolic disorders
Velingkar, A., Vuree, S., Prabhakar, P. K., Kalashikam, R. R., Banerjee, A., & Kondeti, S. (2023) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00244.2022 · Cited by 32 · see citing works
García-Gaytán, A. C., Miranda‐Anaya, M., Turrubiate, I., Portugal, L. L.-D., Bocanegra-Botello, G. N., López-Islas, A., Díaz‐Muñoz, M., & Méndez, I. G. (2020) · Scientific Reports · doi:10.1038/s41598-020-66538-0 · Cited by 30 · see citing works
Xiao, F., Guo, Y., Deng, J., Yuan, F., Xiao, Y., Hui, L., Li, Y., Hu, Z., Zhou, Y., Li, K., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.12.003 · Cited by 28 · see citing works
Góralska, J., Raźny, U., Polus, A., Dziewońska, A., Gruca, A., Zdzienicka, A., Dembinska-Kiec, A., Solnica, B., Micek, A., Kapusta, M., et al. (2020) · Nutrients · doi:10.3390/nu12020476 · Cited by 25 · see citing works
Rebollo‐Hernanz, M., Aguilera, Y., Martin-Cabrejas, M. A., & de Mejı́a, E. G. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.866233 · Cited by 27 · see citing works
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 · see citing works
Yamamoto, S., Koyama, D., Igarashi, R., Maki, T., Mizuno, H., Furukawa, Y., & Kuro‐o, M. (2020) · Internal Medicine · doi:10.2169/internalmedicine.3597-19 · Cited by 23 · see citing works
“Importantly, mice deficient in αKlotho or FGF23 suffer from a disturbed mineral metabolism associated with accelerated aging (17), whereas transgenic mice that overexpress αKlotho (18) or FGF21 (13, 19) have longer life spans than normal mice.”
BackgroundYang, B. C., Wu, S. Y., & Leung, P. S. (2020) · Annals of Translational Medicine · doi:10.21037/atm.2020.02.129 · Cited by 22 · see citing works
“Chronic FGF21 administration has been reported to increase pancreatic islet numbers, increase insulin biosynthesis, and promote β-cell survival in db/db mice (7,8).”
BackgroundCausal Associations of Urate With Cardiovascular Risk Factors: Two-Sample Mendelian Randomization
Lukkunaprasit, T., Rattanasiri, S., Ongphiphadhanakul, B., McKay, G. J., Attia, J., & Thakkinstian, A. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.687279 · Cited by 21 · see citing works
“Another potential mechanism may be mediated through fibroblast growth factor 21 (FGF21), a metabolic regulator that demonstrates glucose and lipid-lowering effects in various animal models (Xie and Leung, 2017).”
BackgroundMoon, H., Choi, J., Song, B., Kim, I.-K., Lim, S., Lee, S., Han, G., Hwang, K., & Kim, S. W. (2022) · Cells · doi:10.3390/cells11030567 · Cited by 20 · see citing works
Takeuchi, K., Yamaguchi, K., Takahashi, Y., Yano, K., Okishio, S., Ishiba, H., Tochiki, N., Kataoka, S., Fujii, H., Iwai, N., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-75107-8 · Cited by 21 · see citing works
“5E) suggests the autocrine effect of liver-derived GDF15 and the involvement of signaling pathways downstream of GDF15, such as p38 and mitogen-activated protein kinase, as previously reported 42,43 .”
The endocrine role of hepatokines: implications for human health and disease
Iglesias, P. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1663353 · Cited by 22 · see citing works
Li, X., Shen, H., Zhou, T., Cao, X., Chen, Y., Liang, Y., Lu, T., He, J., Dou, Z., Liu, C., et al. (2021) · Respiratory Research · doi:10.1186/s12931-021-01778-w · Cited by 18 · see citing works
Cai, M., Ye, H., Zhu, X., Li, X., Cai, L., Jin, J., Chen, Q., Shi, Y., Yang, L., Wang, L., et al. (2023) · Inflammation · doi:10.1007/s10753-023-01905-3 · Cited by 17 · see citing works
“FGF21 is a critical regulator of lipid and glucose metabolism [30, 31].”
