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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2013, Vol. 7 Issue (1) : 25-30     DOI: 10.1007/s11684-013-0244-8
Fibroblast growth factor 21: a novel metabolic regulator from pharmacology to physiology
Huating Li, Jing Zhang, Weiping Jia()
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center of Diabetes, Shanghai 200233, China
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Fibroblast growth factor 21 (FGF21) is a member of the fibroblast growth factor family. It actually functions as endocrine hormones but does not regulate cell growth and differentiation. It is demonstrated that FGF21 acts on multiple tissue to coordinate carbohydrate and lipid metabolism, including enhancing insulin sensitivity, decreasing triglyceride concentrations, causing weight loss, ameliorating obesity-associated hyperglycemia and hyperlipidemia. Moreover, FGF21 also plays important roles in some physiological processes, such as fasting and feeding, growth hormone axis and thermogenic function of brown adipose tissue. Clinical relevance of FGF21 in humans is still unclear, and the basis and consequences of increased FGF21 in metabolic disease remain to be determined. Both the pharmacological actions and physiological roles make FGF21 attractive drug candidates for treating metabolic disease, but some questions remain to be answered. This article concentrates on recent advances in our understanding of FGF21.

Keywords FGF21      metabolism      pharmacology      physiology      clinical relevance     
Corresponding Authors: Jia Weiping,   
Issue Date: 05 March 2013
URL:     OR
Pharmaceutical effects
Improve insulin sensitivity
Improve dyslipidemia
Weight loss
Improve hepatic steatosis
Increase energy expenditure
Known adverse effect
Bone loss
Tab.1  Pharmacology and adverse effects of recombinant FGF21
Fig.1  Physiological actions of FGF21. (A) In response to fasting or fibrate drugs, FGF21 expression is induced in the liver by the PPARα/RXR heterodimer, and then causes ketogenesis, gluconeogenesis, and torpor; (B) In response to feeding or thiazolidinedione drugs (TZDs), FGF21 expression is induced by the PPARγ/RXR heterodimer in WAT, where FGF21 acts to stimulate PPARγ activity; (C) FGF21 acts as a negative feedback signal to block GH-stimulated lipolysis in adipocytes. FGF21 inhibits growth as part of its broader role in promoting energy conservation during starvation; (D) FGF21 acts to activate and expand the thermogenic machinery to provide the defense against hypothermia.
Fig.1  Physiological actions of FGF21. (A) In response to fasting or fibrate drugs, FGF21 expression is induced in the liver by the PPARα/RXR heterodimer, and then causes ketogenesis, gluconeogenesis, and torpor; (B) In response to feeding or thiazolidinedione drugs (TZDs), FGF21 expression is induced by the PPARγ/RXR heterodimer in WAT, where FGF21 acts to stimulate PPARγ activity; (C) FGF21 acts as a negative feedback signal to block GH-stimulated lipolysis in adipocytes. FGF21 inhibits growth as part of its broader role in promoting energy conservation during starvation; (D) FGF21 acts to activate and expand the thermogenic machinery to provide the defense against hypothermia.
1 Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 2000; 1492(1): 203-206
doi: 10.1016/S0167-4781(00)00067-1 pmid:10858549
2 Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 2005; 16(2): 159-178
doi: 10.1016/j.cytogfr.2005.01.004 pmid:15863032
3 Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 2004; 20(11): 563-569
doi: 10.1016/j.tig.2004.08.007 pmid:15475116
4 Econs MJ, Strom TM, White KE, Evans WE, O’Riordan JLH, Speer MC, Lorenz-Depiereux B, Grabowski M, Meitinger T, 0. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26(3): 345-348
doi: 10.1038/81664 pmid:11062477
5 Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 2001; 98(11): 6500-6505
doi: 10.1073/pnas.101545198 pmid:11344269
6 Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 2000; 277(2): 494-498
doi: 10.1006/bbrc.2000.3696 pmid:11032749
7 Nishimura T, Utsunomiya Y, Hoshikawa M, Ohuchi H, Itoh N. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim Biophys Acta 1999; 1444(1): 148-151
doi: 10.1016/S0167-4781(98)00255-3 pmid:9931477
8 Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005; 2(4): 217-225
doi: 10.1016/j.cmet.2005.09.001 pmid:16213224
9 Lund?sen T, G?lman C, Angelin B, Rudling M. Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med 2006; 260(6): 530-536
doi: 10.1111/j.1365-2796.2006.01731.x pmid:17116003
