Therapeutic Role of Fibroblast Growth Factor 21 (FGF21) in the Amelioration of Chronic Diseases

  • Yeboah Kwaku Opoku
  • Zhihang Liu
  • Justice Afrifa
  • Mir Hassan Khoso
  • Guiping RenEmail author
  • Deshan LiEmail author


Fibroblast growth factor-21 (FGF21) is a member of the family of fibroblast growth factors (FGFs). FGF21 (synthesized by many organs) has been studied extensively for its role in the regulation of energy homeostasis. FGF21 came into the spotlight after its beneficial metabolic effects in reducing blood glucose, and weight in obesity were identified. Since then, FGF21 has been extensively exploited for therapeutic purposes and clinical applications with significant achievements. Its therapeutic roles in diabetes, obesity, cardiovascular diseases, fibrosis, cancer and aging among others have been studied over the last decade with significant strides making it a promising candidate for the management of chronic diseases. Here we review the therapeutic prospects of FGF21 with emphasis on the management of chronic diseases, and breakthroughs in its shortfalls. The future of FGF21 as a therapeutic agent is auspicious and will help revolutionize the world of medicine.


Fibroblast growth factor 21 (FGF21) Inflammation Therapeutic Chronic diseases 



Superoxide dismutase






Peroxisome proliferator-activated receptor gamma coactivator 1α


Signal transducer and activator of transcription


5′ adenosine monophosphate-activated protein kinase


Nicotinamide adenine dinucleotide


Mammalian target of rapamycin


Growth/differentiation factor


Glutathione peroxidase






Uncoupling protein 3


Compliance with Ethical Standards

Conflict of interest

Authors declared that they have no conflict of interest.