Characterization of fibroblast growth factor 1 in obese children and adolescents
Wang, A., Yan, X., Zhang, C., Du, C., Long, W., Zhan, D., & Luo, X. (2018) · Endocrine Connections · doi:10.1530/ec-18-0141 · Cited by 13 · see citing works
Huang, K., Liang, J., Lin, Y. Q., Zhu, J., Ma, J.-Q., & Wang, Y. (2020) · animal · doi:10.1017/s1751731120001160 · Cited by 13 · see citing works
Adipose MDM2 regulates systemic insulin sensitivity
Hallenborg, P., Jensen, B. A. H., Fjære, E., Petersen, R. K., Belmaáti, M.-S., Rasmussen, S. S., Gunnarsson, J. P., Lauritzen, P., Cheng, K. K. Y., Hermansson, M., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-01240-3 · Cited by 12 · see citing works
Ding, Y., Su, J., Shan, B., Fu, X., Zheng, G., Wang, J., Wu, L., Wang, F., Chai, X., Sun, H., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-69356-w · Cited by 12 · see citing works
The effects of macronutrients metabolism on cellular and organismal aging
Nehme, J., Altulea, A., Gheorghe, T., & Demaria, M. (2023) · Biomedical Journal · doi:10.1016/j.bj.2023.02.005 · Cited by 12 · see citing works
“Fibroblast growth factor 21 (FGF21) is an insulin-sensitizing hormone associated with a better metabolic health and longevity [102].”
BackgroundShariat‐Madar, Z., & Mahdi, F. (2025) · Molecules · doi:10.3390/molecules30224448 · Cited by 13 · see citing works
Physical activity to reduce PCSK9 levels
Tirandi, A., Montecucco, F., & Liberale, L. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.988698 · Cited by 10 · see citing works
“Among, adipocytokines, fibroblast growth factor 21 is a peptide implied in fatty acids and glucose metabolism (51) under both physiological and pathological conditions including obesity and metabolic syndrome (52).”
BackgroundParsing the Potential Neuroendocrine Actions of FGF21 in Primates
Gillum, M. P. (2018) · Endocrinology · doi:10.1210/en.2018-00208 · Cited by 9 · see citing works
Hui, Q., Huang, Z., Pang, S., Yang, X., Li, J., Yu, B., Tang, L., Li, X., & Wang, X. (2018) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-018-9470-y · Cited by 10 · see citing works
Gao, M. H., Giamouridis, D., Lai, N. C., Guo, T., Xia, B., Kim, Y. C., Huu, V. A. N., Skowronska‐Krawczyk, D., Lantier, L., Bhargava, R., et al. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.12.002 · Cited by 10 · see citing works
En, M., Yakovleva, T. V., Balybina, N., Baranov, K. O., Denisova, E. I., Dubinina, A., Feofanova, N. A., & Бажан, Н. М. (2020) · Vavilov Journal of Genetics and Breeding · doi:10.18699/vj20.40-o · Cited by 10 · see citing works
Vázquez, P., Hernández‐Sánchez, C., Escalona-Garrido, C., Pereira, L., Contreras, C., López, M., Balsinde, J., de Pablo, F., & Valverde, Á. M. (2018) · Journal of Lipid Research · doi:10.1194/jlr.m085209 · Cited by 10 · see citing works
Geidl, B., Hochuli, M., Spinas, G. A., & Gerber, P. A. (2022) · Nutrients · doi:10.3390/nu14194169 · Cited by 8 · see citing works
Roles of FGF21 and irisin in obesity-related diabetes and pancreatic diseases
Xie, T., & Leung, P. S. (2020) · Journal of Pancreatology · doi:10.1097/jp9.0000000000000039 · Cited by 7 · see citing works
Dâmaso, A. R., Machado, P. P., Rhein, S. O., Masquio, D. C. L., Oyama, L. M., Boldarine, V. T., Oliveira, G. I., Tock, L., Thivel, D., & Campos, R. M. D. S. (2021) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000419 · Cited by 7 · see citing works
“Corroborating this, a previous review of publications reported that FGF21 is considered a biomarker of many metabolic diseases, and experimental studies have shown that the administration of FGF21 in obesity can reduce body weight, glucose and triglyceride, improve insulin sensitivity and increase the mass of brown ad…”
BackgroundResultThe burn repair molecule? Evaluating FGF-21 in thermal injury – A systematic review