10 Fukumoto S, Yamashita T. FGF23 is a hormone-regulating phosphate metabolism—unique biological characteristics of FGF23. Bone 2007; 40(5): 1190-1195
doi: 10.1016/j.bone.2006.12.062 pmid:17276744
11 Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115(6): 1627-1635
doi: 10.1172/JCI23606 pmid:15902306
12 Kharitonenkov A, Shanafelt AB. Fibroblast growth factor-21 as a therapeutic agent for metabolic diseases. BioDrugs 2008; 22(1): 37-44
doi: 10.2165/00063030-200822010-00004 pmid:18215089
13 Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281(10): 6120-6123
doi: 10.1074/jbc.C500457200 pmid:16436388
14 Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444(7120): 770-774
doi: 10.1038/nature05315 pmid:17086194
15 Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 2007; 282(37): 26687-26695
doi: 10.1074/jbc.M704165200 pmid:17623664
16 Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R, Eliseenkova AV, Mohammadi M, Kuro-o M. BetaKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci USA 2007; 104(18): 7432-7437
doi: 10.1073/pnas.0701600104 pmid:17452648
17 Kharitonenkov A, Dunbar JD, Bina HA, Bright S, Moyers JS, Zhang C, Ding L, Micanovic R, Mehrbod SF, Knierman MD, Hale JE, Coskun T, Shanafelt AB. FGF-21/FGF-21 receptor interaction and activation is determined by betaKlotho. J Cell Physiol 2008; 215(1): 1-7
doi: 10.1002/jcp.21357 pmid:18064602
18 Ding X, Boney-Montoya J, Owen BM, Bookout AL, Coate KC, Mangelsdorf DJ, Kliewer SA. βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 2012; 16(3): 387-393
doi: 10.1016/j.cmet.2012.08.002 pmid:22958921
19 Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 2008; 149(12): 6018-6027
doi: 10.1210/en.2008-0816 pmid:18687777
20 Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA, Chen JL, Jung DY, Zhang Z, Ko HJ, Kim JK, Véniant MM. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009; 58(1): 250-259
doi: 10.2337/db08-0392 pmid:18840786
21 Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, Hansen BC, Shanafelt AB, Etgen GJ. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007; 148(2): 774-781
doi: 10.1210/en.2006-1168 pmid:17068132
22 Wente W, Efanov AM, Brenner M, Kharitonenkov A, K?ster A, Sandusky GE, Sewing S, Treinies I, Zitzer H, Gromada J. Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 2006; 55(9): 2470-2478
doi: 10.2337/db05-1435 pmid:16936195
23 Berglund ED, Li CY, Bina HA, Lynes SE, Michael MD, Shanafelt AB, Kharitonenkov A, Wasserman DH. Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity. Endocrinology 2009; 150(9): 4084-4093
doi: 10.1210/en.2009-0221 pmid:19470704
24 Wei W, Dutchak PA, Wang X, Ding X, Wang X, Bookout AL, Goetz R, Mohammadi M, Gerard RD, Dechow PC, Mangelsdorf DJ, Kliewer SA, Wan Y. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. Proc Natl Acad Sci USA 2012; 109(8): 3143-3148
doi: 10.1073/pnas.1200797109 pmid:22315431
25 Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007; 5(6): 426-437
doi: 10.1016/j.cmet.2007.05.002 pmid:17550778
26 Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 2007; 5(6): 415-425
doi: 10.1016/j.cmet.2007.05.003 pmid:17550777
27 Lund?sen T, Hunt MC, Nilsson LM, Sanyal S, Angelin B, Alexson SE, Rudling M. PPARalpha is a key regulator of hepatic FGF21. Biochem Biophys Res Commun 2007; 360(2): 437-440
doi: 10.1016/j.bbrc.2007.06.068 pmid:17601491
28 Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F. Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab 2010; 11(3): 206-212
doi: 10.1016/j.cmet.2010.02.001 pmid:20197053
29 Reitman ML. FGF21: a missing link in the biology of fasting. Cell Metab 2007; 5(6): 405-407
doi: 10.1016/j.cmet.2007.05.010 pmid:17550773
30 Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, Kliewer SA. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 2012; 148(3): 556-567
doi: 10.1016/j.cell.2011.11.062 pmid:22304921
31 Thissen JP, Ketelslegers JM, Underwood LE. Nutritional regulation of the insulin-like growth factors. Endocr Rev 1994; 15(1): 80-101
32 Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA. Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab 2008; 8(1): 77-83
doi: 10.1016/j.cmet.2008.05.006 pmid:18585098
33 Chen W, Hoo RL, Konishi M, Itoh N, Lee PC, Ye HY, Lam KS, Xu A. Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes. J Biol Chem 2011; 286(40): 34559-34566
doi: 10.1074/jbc.M111.285965 pmid:21849508
34 Chartoumpekis DV, Habeos IG, Ziros PG, Psyrogiannis AI, Kyriazopoulou VE, Papavassiliou AG. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med 2011; 17(7-8): 736-740
doi: 10.2119/molmed.2011.00075 pmid: PMID:21373720
35 Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011; 286(15): 12983-12990
doi: 10.1074/jbc.M110.215889 pmid:21317437