  1. Adams AC, Coskun T, Rovira ARI, Schneider MA, Raches DW, Micanovic R, Bina HA, Dunbar JD, Kharitonenkov A (2012) Fundamentals of FGF19 & FGF21 action in vitro and in vivo. PLoS ONE 7(5):e38438CrossRefPubMedPubMedCentralGoogle Scholar
  2. Aggarwal BB (2004) Nuclear factor-κB: the enemy within. Cancer Cell 6(3):203–208CrossRefPubMedGoogle Scholar
  3. Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, Dey S, Sung B (2009a) Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci 1171(1):59–76CrossRefPubMedPubMedCentralGoogle Scholar
  4. Aggarwal BB, Vijayalekshmi R, Sung B (2009b) Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 15(2):425–430CrossRefPubMedGoogle Scholar
  5. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? The lancet 357(9255):539–545CrossRefGoogle Scholar
  6. Barzilai N, Huffman DM, Muzumdar RH, Bartke A (2012) The critical role of metabolic pathways in aging. Diabetes 61(6):1315–1322CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Investig 115(2):209–218CrossRefPubMedGoogle Scholar
  8. Benazzi F, Akiskal H (2006) The duration of hypomania in bipolar-II disorder in private practice: methodology and validation. J Affect Disord 96(3):189–196CrossRefPubMedGoogle Scholar
  9. Bobbert T, Schwarz F, Fischer-Rosinsky A, Pfeiffer AF, Möhlig M, Mai K, Spranger J (2012) Fibroblast growth factor 21 predicts the metabolic syndrome and diabetes type 2 mellitus in Caucasians. Diabetes Care 36(1):145–149CrossRefPubMedPubMedCentralGoogle Scholar
  10. Camacho RC, Zafian PT, Achanfuo-Yeboah J, Manibusan A, Berger JP (2013) Pegylated Fgf21 rapidly normalizes insulin-stimulated glucose utilization in diet-induced insulin resistant mice. Eur J Pharmacol 715(1–3):41–45CrossRefPubMedGoogle Scholar
  11. Chartoumpekis DV, Habeos IG, Ziros PG, Psyrogiannis AI, Kyriazopoulou VE, Papavassiliou AG (2011) Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med 17(7–8):736PubMedPubMedCentralGoogle Scholar
  12. Chu H, Shi Y, Jiang S, Zhong Q, Zhao Y, Liu Q, Ma Y, Shi X, Ding W, Zhou X (2017) Treatment effects of the traditional Chinese medicine Shenks in bleomycin-induced lung fibrosis through regulation of TGF-beta/Smad3 signaling and oxidative stress. Sci Rep 7(1):2252CrossRefPubMedPubMedCentralGoogle Scholar
  13. Cimen M, Çimen Ö, Kacmaz M, Öztürk H, Yorgancioğlu R, Durak I (2000) Oxidant/antioxidant status of the erythrocytes from patients with rheumatoid arthritis. Clin Rheumatol 19(4):275–277CrossRefPubMedGoogle Scholar
  14. Cong W-T, Ling J, Tian H-S, Ling R, Wang Y, Huang B-B, Zhao T, Duan Y-M, Jin L-T, Li XK (2013) Proteomic study on the protective mechanism of fibroblast growth factor 21 to ischemia–reperfusion injury. Can J Physiol Pharmacol 91(11):973–984CrossRefPubMedGoogle Scholar
  15. Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A (2008) Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149(12):6018–6027CrossRefPubMedGoogle Scholar
  16. Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180(9):5771–5777CrossRefPubMedGoogle Scholar
  17. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860CrossRefPubMedPubMedCentralGoogle Scholar
  18. Degirolamo C, Sabbà C, Moschetta A (2016) Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discovery 15(1):51CrossRefPubMedGoogle Scholar
  19. Ding X, Boney-Montoya J, Owen BM, Bookout AL, Coate KC, Mangelsdorf DJ, Kliewer SA (2012) βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 16(3):387–393CrossRefPubMedPubMedCentralGoogle Scholar