Niederegger, T., Schaschinger, T., Brandt, J., Knoedler, L., Knoedler, S. A., Palackic, A., Klimitz, F. J., Noll, D., Most, P., Ritterhoff, J., et al. (2025) · Burns · doi:10.1016/j.burns.2025.107785 · Cited by 6 · see citing works
Potential Biomarkers of Mitochondrial Dysfunction Associated with COVID-19 Infection
Turton, N., Millichap, L. E., & Hargreaves, I. P. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-28012-2_11 · Cited by 6 · see citing works
Tseng, C.-M. L., Balic, K., Charlton, R. W., Margalit, M., Mansbach, H., & Savić, R. M. (2023) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3046 · Cited by 6 · see citing works
Furuhashi, M., Higashiura, Y., Sakai, A., Koyama, M., Tanaka, M., Saitoh, S., Shimamoto, K., & Ohnishi, H. (2022) · Metabolites · doi:10.3390/metabo12030237 · Cited by 6 · see citing works
Senesi, P., Ferrulli, A., Luzi, L., & Terruzzi, I. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.975509 · Cited by 6 · see citing works
Wiszniewski, M., Mori, D., Puch, S. I. S., Calejman, C. M., Cymeryng, C. B., & Repetto, E. M. (2025) · Biology · doi:10.3390/biology14081058 · Cited by 5 · see citing works
“Levels of FGF21 are increased under a variety of physical conditions including high carbohydrate diets [16], and its highest expression is achieved with the combination of high-carbohydrate and low-protein diets [16].”
Dushay, J. R., & Lai, M. (2019) · Hepatology · doi:10.1002/hep.30789 · Cited by 5 · see citing works
“(5,6) In rodent models of obesity and NAFLD, exogenous administration of both native and recombinant FGF21 has been shown to cause significant weight loss, improvement in several metabolic disease markers, and improvement in NAFLD disease severity, including histological improvement.(7) Some nutritional interventions,…”
BackgroundMatsui, M., Kosaki, K., Myoenzono, K., Yoshikawa, T., Park, J., Kuro‐o, M., & Maeda, S. (2022) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-1902-3872 · Cited by 5 · see citing works
“FGF21 was recently identified as a novel hormone that regulates postprandial blood glucose elevation [30].”
BackgroundMiyahara, H., Tamai, C., Inoue, M., Sekiguchi, K., Tahara, D., Tahara, N., Takeda, K., Arafuka, S., Moriyoshi, H., Koizumi, R., et al. (2023) · Brain Pathology · doi:10.1111/bpa.13199 · Cited by 5 · see citing works
“However, serum GDF15 levels are also known to be increased in acute respiratory distress syndrome [33], pulmonary hypertension [34], cardiac failure [35], cancer [36], and aging [37], and serum FGF21 levels are increased in obesity, type 2 DM [38, 39], and nonalcoholic fatty liver disease [17].”
Benkhedir, A., Boussekine, S., Saker, H., Gasmi, S., & Benali, Y. (2022) · Journal of Microbiology Biotechnology and Food Sciences · doi:10.55251/jmbfs.9507 · Cited by 5 · see citing works
FGF21 activation-mediated Islet Autophagy in Type 2 Diabetes With Pharmacotherapeutic Potential
Leung, P. S. (2019) · Future Medicinal Chemistry · doi:10.4155/fmc-2018-0491 · Cited by 5 · see citing works
The Myokine FGF-21 Responds in a Time-Dependent Manner to Three Different Types of Acute Exercise
Thrones, M., Rawliuk, T., Cordingley, D. M., & Cornish, S. M. (2026) · Muscles · doi:10.3390/muscles5010003 · Cited by 4 · see citing works
“FGF-21 is a potent endocrine myokine and hepatokine that has effects https://doi.org/10.3390/muscles5010003 on glucose and lipid metabolism as well as influences on insulin sensitivity in skeletal muscle [17].”
InfluentialAlamgir, M., Sohal, A., & Kowdley, K. V. (2026) · Drug Design Development and Therapy · doi:10.2147/dddt.s560039 · Cited by 5 · see citing works
“7 While resmetirom and semaglutide exert their anti-fibrotic effects primarily through metabolic improvements, FGF-21 analogues offer a dual mechanism, combining metabolic improvements with a direct anti-fibrotic effect via hepatic stellate cells (HSC)/ macrophage pathways.”
