FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting
Abstract
Hepatic gluconeogenesis is a main source of blood glucose during prolonged fasting and is orchestrated by endocrine and neural pathways. Here we show that the hepatocyte-secreted hormone fibroblast growth factor 21 (FGF21) induces fasting gluconeogenesis via the brain-liver axis. Prolonged fasting induces activation of the transcription factor peroxisome proliferator-activated receptor α (PPARα) in the liver and subsequent hepatic production of FGF21, which enters into the brain to activate the hypothalamic-pituitary-adrenal (HPA) axis for release of corticosterone, thereby stimulating hepatic gluconeogenesis. Fasted FGF21 knockout (KO) mice exhibit severe hypoglycemia and defective hepatic gluconeogenesis due to impaired activation of the HPA axis and blunted release of corticosterone, a phenotype similar to that observed in PPARα KO mice. By contrast, intracerebroventricular injection of FGF21 reverses fasting hypoglycemia and impairment in hepatic gluconeogenesis by restoring corticosterone production in both FGF21 KO and PPARα KO mice, whereas all these central effects of FGF21 were abrogated by blockage of hypothalamic FGF receptor-1. FGF21 acts directly on the hypothalamic neurons to activate the mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2), thereby stimulating the expression of corticotropin-releasing hormone by activation of the transcription factor cAMP response element binding protein. Therefore, FGF21 maintains glucose homeostasis during prolonged fasting by fine tuning the interorgan cross talk between liver and brain.
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?
FGF21 increases glucocorticoid action and the secretion of adiponectin.
“FGF21 was determined to increase glucocorticoid action [164] and the secretion of adiponectin [165], while follistatin was found to bind and inactivate myostatin [184] (8), further inhibiting its proinflammatory effects.”
KLB expression is primarily restricted to specific metabolic tissues (liver, pancreas, adipose) and lower in brain; KLB is not expressed in muscle.
“KLB expression is primarily restricted to specific metabolic tissues (for example, the liver, pancreas and adipose tissue)5, and lower expression is observed in the brain22,48–50. Despite some reports to the contrary51,52, KLB is not expressed in muscle5,41.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [50]
FGF21 does not act directly on the liver to mediate effects on hepatic metabolism.
“An important observation made during these studies was that FGF21 does not act directly on the liver to mediate these effects on hepatic metabolism.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [81]
Administration of FGF21 to the PVN of the hypothalamus restored corticosterone production and reversed impaired hepatic gluconeogenesis in Fgf21 knockout mice.
“Administration of FGF21 to the PVN of the hypothalamus restored corticosterone production and reversed the impaired hepatic gluconeogenesis observed in Fgf21 knockout mice (81).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [81]
FGF21 elicits its effects on hepatic gluconeogenesis through actions in the hypothalamus that activate the HPA axis to release corticosterone.