  20. Do HT, Tselykh TV, Mäkelä J, Ho TH, Olkkonen VM, Bornhauser BC, Korhonen L, Zelcer N, Lindholm D (2012) Fibroblast growth factor-21 (FGF21) regulates low-density lipoprotein receptor (LDLR) levels in cells via the E3-ubiquitin ligase Mylip/Idol and the Canopy2 (Cnpy2)/Mylip-interacting saposin-like protein (Msap). J Biol Chem 287(16):12602–12611CrossRefPubMedPubMedCentralGoogle Scholar
  21. Dong B, Wu M, Cao A, Li H, Liu J (2011) Suppression of Idol expression is an additional mechanism underlying statin-induced up-regulation of hepatic LDL receptor expression. Int J Mol Med 27(1):103–110PubMedGoogle Scholar
  22. Dong JQ, Rossulek M, Somayaji VR, Baltrukonis D, Liang Y, Hudson K, Hernandez-Illas M, Calle RA (2015) Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study. Br J Clin Pharmacol 80(5):1051–1063CrossRefPubMedPubMedCentralGoogle Scholar
  23. Feingold KR, Grunfeld C, Heuer JG, Gupta A, Cramer M, Zhang T, Shigenaga JK, Patzek SM, Chan ZW, Moser A (2012) FGF21 is increased by inflammatory stimuli and protects leptin-deficient ob/ob mice from the toxicity of sepsis. Endocrinology 153(6):2689–2700CrossRefPubMedPubMedCentralGoogle Scholar
  24. Finkel T (2015) The metabolic regulation of aging. Nat Med 21(12):1416CrossRefPubMedGoogle Scholar
  25. Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, Goetz R, Mohammadi M, Kuro-o M, Mangelsdorf DJ (2010) Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 24(10):2050–2064CrossRefPubMedPubMedCentralGoogle Scholar
  26. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE (2013) The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 18(3):333–340CrossRefPubMedGoogle Scholar
  27. Ge X, Chen C, Hui X, Wang Y, Lam KS, Xu A (2011) Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes. J Biol Chem 286(40):34533–34541CrossRefPubMedPubMedCentralGoogle Scholar
  28. Guo J, Friedman SL (2007) Hepatic fibrogenesis. Semin Liver Dis 2007;27(4):413–426CrossRefPubMedGoogle Scholar
  29. Gupta SC, Sundaram C, Reuter S, Aggarwal BB (2010) Inhibiting NF-κB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta 1799(10):775–787CrossRefPubMedPubMedCentralGoogle Scholar
  30. Hager T, Spahr C, Xu J, Salimi-Moosavi H, Hall M (2013) Differential enzyme-linked immunosorbent assay and ligand-binding mass spectrometry for analysis of biotransformation of protein therapeutics: application to various FGF21 modalities. Anal Chem 85(5):2731–2738CrossRefPubMedGoogle Scholar
  31. Han X, Chen C, Cheng G, Xie C, Yang M, Shou X, Sun C (2015) Serum fibroblast growth factor 21 levels are increased in atrial fibrillation patients. Cytokine 73(1):176–180CrossRefPubMedGoogle Scholar
  32. Hanks LJ, Gutiérrez OM, Bamman MM, Ashraf A, McCormick KL, Casazza K (2015) Circulating levels of fibroblast growth factor-21 increase with age independently of body composition indices among healthy individuals. J Clin Transl Endocrinol 2(2):77–82PubMedPubMedCentralGoogle Scholar
  33. Hecht R, Li Y-S, Sun J, Belouski E, Hall M, Hager T, Yie J, Wang W, Winters D, Smith S (2012) Rationale-based engineering of a potent long-acting FGF21 analog for the treatment of type 2 diabetes. PLoS ONE 7(11):e49345CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hermansen K, Davies M (2007) Does insulin detemir have a role in reducing risk of insulin-associated weight gain? Diabetes. Obes Metab 9(3):209–217CrossRefGoogle Scholar
  35. Houten SM, Auwerx J (2004) PGC-1α: turbocharging mitochondria. Cell 119(1):5–7CrossRefPubMedGoogle Scholar
  36. Hsuchou H, Pan W, Kastin AJ (2007) The fasting polypeptide FGF21 can enter brain from blood. Peptides 28(12):2382–2386CrossRefPubMedPubMedCentralGoogle Scholar