Kukla, M., Kierach, R., Skonieczna, M., Hudy, D., Dąbrowski, K., Menżyk, T., Derra, A., Boroń, D., & Grabarek, B. O. (2021) · Clinical and Experimental Hepatology · doi:10.5114/ceh.2021.104419 · Cited by 4 · see citing works
“It is mainly produced in the liver and in smaller amounts by several metabolically active tissue organs, such as adipose tissue, skeletal muscle, and pancreas [9, 10].”
BackgroundInflammatory related plasma proteins involved in acute preschool wheeze
Holmdahl, I., Chakraborty, S., Hoyer, A., Filiou, A., Asarnoj, A., Sjölander, A., Borres, M. P., van Hage, M., Hedlin, G., Konradsen, J. R., et al. (2023) · Clinical and Translational Allergy · doi:10.1002/clt2.12308 · Cited by 3 · see citing works
“36 FGF21 has been shown to correlate with the frequency of circulating mast cells in asthmatic patients 37,38 and is involved in energy homoeostasis.”
BackgroundResultMichaëlsson, K., Lemming, E. W., Larsson, S. C., Höijer, J., Melhus, H., Svennblad, B., Baron, J. A., Wolk, A., & Byberg, L. (2024) · BMC Medicine · doi:10.1186/s12916-024-03651-1 · Cited by 4 · see citing works
“Genetically determined lower circulating concentrations of FGF21 in humans seem to lead to higher plasma cholesterol and apolipoprotein B, higher CRP, higher liver enzyme concentrations, and impaired insulin sensitivity [54, 55, 62].”
BackgroundSaponins from Panax japonicus Enhance Lipolysis via Acting on FGF21-β-Klotho/FGFR1 in Obese Mice
Wang, T., Huang, Y., Hu, M., Huang, X., Yu, D., Jia, L., Zhi, W., Mu, Y., Zhou, Z., & Wang, J. (2025) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5c01012 · Cited by 4 · see citing works
Matsui, M., Kosaki, K., Kuro‐o, M., Saito, C., Yamagata, K., & Maeda, S. (2021) · Hypertension Research · doi:10.1038/s41440-021-00782-3 · Cited by 4 · see citing works
Dual Role of Fibroblast Growth Factor Pathways in Sleep Regulation
Forouzanfar, F., & Negah, S. S. (2022) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530322666220802161031 · Cited by 4 · see citing works
Dahl, K., Friedrichsen, M. H., Ribel‐Madsen, R., Hansen, J. S., Clausen, J. O., Axelsen, M. B., Palle, M. S., Lippert, S. L., Björkdahl, O., Toubro, S., et al. (2025) · Clinical and Translational Science · doi:10.1111/cts.70435 · Cited by 3 · see citing works
Circadian Regulation of Endocrine Fibroblast Growth Factors on Systemic Energy Metabolism
Yang, Z., Zarbl, H., & Guo, G. L. (2024) · Molecular Pharmacology · doi:10.1124/molpharm.123.000831 · Cited by 3 · see citing works
Xu, J., Wu, F., Li, Y., Wang, F., Lin, W., Song, Q., Li, H., Fan, Y., Li, H., Chen, L., et al. (2021) · BMC Neuroscience · doi:10.1186/s12868-021-00676-7 · Cited by 3 · see citing works
“FGF21 is considered an important pharmacological regulator and has the potential to serve as a biomarker for many diseases [21].”
BackgroundWang, X., Li, S., Liu, J., Sun, W., Zhao, H. Q., Han, Q., Liu, Y., Cao, X., Li, Q., Jin, Y., et al. (2023) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-023-02540-3 · Cited by 3 · see citing works
“Previous studies have indicated that fibroblast growth factor-21 (FGF-21) is a cytokine mainly secreted by the liver and plays a variety of biological functions such as regulating lipid and sugar metabolism, anti-oxidative, and anti-inflammatory effects (Xie and Leung 2017).”