36 Klingenspor M. Cold-induced recruitment of brown adipose tissue thermogenesis. Exp Physiol 2003; 88(1): 141-148
doi: 10.1113/eph8802508 pmid:12525862
37 Scarpace PJ, Tse C, Matheny M. Thermoregulation with age: restoration of beta(3)-adrenergic responsiveness in brown adipose tissue by cold exposure. Proc Soc Exp Biol Med 1996; 211(4): 374-380
38 Takahashi A, Shimazu T, Maruyama Y. Importance of sympathetic nerves for the stimulatory effect of cold exposure on glucose utilization in brown adipose tissue. Jpn J Physiol 1992; 42(4): 653-664
doi: 10.2170/jjphysiol.42.653 pmid:1474682
39 Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos-Flier E, Spiegelman BM. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012; 26(3): 271-281
doi: 10.1101/gad.177857.111 pmid:22302939
40 G?lman C, Lund?sen T, Kharitonenkov A, Bina HA, Eriksson M, Hafstr?m I, Dahlin M, Amark P, Angelin B, Rudling M. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab 2008; 8(2): 169-174
doi: 10.1016/j.cmet.2008.06.014 pmid:18680716
41 Christodoulides C, Dyson P, Sprecher D, Tsintzas K, Karpe F. Circulating fibroblast growth factor 21 is induced by peroxisome proliferator-activated receptor agonists but not ketosis in man. J Clin Endocrinol Metab 2009; 94(9): 3594-3601
doi: 10.1210/jc.2009-0111 pmid:19531592
42 Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM, Badman MK, Martinez-Chantar ML, Maratos-Flier E. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 2010; 139(2): 456-463
doi: 10.1053/j.gastro.2010.04.054 pmid:20451522
43 Dostálová I, Kaválková P, Haluzíková D, Lacinová Z, Mráz M, Papezová H, Haluzík M. Plasma concentrations of fibroblast growth factors 19 and 21 in patients with anorexia nervosa. J Clin Endocrinol Metab 2008; 93(9): 3627-3632
doi: 10.1210/jc.2008-0746 pmid:18559909
44 Fazeli PK, Misra M, Goldstein M, Miller KK, Klibanski A. Fibroblast growth factor-21 may mediate growth hormone resistance in anorexia nervosa. J Clin Endocrinol Metab 2010; 95(1): 369-374
doi: 10.1210/jc.2009-1730 pmid:19926712
45 Chen WW, Li L, Yang GY, Li K, Qi XY, Zhu W, Tang Y, Liu H, Boden G. Circulating FGF-21 levels in normal subjects and in newly diagnose patients with Type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 2008; 116(1): 65-68
doi: 10.1055/s-2007-985148 pmid:17926232
46 Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, Defronzo RA, Tripathy D. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care 2009; 32(8): 1542-1546
doi: 10.2337/dc09-0684 pmid:19487637
47 Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D, Matoulek M, Dostalova I, Humenanska V, Haluzik M. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol (Oxf) 2009; 71(3): 369-375
doi: 10.1111/j.1365-2265.2008.03502.x pmid:19702724
48 Cuevas-Ramos D, Almeda-Valdes P, Gómez-Pérez FJ, Meza-Arana CE, Cruz-Bautista I, Arellano-Campos O, Navarrete-López M, Aguilar-Salinas CA. Daily physical activity, fasting glucose, uric acid, and body mass index are independent factors associated with serum fibroblast growth factor 21 levels. Eur J Endocrinol 2010; 163(3): 469-477
doi: 10.1530/EJE-10-0454 pmid:20566587
49 Li H, Bao Y, Xu A, Pan X, Lu J, Wu H, Lu H, Xiang K, Jia W. Serum fibroblast growth factor 21 is associated with adverse lipid profiles and gamma-glutamyltransferase but not insulin sensitivity in Chinese subjects. J Clin Endocrinol Metab 2009; 94(6): 2151-2156
doi: 10.1210/jc.2008-2331 pmid:19318452
50 Li H, Fang Q, Gao F, Fan J, Zhou J, Wang X, Zhang H, Pan X, Bao Y, Xiang K, Xu A, Jia W. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol 2010; 53(5): 934-940
doi: 10.1016/j.jhep.2010.05.018 pmid:20675007
51 Matuszek B, Lenart-Lipińska M, Duma D, Solski J, Nowakowski A. Evaluation of concentrations of FGF-21- a new adipocytokine in type 2 diabetes. Endokrynol Pol 2010; 61(1): 50-54
52 Yilmaz Y, Eren F, Yonal O, Kurt R, Aktas B, Celikel CA, Ozdogan O, Imeryuz N, Kalayci C, Avsar E. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Invest 2010; 40(10): 887-892
doi: 10.1111/j.1365-2362.2010.02338.x pmid:20624171
53 Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 2008; 57(5): 1246-1253
doi: 10.2337/db07-1476 pmid:18252893
54 Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, Maratos-Flier E. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 2010; 59(11): 2781-2789
doi: 10.2337/db10-0193 pmid:20682689
55 Hale C, Chen MM, Stanislaus S, Chinookoswong N, Hager T, Wang M, Véniant MM, Xu J. Lack of overt FGF21 resistance in two mouse models of obesity and insulin resistance. Endocrinology 2012; 153(1): 69-80
doi: 10.1210/en.2010-1262 pmid:22067317
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