“A subsequent study validated these results and also revealed that FGF21 elicits its effects on hepatic gluconeogenesis through actions in the hypothalamus that activate the hypothalamic–pituitary–adrenal axis to release corticosterone (81).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [81]
Cites
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859 · see citing works
mouse brain in stereotaxic coordinates
Franklin, K. B. J., & Paxinos, G. (1997) · Cited by 3,258 · 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
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
Peroxisome proliferator–activated receptor α mediates the adaptive response to fasting
Kersten, S., Seydoux, J., Peters, J. M., Gonzalez, F. J., Desvergne, B., & Wahli, W. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6223 · Cited by 1,649 · 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
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
Endogenous glucose production is inhibited by the adipose-derived protein Acrp30
Combs, T. P., Berg, A. H., Obici, S., Scherer, P. E., & Rossetti, L. (2001) · Journal of Clinical Investigation · doi:10.1172/jci14120 · Cited by 935 · 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
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
Lin, Z., Tian, H., Lam, K. S. L., Lin, S., Hoo, R. C. L., Konishi, M., Itoh, N., Wang, Y., Bornstein, S. R., Xu, A., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.005 · Cited by 691 · 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
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 · 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
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
Fibroblast Growth Factor 21-Deficient Mice Demonstrate Impaired Adaptation to Ketosis
Badman, M. K., Koester, A., Flier, J. S., Kharitonenkov, A., & Maratos-Flier, E. (2009) · Endocrinology · doi:10.1210/en.2009-0532 · Cited by 362 · see citing works
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 · 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
Sarruf, D. A., Thaler, J. P., Morton, G. J., German, J. P., Fischer, J. D., Ogimoto, K., & Schwartz, M. W. (2010) · Diabetes · doi:10.2337/db09-1878 · Cited by 287 · 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
A comprehensive analysis of the distribution of FGF-2 and FGFR1 in the rat brain
Gonzalez, A. M., Berry, M., Maher, P. A., Logan, A., & Baird, A. (1995) · Brain Research · doi:10.1016/0006-8993(95)01002-x · Cited by 262 · see citing works
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 · see citing works
The molecular physiology of CRH neurons
Aguilera, G., & Liu, Y. (2012) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2011.08.002 · Cited by 198 · 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
Chen, W., Hoo, R. L. C., Konishi, M., Itoh, N., Lee, P.-C., Ye, H., Lam, K. S. L., & Xu, A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.285965 · Cited by 141 · see citing works
Adams, A. C., Astapova, I. I., Fisher, F. M., Badman, M. K., Kurgansky, K. E., Flier, J. S., Hollenberg, A. N., & Maratos–Flier, E. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.c110.107375 · Cited by 141 · see citing works
Adrenocortical dysfunction in liver disease: A systematic review
Fede, G., Spadaro, L., Tomaselli, T., Privitera, G., Germani, G., Tsochatzis, E. A., Thomas, M., Bouloux, P.-M. G., Burroughs, A. K., & Purrello, F. (2012) · Hepatology · doi:10.1002/hep.25573 · Cited by 134 · see citing works
Cheng, K. K. Y., Iglesias, M. A., Lam, K. S. L., Wang, Y., Sweeney, G., Zhu, W., Vanhoutte, P. M., Kraegen, E. W., & Xu, A. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.03.013 · Cited by 130 · 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
Song, X., Cao, J., Xu, Y., He, J., Zhang, L., & Yin-ming, Z. (2005) · Acta Pharmacologica Sinica · doi:10.1111/j.1745-7254.2005.00123.x · Cited by 128 · see citing works