BackgroundBatokine in Central Nervous System Diseases
Shen, M., Zhang, M., Mao, N., & Lin, Z. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03490-w · Cited by 3 · see citing works
“Compared with other FGFs, FGF21 exerts almost no mitogenic effects [19].”
BackgroundZheng, P., Wang, F., Li, H., Chen, H., Li, M.-T., Ma, H., He, J., Chen, L., Liu, Y., & Xu, H. (2024) · Endocrine Connections · doi:10.1530/ec-24-0016 · Cited by 3 · see citing works
“It targets these tissues and improves glucose and/ or lipid homeostasis (65, 66).”
BackgroundБелок клото и сердечно-сосудистая система
Тюренков, И. Н., Perfilova, V. N., Нестерова, А. А., & Глинка, Е. Ю. (2021) · Biochemistry (Moscow) · doi:10.31857/s0320972521020020 · Cited by 3 · see citing works
Wu, C.-C., Hung, C.-J., Wang, Y., Lin, S., Chen, W., Kuan, Y., Liao, S., Yang, C., & Chen, C. (2020) · Molecules · doi:10.3390/molecules25143229 · Cited by 2 · see citing works
Next-Generation Therapies for Type 2 Diabetes Mellitus
Patra, D., Roy, S., Ramprasad, P., & Pal, D. (2024) · Smart nanomaterials technology · doi:10.1007/978-981-99-6597-7_13 · Cited by 2 · see citing works
Evaluating Fibroblast Growth Factor 21 (FGF21) Levels Post-Gastric Sleeve Surgery in Obese Patients
Al-Regaiey, K., Iqbal, M., Alzaid, M., Alkaoud, O. A., Alhadyani, M. A., Alagel, O. A., Alshehri, S. S., Altamimi, I., & Alsofayan, S. M. (2024) · Cureus · doi:10.7759/cureus.66122 · Cited by 3 · see citing works
“Administration of FGF21 has been shown to reduce body weight, lower blood glucose and TG levels, enhance insulin sensitivity, maintain β -cell function, decrease LDL, and increase HDL [21].”
BackgroundLi, X., Shen, H., Zhou, T., Cao, X., Chen, Y., Liang, Y., Lu, T., He, J., Dou, Z., Liu, C., et al. (2021) · Research Square · doi:10.21203/rs.3.rs-349444/v1 · Cited by 2 · see citing works
Sepsis and Fibroblast Growth Factor 21: A New Acute Phase Reactant?
Deveci, S., Koca, A. O., Ertuğrul, D. T., Akkan, T., & Beyan, E. (2021) · Türk yoğun bakım derneği dergisi/Türk yoğun bakım dergisi · doi:10.4274/tybd.galenos.2021.13008 · Cited by 1 · see citing works
“There are many findings in the literature showing that FGF 21 is increased in chronic metabolic conditions such as polycystic ovarian syndrome (PCOS), nonalcoholic steatohepatitis (NASH), diabetes mellitus (DM), and chronic kidney failure (CKD) (16-20).”
BackgroundAdipokines Play Important Role in Cell Proliferation and Anti-proliferation
Maurya, S. K., Bhattacharya, N., Bhattacharya, A., & Senapati, S. (2021) · Springer eBooks · doi:10.1007/978-981-16-1846-8_4 · Cited by 1 · see citing works
Cronjé, H. T., Hu, S., Gurrell, R., Vujković, M., Larsson, S. C., Mason, R., Butt, R. P., & Gill, D. (2026) · BMC Medicine · doi:10.1186/s12916-026-04807-x · Cited by 2 · see citing works
“Fibroblast growth factor 21 (FGF21) is a circulating hormone that is primarily produced in the liver and has been implicated in glucose and lipid metabolism [1].”
Hu, R., Zhang, X., Hu, L., Li, X., Hu, Q., & Jin, H. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1868285 · Cited by 1 · see citing works
Wali, J. A., Ramos-Nieves, J. M., Binia, A., & van der Beek, E. M. (2026) · Advances in Nutrition · doi:10.1016/j.advnut.2026.100713 · Cited by 1 · see citing works
“…FGF21-FGFR1c-β -Klotho complex causes phosphorylation of FGFR substrate 2 α (FRS2 α ) and activation of downstream signaling pathways including the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase and the phosphoinositide 3-kinase/protein kinase B pathways [2,20, 73].”