  37. Hu Z, Evarts RP, Fujio K, Omori N, Omori M, Marsden ER, Thorgeirsson SS (1996) Cancer biology: expression of transforming growth factor alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met and acidic fibroblast growth factor/fibroblast growth factor receptors during hepatocarcinogenesis. Carcinogenesis 17(5):931–938CrossRefPubMedGoogle Scholar
  38. Huang X, Yu C, Jin C, Yang C, Xie R, Cao D, Wang F, WL McKeehan (2006) Forced expression of hepatocyte-specific fibroblast growth factor 21 delays initiation of chemically induced hepatocarcinogenesis. Mol Carcinog 45(12): 934–942CrossRefPubMedGoogle Scholar
  39. Hulbert A, Pamplona R, Buffenstein R, Buttemer W (2007) Life and death: metabolic rate, membrane composition, and life span of animals. Physiol Rev 87(4):1175–1213CrossRefPubMedGoogle Scholar
  40. Hulejová H, Cerezo LA, Kuklová M, Pecha O, Vondracek T, Pavelka K, Vencovský J, Haluzík M, Senolt L (2012) Novel adipokine fibroblast growth factor 21 is increased in rheumatoid arthritis. Physiol Res 61(5):489PubMedGoogle Scholar
  41. Hussain SP, Hofseth LJ, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3(4):276CrossRefPubMedGoogle Scholar
  42. Inagaki T (2015) Research perspectives on the regulation and physiological functions of FGF21 and its association with NAFLD. Front Endocrinol (Lausanne) 6:147CrossRefGoogle Scholar
  43. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2(4):217–225CrossRefPubMedGoogle Scholar
  44. Itoh N (2010) Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease. Cell Tissue Res 342(1):1–11CrossRefPubMedPubMedCentralGoogle Scholar
  45. Itoh N, Ornitz DM (2004) Evolution of the Fgf and Fgfr gene families. Trends Genet 20(11):563–569CrossRefPubMedGoogle Scholar
  46. Jin Q-R, Bando Y, Miyawaki K, Shikama Y, Kosugi C, Aki N, Funaki M, Noji S (2014) Correlation of fibroblast growth factor 21 serum levels with metabolic parameters in Japanese subjects. J Med Invest 61(1.2):28–34CrossRefPubMedGoogle Scholar
  47. Joki Y, Ohashi K, Yuasa D, Shibata R, Ito M, Matsuo K, Kambara T, Uemura Y, Hayakawa S, Hiramatsu-Ito M (2015) FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism. Biochem Biophys Res Commun 459(1):124–130CrossRefPubMedGoogle Scholar
  48. Jones DS, Podolsky SH, Greene JA (2012) The burden of disease and the changing task of medicine. New Engl J Med 366(25):2333–2338CrossRefPubMedGoogle Scholar
  49. Kan M, Wu X, Wang F, WL McKeehan (1999) Specificity for fibroblast growth factors determined by heparan sulfate in a binary complex with the receptor kinase. J Biol Chem 274(22): 15947–15952CrossRefPubMedGoogle Scholar
  50. Kharitonenkov A, Larsen P (2011) FGF21 reloaded: challenges of a rapidly growing field. Trends Endocrinol Metab 22(3):81–86CrossRefPubMedGoogle Scholar
  51. Kharitonenkov A, Shanafelt AB (2008) Fibroblast growth factor-21 as a therapeutic agent for metabolic diseases. Biodrugs 22(1):37–44CrossRefPubMedGoogle Scholar
  52. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA (2005) FGF-21 as a novel metabolic regulator. J Clin Investig 115(6):1627–1635CrossRefPubMedGoogle Scholar
  53. Kharitonenkov A, Wroblewski VJ, Koester A, Chen Y-F, Clutinger CK, Tigno XT, Hansen BC, Shanafelt AB, Etgen GJ (2007) The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148(2): 774–781CrossRefPubMedGoogle Scholar
  54. Kharitonenkov A, Dunbar JD, Bina HA, Bright S, Moyers JS, Zhang C, Ding L, Micanovic R, Mehrbod SF, Knierman MD (2008) FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho. J Cell Physiol 215(1):1–7CrossRefPubMedGoogle Scholar