Neuronal regulation of homeostasis by nutrient sensing
Lam, T. K. T. (2010) · Nature Medicine · doi:10.1038/nm0410-392 · Cited by 125 · see citing works
Hypothalamic glucagon signaling inhibits hepatic glucose production
Mighiu, P. I., Yue, J. T. Y., Filippi, B., Abraham, M. A., Chari, M., Lam, C., Yang, C. S., Christian, N. R., Charron, M. J., & Lam, T. K. T. (2013) · Nature Medicine · doi:10.1038/nm.3115 · Cited by 117 · see citing works
Role of PPAR in Hepatic Carbohydrate Metabolism
Peeters, A., & Baes, M. I. (2010) · PPAR Research · doi:10.1155/2010/572405 · Cited by 102 · see citing works
Fasting‐Induced Activation of Mitogen‐Activated Protein Kinases (ERK/p38) in the Mouse Hypothalamus
Morikawa, Y., Ueyama, E., & Senba, E. (2004) · Journal of Neuroendocrinology · doi:10.1111/j.0953-8194.2004.01135.x · Cited by 86 · see citing works
Im, S., Kim, M., Kwon, S.-K., Kim, T. H., Bae, J.-S., Kim, H., Kim, K., Oh, G.-T., & Ahn, Y. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.157875 · Cited by 66 · see citing works
Tadross, J. A., Patterson, M., Suzuki, K., Beale, K., Boughton, C. K., Smith, K., Moore, S., Ghatei, M. A., & Bloom, S. R. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00655.x · Cited by 25 · see citing works
Chen, X., Li, M., Sun, W., Bi, Y., Cai, M., Liang, H., Yu, Q.-Q., He, X., & Weng, J. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.01.152 · Cited by 16 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Understanding the Physiology of FGF21
Fisher, F. M., & Maratos-Flier, E. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105339 · Cited by 912 · see citing works
FGF/FGFR signaling in health and disease
Xie, Y., Su, N., Yang, J., Tan, Q., Huang, S., Jin, M., Ni, Z., Zhang, B., Zhang, D., Luo, F., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00222-7 · Cited by 904 · see citing works
Physical activity and muscle-brain crosstalk
Pedersen, B. K. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0174-x · Cited by 772 · see citing works
The endocrine function of adipose tissues in health and cardiometabolic disease
Scheja, L., & Heeren, J. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0230-6 · Cited by 663 · see citing works
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 · 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
Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23
Degirolamo, C., Sabbà, C., & Moschetta, A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.9 · Cited by 424 · see citing works
Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies
Musso, G., Cassader, M., & Gambino, R. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.3 · Cited by 415 · 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
Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication
Funcke, J., & Scherer, P. E. (2019) · Journal of Lipid Research · doi:10.1194/jlr.r094060 · Cited by 337 · see citing works
Flippo, K. H., & Potthoff, M. J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00354-2 · Cited by 311 · see citing works
Bile acid signaling pathways from the enterohepatic circulation to the central nervous system
Mertens, K. L., Kalsbeek, A., Soeters, M. R., & Eggink, H. M. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00617 · Cited by 287 · see citing works
Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21
Owen, B. M., Mangelsdorf, D. J., & Kliewer, S. A. (2015) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2014.10.002 · Cited by 286 · see citing works
Cytokines and abnormal glucose and lipid metabolism
Shi, J., Fan, J., Su, Q., & Yang, Z. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00703 · Cited by 282 · see citing works
Gonzalez-Gil, A. M., & Elizondo-Montemayor, L. (2020) · Nutrients · doi:10.3390/nu12061899 · Cited by 278 · see citing works
A Dozen Years of Discovery: Insights into the Physiology and Pharmacology of FGF21
