Frontiers of Medicine

, Volume 7, Issue 1, pp 25–30

Fibroblast growth factor 21: a novel metabolic regulator from pharmacology to physiology

Review

Abstract

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 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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): 203–206PubMedCrossRefGoogle Scholar
  2. 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): 159–178PubMedCrossRefGoogle Scholar
  3. 3.
    Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 2004; 20(11): 563–569PubMedCrossRefGoogle Scholar
  4. 4.
    White KE, Evans WE, O’Riordan JLH, Speer MC, Econs MJ, Lorenz-Depiereux B, Grabowski M, Meitinger T, Strom TM. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; 26(3): 345–348CrossRefGoogle Scholar
  5. 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): 6500–6505PubMedCrossRefGoogle Scholar
  6. 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): 494–498PubMedCrossRefGoogle Scholar
  7. 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): 148–151PubMedCrossRefGoogle Scholar
  8. 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): 217–225PubMedCrossRefGoogle Scholar
  9. 9.
    Lundåsen T, Gälman 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): 530–536PubMedCrossRefGoogle Scholar
  10. 10.
    Fukumoto S, Yamashita T. FGF23 is a hormone-regulating phosphate metabolism-unique biological characteristics of FGF23. Bone 2007; 40(5): 1190–1195PubMedCrossRefGoogle Scholar
  11. 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): 1627–1635PubMedCrossRefGoogle Scholar
  12. 12.
    Kharitonenkov A, Shanafelt AB. Fibroblast growth factor-21 as a therapeutic agent for metabolic diseases. BioDrugs 2008; 22(1): 37–44PubMedCrossRefGoogle Scholar
  13. 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): 6120–6123PubMedCrossRefGoogle Scholar
  14. 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): 770–774PubMedCrossRefGoogle Scholar
  15. 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): 26687–26695PubMedCrossRefGoogle Scholar
  16. 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): 7432–7437PubMedCrossRefGoogle Scholar
  17. 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): 1–7PubMedCrossRefGoogle Scholar
  18. 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): 387–393PubMedCrossRefGoogle Scholar
  19. 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): 6018–6027PubMedCrossRefGoogle Scholar
  20. 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): 250–259PubMedCrossRefGoogle Scholar
  21. 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): 774–781PubMedCrossRefGoogle Scholar
  22. 22.
    Wente W, Efanov AM, Brenner M, Kharitonenkov A, Köster 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): 2470–2478PubMedCrossRefGoogle Scholar
  23. 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): 4084–4093PubMedCrossRefGoogle Scholar
  24. 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): 3143–3148PubMedCrossRefGoogle Scholar
  25. 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): 426–437PubMedCrossRefGoogle Scholar
  26. 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 PPARalphamediated induction of fibroblast growth factor 21. Cell Metab 2007; 5(6): 415–425PubMedCrossRefGoogle Scholar
  27. 27.
    Lundåsen 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): 437–440PubMedCrossRefGoogle Scholar
  28. 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): 206–212PubMedCrossRefGoogle Scholar
  29. 29.
    Reitman ML. FGF21: a missing link in the biology of fasting. Cell Metab 2007; 5(6): 405–407PubMedCrossRefGoogle Scholar
  30. 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): 556–567PubMedCrossRefGoogle Scholar
  31. 31.
    Thissen JP, Ketelslegers JM, Underwood LE. Nutritional regulation of the insulin-like growth factors. Endocr Rev 1994; 15(1): 80–101PubMedGoogle Scholar
  32. 32.
    Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA. Inhibition of growth hormone signaling by the fastinginduced hormone FGF21. Cell Metab 2008; 8(1): 77–83PubMedCrossRefGoogle Scholar
  33. 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): 34559–34566PubMedCrossRefGoogle Scholar
  34. 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): 736–740PubMedGoogle Scholar
  35. 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): 12983–12990PubMedCrossRefGoogle Scholar
  36. 36.
    Klingenspor M. Cold-induced recruitment of brown adipose tissue thermogenesis. Exp Physiol 2003; 88(1): 141–148PubMedCrossRefGoogle Scholar
  37. 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): 374–380PubMedGoogle Scholar
  38. 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): 653–664PubMedCrossRefGoogle Scholar
  39. 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): 271–281PubMedCrossRefGoogle Scholar
  40. 40.
    Gälman C, Lundåsen T, Kharitonenkov A, Bina HA, Eriksson M, Hafström 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): 169–174PubMedCrossRefGoogle Scholar
  41. 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): 3594–3601PubMedCrossRefGoogle Scholar
  42. 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): 456–463PubMedCrossRefGoogle Scholar
  43. 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): 3627–3632PubMedCrossRefGoogle Scholar
  44. 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): 369–374PubMedCrossRefGoogle Scholar
  45. 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): 65–68PubMedCrossRefGoogle Scholar
  46. 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): 1542–1546PubMedCrossRefGoogle Scholar
  47. 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): 369–375CrossRefGoogle Scholar
  48. 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): 469–477PubMedCrossRefGoogle Scholar
  49. 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): 2151–2156PubMedCrossRefGoogle Scholar
  50. 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): 934–940PubMedCrossRefGoogle Scholar
  51. 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): 50–54PubMedGoogle Scholar
  52. 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): 887–892PubMedCrossRefGoogle Scholar
  53. 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): 1246–1253PubMedCrossRefGoogle Scholar
  54. 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): 2781–2789PubMedCrossRefGoogle Scholar
  55. 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): 69–80PubMedCrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Endocrinology and MetabolismShanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Center of DiabetesShanghaiChina

Personalised recommendations