Adipose FGF21 signalling mediates the anti‐senescence effects of protein restriction
Yang, X., Wu, Y., Yang, Y., Huang, L., Jin, X., Jiang, X., Jin, C., Feng, B., Che, L., Xu, S., et al. (2026) · The Journal of Physiology · doi:10.1113/jp291341 · Cited by 1 · see citing works
“Through binding to fibroblast growth factor receptor 1c (FGFR1c) and its obligate co-receptor β -Klotho (KLB) (Kharitonenkov et al., 2008; Ogawa et al., 2007), FGF21 exerts pleiotropic metabolic effects on peripheral tissues, including WAT (Xie & Leung, 2017).”
Zhang, X., Zhao, Y., Liang, X., Zhang, L., Li, K., Sun, Z., & Zhao, Y. (2022) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13775 · Cited by 1 · see citing works
Hingole, P., Saha, P., Das, S., Gundu, C., & Kumar, A. (2025) · Molecular Biology Reports · doi:10.1007/s11033-025-10586-0 · Cited by 1 · see citing works
“FGF-21, responsive to mitochondrial stress, regulates energy homeostasis and metabolism [62], with elevated levels noted in COVID-19 patients, indicative of mitochondrial dysfunction.”
From Liver to Muscle: Crosstalk Mechanisms and Interventions in Sarcopenia
Wang, Q., Meng, Y., Wang, X., Lan, X., Fan, G., & Xiang, Y. (2025) · Health and Metabolism · doi:10.53941/hm.2025.100022 · Cited by 1 · see citing works
Oliveira‐Santos, A. A., Salvatori, R., Bueno, A. C., Nogueira, M. C., Campos, V. C., Melo, M. A., Oliveira, C. R. P., Barros-Oliveira, C. S., Marinho, C. G., Damascena, N. P., et al. (2021) · Endocrine · doi:10.1007/s12020-021-02700-6 · Cited by 1 · see citing works
The use of melatonin to mitigate the adverse metabolic side effects of antipsychotics
Romo‐Nava, F., Buijs, R. M., & McElroy, S. L. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-819975-6.00024-8 · Cited by 1 · see citing works
Comment on: “Fibroblast growth factor 21 controls mitophagy and muscle mass” by Oost et al.
Wu, Y., Zhu, B., Chen, Z., Duan, J., & Yang, L. (2019) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12465 · Cited by 1 · see citing works
“FGF21, a member of the FGF family, consists of 209 amino acids and is physiologically decomposed into 181 amino acids for maturity, which is mainly secreted by and acts on target tissues such as liver, fat, pancreas, and muscle.(2) Importantly, there are still great divergences in the physiologic role and mechanism of…”
BackgroundCronjé, H. T., Hu, S., Gurrell, R., Vujković, M., Larsson, S. C., Mason, R., Butt, R., & Gill, D. (2025) · medRxiv · doi:10.1101/2025.11.15.25340305 · Cited by 1 · see citing works
- Authors
- Xie, T., & Leung, P. S.
- Affiliations
- Chinese University of Hong Kong (HK)
- Corresponding author
- Leung, Po Sing
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2017-09-01
- Volume
- 313
- Issue
- 3
- Pages
- E292-E302
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC5625087
- OpenAlex
- W2620038295
- Cited by
- 121
- References
- 110
- Citations by year
- 2026: 15 · 2025: 13 · 2024: 13 · 2023: 12 · 2022: 13 · 2021: 17 · 2020: 14 · 2019: 13 · 2018: 11
- FWCI
- 0.97
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Research Grants Council of Hong Kong (14107415)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
- Keywords
- FGF21, metabolic disorders, healthspan, obesity, type 2 diabetes, glucose metabolism, lipid metabolism, insulin sensitivity, β-Klotho, circadian rhythm, biomarkers, weight loss, adipose tissue, liver
- MeSH terms
- Klotho Proteins, Adipose Tissue, Circadian Rhythm, Diabetes Mellitus, Type 2, Fibroblast Growth Factors, Humans, Insulin Resistance, Liver, Longevity, Membrane Proteins, Obesity, Pancreas, Biomarkers, Muscle, Skeletal
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