Kliewer, S. A., & Mangelsdorf, D. J. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.004 · Cited by 273 · see citing works
Fibroblast Growth Factor 21—Metabolic Role in Mice and Men
Staiger, H., Keuper, M., Berti, L., Hrabě de Angelis, M., & Häring, H.-U. (2017) · Endocrine Reviews · doi:10.1210/er.2017-00016 · Cited by 270 · see citing works
Bile acids and their receptors in metabolic disorders
Fiorucci, S., Distrutti, E., Carino, A., Zampella, A., & Biagioli, M. (2021) · Progress in Lipid Research · doi:10.1016/j.plipres.2021.101094 · Cited by 262 · see citing works
Schumann, G., Liu, C., O’Reilly, P., Gao, H., Song, P., Xu, B., Ruggeri, B., Amin, N., Jia, T., Preis, S., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1611243113 · Cited by 241 · see citing works
FGF21 Signals Protein Status to the Brain and Adaptively Regulates Food Choice and Metabolism
Hill, C. M., Laeger, T., Dehner, M., Albarado, D. C., Clarke, B., Wanders, D., Burke, S. J., Collier, J. J., Qualls-Creekmore, E., Solon-Biet, S. M., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.022 · Cited by 229 · see citing works
Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis
BonDurant, L. D., & Potthoff, M. J. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064800 · Cited by 222 · see citing works
FGF21 and the late adaptive response to starvation in humans
Fazeli, P. K., Lun, M., Kim, S. M., Bredella, M. A., Wright, S., Zhang, Y., Lee, H., Catana, C., Klibanski, A., Patwari, P., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci83349 · Cited by 214 · see citing works
Geng, L., Liao, B., Jin, L., Huang, Z. P., Triggle, C. R., Ding, H., Zhang, J., Huang, Y., Lin, Z., & Xu, A. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.02.014 · Cited by 201 · see citing works
van Zutphen, T., Čiapaitė, J., Bloks, V. W., Ackereley, C., Gerding, A., Jurdzinski, A., de Moraes, R. A., Zhang, L., Wolters, J. C., Bischoff, R., et al. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.05.046 · Cited by 190 · see citing works
Timper, K., del Río-Martín, A., Cremer, A. L., Bremser, S., Alber, J., Giavalisco, P., Varela, L., Heilinger, C., Nolte, H., Trifunovic, A., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.05.001 · Cited by 170 · see citing works
Going Back to the Biology of FGF21: New Insights
Lewis, J. E., Ebling, F. J. P., Samms, R. J., & Tsintzas, K. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.05.007 · Cited by 164 · see citing works
Jensen-Cody, S. O., Flippo, K. H., Claflin, K. E., Yavuz, Y., Sapouckey, S. A., Walters, G. C., Usachev, Y. M., Atasoy, D., Gillum, M. P., & Potthoff, M. J. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.06.008 · Cited by 166 · see citing works
Pan, X., Shao, Y., Wu, F., Wang, Y., Xiong, R., Zheng, J., Tian, H., Wang, B., Wang, Y., Zhang, Y., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.04.002 · Cited by 163 · see citing works
Wang, Q., Yuan, J., Yu, Z., Lin, L., Jiang, Y., Cao, Z., Zhuang, P., Whalen, M. J., Song, B., Wang, X., et al. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0663-7 · Cited by 157 · see citing works
Nitzan, K., Benhamron, S., Valitsky, M., Kesner, E. E., Lichtenstein, M., Ben‐Zvi, A., Ella, E., Segalstein, Y., Saada, A., Lorberboum‐Galski, H., et al. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190853 · Cited by 157 · see citing works
FGF21: A Novel Regulator of Glucose and Lipid Metabolism and Whole-Body Energy Balance
Szczepańska, E., & Gietka‐Czernel, M. (2022) · Hormone and Metabolic Research · doi:10.1055/a-1778-4159 · Cited by 155 · see citing works
Li, X. (2019) · Frontiers of Medicine · doi:10.1007/s11684-019-0711-y · Cited by 139 · see citing works
Zhang, F., Yu, L., Lin, X., Cheng, P., He, L., Li, X., Lu, X., Tan, Y., Yang, H., Cai, L., et al. (2015) · Molecular Endocrinology · doi:10.1210/me.2015-1155 · Cited by 130 · see citing works
Defects in a liver-bone axis contribute to hepatic osteodystrophy disease progression