  55. Kharitonenkov A, Beals JM, Micanovic R, Strifler BA, Rathnachalam R, Wroblewski VJ, Li S, Koester A, Ford AM, Coskun T (2013) Rational design of a fibroblast growth factor 21-based clinical candidate, LY2405319. PLoS ONE 8(3):e58575CrossRefPubMedPubMedCentralGoogle Scholar
  56. Kim KH, Kim SH, Min Y-K, Yang H-M, Lee J-B, Lee M-S (2013) Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS ONE 8(5):e63517CrossRefPubMedPubMedCentralGoogle Scholar
  57. Kin M, Sata M, Ueno T, Torimura T, Inuzuka S, Tsuji R, Sujaku K, Sakamoto M, Sugawara H, Tamaki S (1997) Basic fibroblast growth factor regulates proliferation and motility of human hepatoma cells by an autocrine mechanism. J Hepatol 27(4):677–687CrossRefPubMedGoogle Scholar
  58. Knopp RH (1999) Drug treatment of lipid disorders. New Engl J Med 341(7):498–511CrossRefPubMedGoogle Scholar
  59. Kralisch S, Tönjes A, Krause K, Richter J, Lossner U, Kovacs P, Ebert T, Blüher M, Stumvoll M, Fasshauer M (2013) Fibroblast growth factor-21 serum concentrations are associated with metabolic and hepatic markers in humans. J Endocrinol 216(2):135–143CrossRefPubMedGoogle Scholar
  60. Kubicky RA, Wu S, Kharitonenkov A, De Luca F (2012) Role of fibroblast growth factor 21 (FGF21) in undernutrition-related attenuation of growth in mice. Endocrinology 153(5):2287–2295CrossRefPubMedGoogle Scholar
  61. Kurosu H, Kuro-o M (2008) The Klotho gene family and the endocrine fibroblast growth factors. Curr Opin Nephrol Hypertens 17(4):368–372CrossRefPubMedGoogle Scholar
  62. Lee MS, Choi S-E, Ha ES, An S-Y, Kim TH, Han SJ, Kim HJ, Kim DJ, Kang Y, Lee K-W (2012) Fibroblast growth factor-21 protects human skeletal muscle myotubes from palmitate-induced insulin resistance by inhibiting stress kinase and NF-κB. Metabolism 61(8):1142–1151CrossRefPubMedGoogle Scholar
  63. Lee C, Hui E, Woo Y, Yeung C, Chow W, Yuen M, Fong C, Xu A, Lam K (2015) Circulating fibroblast growth factor 21 levels predict progressive kidney disease in subjects with type 2 diabetes and normoalbuminuria. J Clin Endocrinol Metab 100(4):1368–1375CrossRefPubMedGoogle Scholar
  64. Lelliott CJ, Ahnmark A, Admyre T, Ahlstedt I, Irving L, Keyes F, Patterson L, Mumphrey MB, Bjursell M, Gorman T (2014) Monoclonal antibody targeting of fibroblast growth factor receptor 1c ameliorates obesity and glucose intolerance via central mechanisms. PLoS ONE 9(11):e112109CrossRefPubMedPubMedCentralGoogle Scholar
  65. Leng Y, Wang Z, Tsai L-K, Leeds P, Fessler EB, Wang J, Chuang D-M (2015) FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers. Mol Psychiatry 20(2):215CrossRefPubMedGoogle Scholar
  66. Li J-y, Wang N, Khoso MH, Shen C-b, Guo M-z, Pang X-x, Li D-s, W-f Wang (2018a) FGF-21 elevated IL-10 production to correct LPS-induced inflammation. Inflammation 41(3): 751–759CrossRefPubMedGoogle Scholar
  67. Li S, Wang N, Guo X, Li J, Zhang T, Ren G, Li D (2018b) Fibroblast growth factor 21 regulates glucose metabolism in part by reducing renal glucose reabsorption. Biomed Pharmacother 108:355–366CrossRefPubMedGoogle Scholar
  68. Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell metabolism 1(6):361–370CrossRefPubMedGoogle Scholar
  69. Lin Y, Xiao Y-c, Zhu H, Xu Q-y, Qi L, Wang Y-b, Li X-j, Zheng M-l, Zhong R-s, Zhang Y (2014) Serum fibroblast growth factor 21 levels are correlated with the severity of diabetic retinopathy. J Diabetes Res 2014.
  70. Lin Z, Pan X, Wu F, Ye D, Zhang Y, Wang Y, Jin L, Lian Q, Huang Y, Ding H (2015) Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice. Circulation 131(21):1861–1871CrossRefPubMedPubMedCentralGoogle Scholar
  71. Liu SQ, Tefft BJ, Roberts DT, Zhang L-Q, Ren Y, Li YC, Huang Y, Zhang D, Phillips HR, Wu YH (2012) Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia. Am J Physiol Heart Circ Physiol 303(12):H1446–H1458CrossRefPubMedGoogle Scholar
  72. Liu SQ, Roberts D, Kharitonenkov A, Zhang B, Hanson SM, Li YC, Zhang L-Q, Wu YH (2013) Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue. Sci Rep 3:2767CrossRefPubMedPubMedCentralGoogle Scholar
  73. Liu X, Zhang P, Martin RC, Cui G, Wang G, Tan Y, Cai L, Lv G, Li Y (2016) Lack of fibroblast growth factor 21 accelerates metabolic liver injury characterized by steatohepatities in mice. Am J Cancer Res 6(5):1011PubMedPubMedCentralGoogle Scholar
  74. Lundåsen T, Gälman C, Angelin B, Rudling M (2006) Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med 260(6):530–536CrossRefPubMedGoogle Scholar
  75. Mäkelä J, Tselykh TV, Maiorana F, Eriksson O, Do HT, Mudò G, Korhonen LT, Belluardo N, Lindholm D (2014) Fibroblast growth factor-21 enhances mitochondrial functions and increases the activity of PGC-1α in human dopaminergic neurons via Sirtuin-1. Springerplus 3(1):2CrossRefPubMedPubMedCentralGoogle Scholar
  76. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436CrossRefPubMedGoogle Scholar
  77. Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3(11):e442CrossRefPubMedPubMedCentralGoogle Scholar
  78. McAtee LM (2013) Fitness, nutrition and the molecular basis of chronic disease. Biotechnol Genet Eng Rev 29(1):1–23CrossRefPubMedGoogle Scholar
  79. McCarty TM (2014) GCN2 and FGF21 are likely mediators of the protection from cancer, autoimmunity, obesity, and diabetes afforded by vegan diets. Med Hypotheses 83(3):365–371CrossRefPubMedGoogle Scholar
  80. Murray PJ (2006) Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr Opin Pharm 6(4):379–386CrossRefGoogle Scholar
  81. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384(9945):766–781CrossRefPubMedPubMedCentralGoogle Scholar
  82. Nishimura T, Nakatake Y, Konishi M, Itoh N (2000) Identification of a novel FGF, FGF-21, preferentially expressed in the liver1. Biochim Biophys Acta 1492(1): 203–206CrossRefPubMedGoogle Scholar
  83. Oates GR, Jackson BE, Partridge EE, Singh KP, Fouad MN, Bae S (2017) Sociodemographic patterns of chronic disease: how the mid-south region compares to the rest of the country. Am J Prev Med 52(1):S31–S39CrossRefPubMedPubMedCentralGoogle Scholar
  84. Ogasawara S, Yano H, Iemura A, Hisaka T, Kojiro M (1996) Expressions of basic fibroblast growth factor and its receptors and their relationship to proliferation of human hepatocellular carcinoma cell lines. Hepatology 24(1):198–205CrossRefPubMedGoogle Scholar
  85. Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R, Eliseenkova AV, Mohammadi M, Kuro-o M (2007) βKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci USA 104(18): 7432–7437Google Scholar
  86. Ong K-L, Januszewski AS, O’Connell R, Buizen L, Jenkins AJ, Xu A, Sullivan DR, Barter PJ, Scott RS, Taskinen M-R (2015) Relationship of fibroblast growth factor 21 with baseline and new on-study microvascular disease in the Fenofibrate Intervention and Event Lowering in Diabetes study. Diabetologia 58(9):2035–2044CrossRefPubMedGoogle Scholar
  87. Öztürk HS, Çimen MB, Çimen ÖB, Kacmaz M, Durak I (1999) Oxidant/antioxidant status of plasma samples from patients with rheumatoid arthritis. Rheumatol Int 19(1–2):35–37PubMedGoogle Scholar