Lu, K., Shi, T.-S., Shen, S.-Y., Shi, Y., Gao, H.-L., Wu, J., Lu, X., Gao, X., Ju, H.-X., Wang, W., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.02.006 · Cited by 126 · see citing works
Regulation of longevity by FGF21: interaction between energy metabolism and stress responses
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.05.004 · Cited by 121 · see citing works
FGF21 activates AMPK signaling: impact on metabolic regulation and the aging process
Salminen, A., Kauppinen, A., & Kaarniranta, K. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1477-1 · Cited by 117 · see citing works
Fibroblast Growth Factor 15/19: From Basic Functions to Therapeutic Perspectives
Somm, E., & Jornayvaz, F. R. (2018) · Endocrine Reviews · doi:10.1210/er.2018-00134 · Cited by 118 · see citing works
Single Gene Inactivation with Implications to Diabetes and Multiple Organ Dysfunction Syndrome
Martins, I. J. (2017) · Journal of Clinical Epigenetics · doi:10.21767/2472-1158.100058 · Cited by 116 · see citing works
Mitochondrial stress and mitokines in aging
Burtscher, J., Soltany, A., Visavadiya, N. P., Burtscher, M., Millet, G. P., Khoramipour, K., & Khamoui, A. V. (2023) · Aging Cell · doi:10.1111/acel.13770 · Cited by 116 · see citing works
FGF21 Revolutions: Recent Advances Illuminating FGF21 Biology and Medicinal Properties
Kharitonenkov, A., & DiMarchi, R. D. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.09.007 · Cited by 114 · see citing works
Muscle-to-Brain Signaling Via Myokines and Myometabolites
Rai, M., & Demontis, F. (2022) · Brain Plasticity · doi:10.3233/bpl-210133 · Cited by 121 · see citing works
Geller, S., Arribat, Y., Netzahualcoyotzi, C., Lagarrigue, S., Carneiro, L., Zhang, L., Amati, F., López‐Mejía, I. C., & Pellerin, L. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.08.004 · Cited by 108 · see citing works
The Hormone FGF21 Stimulates Water Drinking in Response to Ketogenic Diet and Alcohol
Song, P., Zechner, C., Hernandez, G., Canovas, J. A., Xie, Y., Sondhi, V., Wagner, M., Stadlbauer, V., Horvath, A., Leber, B., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.04.001 · Cited by 103 · see citing works
FGF21 promotes thermogenic gene expression as an autocrine factor in adipocytes
Abu-Odeh, M., Zhang, Y., Reilly, S. M., Ebadat, N., Keinan, O., Valentine, J. M., Hafezi-Bakhtiari, M., Ashayer, H., Mamoun, L., Zhou, X., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109331 · Cited by 106 · see citing works
Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15
Cimino, I., Kim, H., Tung, Y. C. L., Pedersen, K., Rimmington, D., Tadross, J. A., Kohnke, S., Neves‐Costa, A., Barros, A., Joaquim, S., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2106868118 · Cited by 101 · see citing works
Metabolic fibroblast growth factors (FGFs): Mediators of energy homeostasis
Markan, K. R., & Potthoff, M. J. (2016) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2015.09.021 · Cited by 103 · see citing works
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 · see citing works
The FGF21–adiponectin axis in controlling energy and vascular homeostasis
Hui, X. H., Feng, T., Liu, Q., Gao, Y., & Xu, A. (2016) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjw013 · Cited by 102 · see citing works
Fibroblast growth factor 21 night watch: advances and uncertainties in the field
Kharitonenkov, A., & DiMarchi, R. D. (2016) · Journal of Internal Medicine · doi:10.1111/joim.12580 · Cited by 97 · see citing works
FGF21 and the physiological regulation of macronutrient preference
Hill, C. M., Qualls-Creekmore, E., Berthoud, H.-R., Soto, P., Yu, S., McDougal, D. H., Münzberg, H., & Morrison, C. D. (2020) · Endocrinology · doi:10.1210/endocr/bqaa019 · Cited by 99 · see citing works
Integrated stress response stimulates FGF21 expression: Systemic enhancer of longevity
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.08.009 · Cited by 97 · see citing works
KLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism
Xu, C., Messina, A., Somm, E., Miraoui, H., Kinnunen, T. K., Acierno, J. S., Niederländer, N. J., Bouilly, J., Dwyer, A. A., Sidis, Y., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201607376 · Cited by 94 · see citing works
Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases
Kassouf, T., & Sumara, G. (2020) · Biomolecules · doi:10.3390/biom10091256 · Cited by 93 · see citing works
Kang, S., Choi, M. J., Jung, S.-B., Chung, H. K., Chang, J. Y., Kim, J. T., Kang, Y. E., Lee, J. H., Hong, H. J., Jun, S. M., et al. (2021) · iScience · doi:10.1016/j.isci.2021.102181 · Cited by 89 · see citing works
Fibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges
Martínez‐Garza, Ú., Torres‐Oteros, D., Yarritu, A., Marrero, P. F., Haro, D., & Relat, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194692 · Cited by 87 · see citing works
Fibroblast Growth Factor 21 As an Emerging Therapeutic Target for Type 2 Diabetes Mellitus
So, W. Y., & Leung, P. S. (2016) · Medicinal Research Reviews · doi:10.1002/med.21390 · Cited by 85 · see citing works
Circulating FGF21 Levels in Human Health and Metabolic Disease
Keuper, M., Häring, H., & Staiger, H. (2019) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-0879-2968 · Cited by 82 · see citing works
FGF21 reverses MASH through coordinated actions on the CNS and liver
Rose, J. P., Morgan, D. A., Sullivan, A. I., Fu, X., Inigo-Vollmer, M., Burgess, S. C., Meyerholz, D. K., Rahmouni, K., & Potthoff, M. J. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.04.014 · Cited by 75 · 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
Jackson, T. C., & Kochanek, P. M. (2019) · Therapeutic Hypothermia and Temperature Management · doi:10.1089/ther.2019.0001 · Cited by 77 · see citing works
Defensive responses: behaviour, the brain and the body
Tseng, Y.-T., Schaefke, B., Wei, P., & Wang, L. (2023) · Nature reviews. Neuroscience · doi:10.1038/s41583-023-00736-3 · Cited by 79 · see citing works
Glial cells as integrators of peripheral and central signals in the regulation of energy homeostasis
Nampoothiri, S. S., Nogueiras, R., Schwaninger, M., & Prévot, V. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00610-z · Cited by 75 · see citing works
The potential function and clinical application of FGF21 in metabolic diseases
Chen, Z., Yang, L., Liu, Y., Huang, P., Song, H., & Zheng, P. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1089214 · Cited by 72 · see citing works
Wang, X., Zhu, Y., Sun, C. M., Wang, T., Shen, Y., Cai, W., Sun, J. T., Chi, L., Wang, H., Song, N., et al. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00032 · Cited by 73 · see citing works
The Potential Role of Fibroblast Growth Factor 21 in Lipid Metabolism and Hypertension
Huang, Z. P., Xu, A., & Cheung, B. M. Y. (2017) · Current Hypertension Reports · doi:10.1007/s11906-017-0730-5 · Cited by 71 · see citing works
Samms, R. J., Cheng, C. C., Kharitonenkov, A., Gimeno, R. E., & Adams, A. C. (2016) · Endocrinology · doi:10.1210/en.2015-1722 · Cited by 73 · see citing works
Spann, R. A., Morrison, C. D., & den Hartigh, L. J. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.802541 · Cited by 75 · see citing works
Jin, L., Yang, R., Geng, L., & Xu, A. (2023) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-032322-093904 · Cited by 71 · see citing works
Metabolic Crosstalk between Liver and Brain: From Diseases to Mechanisms
Yang, X., Qiu, K., Jiang, Y., Huang, Y., Zhang, Y., & Liao, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147621 · Cited by 69 · see citing works
Potential roles of fibroblast growth factor 21 in the brain
Sa‐nguanmoo, P., Chattipakorn, N., & Chattipakorn, S. C. (2016) · Metabolic Brain Disease · doi:10.1007/s11011-015-9789-3 · Cited by 67 · see citing works
The FGF21 Receptor Signaling Complex