  88. Pan W, Xiang S, Tu H, Kastin AJ (2006) Cytokines interact with the blood–brain barrier. Blood–Brain Barriers 1:247–264Google Scholar
  89. Pan W, Tu H, Yu C, Hsuchou H, Yang Y, Kastin A (2007) Differential role of TNF receptors in cellular trafficking of intact TNF. Cell Physiol Biochem 20(5):559–568CrossRefPubMedGoogle Scholar
  90. Patel V, Adya R, Chen J, Ramanjaneya M, Bari MF, Bhudia SK, Hillhouse EW, Tan BK, HS Randeva (2014) Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts. PLoS ONE 9(2): e87102CrossRefPubMedPubMedCentralGoogle Scholar
  91. Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C, Iglesias R, Gabrielli L, Sitges M, Giralt M, Van Bilsen M (2013) Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun 4: 2019Google Scholar
  92. Planavila A, Ribas F, Garrabou G, Casademont J, Giralt M, Villarroya F (2015) Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovasc Res 106:9–31CrossRefGoogle Scholar
  93. Prasad S, Aggarwal B (2014) Chronic diseases caused by chronic inflammation require chronic treatment: anti-inflammatory role of dietary spices. J Clin Cell Immunol 5(238):10.4172Google Scholar
  94. Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16(2):159–178CrossRefPubMedGoogle Scholar
  95. Riera CE, Dillin A (2015) Tipping the metabolic scales towards increased longevity in mammals. Nat Cell Biol 17(3):196CrossRefPubMedGoogle Scholar
  96. Sahiner Z, Karaca A, Bakar F, Akgul G, Ali GM, Gulcelik NE (2018) FGF21 levels in patients with breast cancer. In: 20th European Congress of Endocrinology, BioScientificaGoogle Scholar
  97. Sa-nguanmoo P, Chattipakorn N, Chattipakorn SC (2016a) Potential roles of fibroblast growth factor 21 in the brain. Metab Brain Dis 31(2):239–248CrossRefPubMedGoogle Scholar
  98. Sa-nguanmoo P, Tanajak P, Kerdphoo S, Satjaritanun P, Wang X, Liang G, Li X, Jiang C, Pratchayasakul W, Chattipakorn N (2016b) FGF21 improves cognition by restored synaptic plasticity, dendritic spine density, brain mitochondrial function and cell apoptosis in obese-insulin resistant male rats. Horm Behav 85:86–95CrossRefPubMedGoogle Scholar
  99. Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD, Ogimoto K, Schwartz MW (2010) FGF21 Action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes 59(7):1817–1824CrossRefPubMedPubMedCentralGoogle Scholar
  100. Shen Y, Ma X, Zhou J, Pan X, Hao Y, Zhou M, Lu Z, Gao M, Bao Y, Jia W (2013) Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc Diabetol 12(1):124CrossRefPubMedPubMedCentralGoogle Scholar
  101. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2001) Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 98(11):6500–6505CrossRefPubMedGoogle Scholar
  102. Singhal G, Kumar G, Chan S, Ma Y, Vardeh HG, Nasser IA, Flier JS, Maratos-Flier E (2018) Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet. Mol Metab 13:56–66CrossRefPubMedPubMedCentralGoogle Scholar
  103. Speakman JR (2005) Body size, energy metabolism and lifespan. J Exp Biol 208(9):1717–1730CrossRefPubMedGoogle Scholar
  104. Suh JM, Jonker JW, Ahmadian M, Goetz R, Lackey D, Osborn O, Huang Z, Liu W, Yoshihara E, TH van Dijk (2014) Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature 513(7518): 436CrossRefPubMedPubMedCentralGoogle Scholar
  105. Suomalainen A (2013) Fibroblast growth factor 21: a novel biomarker for human muscle-manifesting mitochondrial disorders. Expert Opin Med Diagn 2013;7(4):313–317CrossRefPubMedGoogle Scholar