Kilkenny, D. M., & Rocheleau, J. V. (2016) · Vitamins and hormones · doi:10.1016/bs.vh.2016.02.008 · Cited by 68 · see citing works
Phan, P., Saikia, B. B., Sonnaila, S., Agrawal, S., Alraawi, Z., Kumar, T. K. S., & Iyer, S. (2021) · Cells · doi:10.3390/cells10092418 · Cited by 67 · see citing works
Mueller, K. M., Hartmann, K., Kaltenecker, D., Vettorazzi, S., Bauer, M., Mauser, L., Amann, S., Jall, S., Fischer, K., Esterbauer, H., et al. (2016) · Diabetes · doi:10.2337/db16-0381 · Cited by 66 · see citing works
Yang, Z., Mi, J., Wang, Y., Xue, L., Liu, J., Fan, M., Zhang, D., Wang, L., Qian, H., & Li, Y. (2021) · Nutrition · doi:10.1016/j.nut.2021.111230 · Cited by 65 · see citing works
Methionine restriction - Association with redox homeostasis and implications on aging and diseases
Zhang, Y., Jelleschitz, J., Grune, T., Chen, W., Zhao, Y., Jia, M., Wang, Y., Liu, Z., & Höhn, A. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102464 · Cited by 69 · see citing works
FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs
Kim, K. H., & Lee, M. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0160 · Cited by 63 · see citing works
Metabolic role of fibroblast growth factor 21 in liver, adipose and nervous system tissues
Lin, X., Liu, Y. B., & Hu, H. (2017) · Biomedical Reports · doi:10.3892/br.2017.890 · Cited by 61 · see citing works
Distribution of fibroblast growth factors and their roles in skin fibroblast cell migration
Song, Y. H., Zhu, Y. T., Ding, J. H., Zhou, F., Xue, J. X., Jung, J. H., Li, Z. J., & Gao, W. (2016) · Molecular Medicine Reports · doi:10.3892/mmr.2016.5646 · Cited by 61 · see citing works
Fibroblast growth factor‐21 protects against fibrosis in hypertensive heart disease
Ferrer‐Curriu, G., Redondo‐Angulo, I., Guitart‐Mampel, M., Rupérez, C., Mas‐Stachurska, A., Sitges, M., Garrabou, G., Villarroya, F., Fernández‐Solà, J., & Planavila, A. (2018) · The Journal of Pathology · doi:10.1002/path.5226 · Cited by 60 · see citing works
Decoding FGF/FGFR Signaling: Insights into Biological Functions and Disease Relevance
Edirisinghe, O., Ternier, G., Alraawi, Z., & Kumar, T. K. S. (2024) · Biomolecules · doi:10.3390/biom14121622 · Cited by 60 · see citing works
Hepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis
Han, H.-S., Choi, B. H., Kim, J. S., Kang, G. W., & Koo, S. (2017) · Nature Communications · doi:10.1038/s41467-017-01878-6 · Cited by 58 · see citing works
Somm, E., Henry, H., Bruce, S. J., Aeby, S., Rosikiewicz, M., Sykiotis, G. P., Asrih, M., Jornayvaz, F. R., Denechaud, P., Albrecht, U., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.91809 · Cited by 57 · see citing works
Guo, J. (2017) · Chinese Journal of Integrative Medicine · doi:10.1007/s11655-017-2811-3 · Cited by 58 · see citing works
Fougerat, A., Bruse, J., Polizzi, A., Montagner, A., Guillou, H., & Wahli, W. (2024) · Progress in Lipid Research · doi:10.1016/j.plipres.2024.101303 · Cited by 54 · see citing works
Curcumin supplementation mitigates NASH development and progression in female Wistar rats
Cunningham, R. P., Moore, M. P., Moore, A. N., Healy, J. C., Roberts, M. D., Rector, R. S., & Martin, J. S. (2018) · Physiological Reports · doi:10.14814/phy2.13789 · Cited by 52 · see citing works
Fibroblast growth factor-21 potentiates glucose transport in skeletal muscle fibers
Rosales‐Soto, G., Díaz‐Vegas, A., Casas, M., Contreras‐Ferrat, A. E., & Jaimovich, E. (2020) · Journal of Molecular Endocrinology · doi:10.1530/jme-19-0210 · Cited by 52 · see citing works
Jin, L., Lin, Z., & Xu, A. (2016) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2016.40.1.22 · Cited by 52 · see citing works
Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK
Vernia, S., Cavanagh, J., Barrett, T., Tournier, C., & Davis, R. J. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.02.026 · Cited by 48 · see citing works
FGF21 and DPP-4 inhibitor equally prevents cognitive decline in obese rats
Sa‐nguanmoo, P., Tanajak, P., Kerdphoo, S., Jaiwongkam, T., Wang, X., Liang, G., Li, X., Jiang, C., Pratchayasakul, W., Chattipakorn, N., et al. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.12.021 · Cited by 48 · see citing works
Gut Commensal Barnesiella Intestinihominis Ameliorates Hyperglycemia and Liver Metabolic Disorders
Zhang, Y., Xu, D., Cai, X., Xing, X., Shao, X., Yin, A., Zhao, Y., Wang, M., Fan, Y., Liu, B., et al. (2024) · Advanced Science · doi:10.1002/advs.202411181 · Cited by 50 · see citing works
FGF-based drug discovery: advances and challenges
Chen, G., Chen, L., Li, X., & Mohammadi, M. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01125-w · Cited by 51 · see citing works
Bridging systemic metabolic dysfunction and Alzheimer’s disease: the liver interface
Song, D., Yang, L., Yang, L.-L., Luo, Y., & Yao, X. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00849-6 · Cited by 53 · see citing works
Metabolic roles of endocrine fibroblast growth factors
Fernandes-Freitas, I., & Owen, B. M. (2015) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2015.09.014 · Cited by 45 · see citing works
Leng, Y., Wang, J., Wang, Z., Liao, H., Wei, M. H., Leeds, P. R., & Chuang, D. (2016) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyw035 · Cited by 46 · see citing works
Non-Neuronal Cells in the Hypothalamic Adaptation to Metabolic Signals
Freire‐Regatillo, A., Argente-Arizón, P., Argente, J., García‐Segura, L. M., & Chowen, J. A. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00051 · Cited by 45 · see citing works
Santoso, P., Nakata, M., Shiizaki, K., Boyang, Z., Parmila, K., Otgon-Uul, Z., Hashimoto, K., Satoh, T., Mori, M., Kuro‐o, M., et al. (2017) · Scientific Reports · doi:10.1038/srep45819 · Cited by 45 · see citing works
FGF, Mechanism of Action, Role in Parkinson’s Disease, and Therapeutics
Liu, Y., Deng, J., Liu, Y., Li, W., & Nie, X. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.675725 · Cited by 45 · see citing works
Hepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation
Huen, S. C., Wang, A., Feola, K. C., Desrouleaux, R., Luan, H. H., Hogg, R. T., Zhang, C., Zhang, Q.-J., Liu, Z., & Medzhitov, R. M. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20202151 · Cited by 46 · see citing works
Fibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite
von Holstein‐Rathlou, S., & Gillum, M. P. (2019) · The Journal of Physiology · doi:10.1113/jp277117 · Cited by 44 · see citing works
- Authors
- Liang, Q., Zhong, L., Zhang, J., Wang, Y., Bornstein, S. R., Triggle, C. R., Ding, H., Lam, K. S. L., & Xu, A.
- Affiliations
- University of Hong Kong (HK)
- Technische Universität Dresden (DE)
- Weill Cornell Medical College in Qatar (QA)
- Corresponding author
- Xu, Aimin
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2014-11-13
- Volume
- 63
- Issue
- 12
- Pages
- 4064-4075
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2106745402
- Cited by
- 299
- References
- 39
- Citations by year
- 2026: 16 · 2025: 33 · 2024: 31 · 2023: 18 · 2022: 32 · 2021: 29 · 2020: 26 · 2019: 24 · 2018: 17 · 2017: 32 · 2016: 25 · 2015: 13 · 2014: 3
- FWCI
- 9.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Site cant be reached (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- FGF21, glucose homeostasis, prolonged fasting, hepatic gluconeogenesis, liver-brain axis, PPARα, hypothalamic-pituitary-adrenal axis, corticosterone, FGF receptor 1, ERK signaling, CREB, corticotropin-releasing factor, hypoglycemia
- MeSH terms
- Animals, Brain, Fasting, Fibroblast Growth Factors, Gluconeogenesis, Glucose, Homeostasis, Hypoglycemia, Hypothalamo-Hypophyseal System, Hypothalamus, Liver, Mice, Inbred C57BL, Pituitary-Adrenal System, Cyclic AMP Response Element-Binding Protein, Mice, Knockout, MAP Kinase Signaling System, Mice, Receptor, Fibroblast Growth Factor, Type 1
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