  106. Tan BK, Hallschmid M, Adya R, Kern W, Lehnert H, Randeva HS (2011) Fibroblast growth factor 21 (FGF21) in human cerebrospinal fluid: relationship with plasma FGF21 and body adiposity. Diabetes 60(11):2758–2762CrossRefPubMedPubMedCentralGoogle Scholar
  107. Turturro A, Witt WW, Lewis S, Hass BS, Lipman RD, Hart RW (1999) Growth curves and survival characteristics of the animals used in the biomarkers of aging program. J Gerontol Ser A 54(11):B492–B501CrossRefGoogle Scholar
  108. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444(7120):770CrossRefPubMedGoogle Scholar
  109. Véniant MM, Komorowski R, Chen P, Stanislaus S, Winters K, Hager T, Zhou L, Wada R, Hecht R, Xu J (2012) Long-acting FGF21 has enhanced efficacy in diet-induced obese mice and in obese rhesus monkeys. Endocrinology 153(9):4192–4203CrossRefPubMedGoogle Scholar
  110. Wang X-M, Xiao H, Liu L-L, Cheng D, Li X-J, Si L-Y (2016) FGF21 represses cerebrovascular aging via improving mitochondrial biogenesis and inhibiting p53 signaling pathway in an AMPK-dependent manner. Exp Cell Res 346(2):147–156CrossRefPubMedGoogle Scholar
  111. Ward BW, Schiller JS, Goodman RA (2014) Peer reviewed: Multiple chronic conditions among us adults: a 2012 update. Prev Chronic Dis 11Google Scholar
  112. Williams L, Bradley L, Smith A, Foxwell B (2004) Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J Immunol 172(1):567–576CrossRefPubMedGoogle Scholar
  113. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, RC Scarpulla (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98(1): 115–124CrossRefPubMedGoogle Scholar
  114. Wu A-L, Kolumam G, Stawicki S, Chen Y, Li J, Zavala-Solorio J, Phamluong K, Feng B, Li L, Marsters S (2011) Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1. Sci Transl Med 3(113): 113ra126-113ra126Google Scholar
  115. Wuyts WA, Agostini C, Antoniou KM, Bouros D, Chambers RC, Cottin V, Egan JJ, Lambrecht BN, Lories R, Parfrey H (2012) The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J 41(5):1207–1218CrossRefPubMedGoogle Scholar
  116. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht SN, Hecht R, Li L, Lindberg RA (2008) FGF21 reverses hepatic steatosis, increases energy expenditure and improves insulin sensitivity in diet-induced obese mice. Diabetes 58(1):250–259CrossRefPubMedGoogle Scholar
  117. Xu J, Bussiere J, Yie J, Sickmier A, An P, Belouski E, Stanislaus S, Walker KW (2013) Polyethylene glycol modified FGF21 engineered to maximize potency and minimize vacuole formation. Bioconj Chem 24(6):915–925CrossRefGoogle Scholar
  118. Xu P, Ye X, Zhang Y, Yuan Q, Liu M, Wu Q, Ren G, Li D (2015) Long-acting hypoglycemic effects of PEGylated FGF21 and insulin glargine in mice with type 1 diabetes. J Diabetes Complic 29(1):5–12CrossRefGoogle Scholar
  119. Xu P, Zhang Y, Jiang X, Li J, Song L, Khoso MH, Liu Y, Wu Q, Ren G, Li D (2016a) Canine fibroblast growth factor 21 ameliorates hyperglycemia associated with inhibiting hepatic gluconeogenesis and improving pancreatic beta-cell survival in diabetic mice and dogs. PLoS ONE 11(5):e0155598CrossRefPubMedPubMedCentralGoogle Scholar
  120. Xu P, Zhang Y, Liu Y, Yuan Q, Song L, Liu M, Liu Z, Yang Y, Li J, Li D (2016b) Fibroblast growth factor 21 attenuates hepatic fibrogenesis through TGF-β/smad2/3 and NF-κB signaling pathways. Toxicol Appl Pharmacol 290:43–53CrossRefPubMedGoogle Scholar
  121. Xu P, Zhang Y, Song L, Khoso MH, Li J, Jiang X, He J, Li J, Ma X, Ren G (2016c) Efficacy of a combination of high and low dosage of PEGylated FGF-21 in treatment of diabetes in db/db mice. Biomed Pharmacother 84:97–105CrossRefPubMedGoogle Scholar
  122. Ye D, Wang Y, Li H, Jia W, Man K, Lo CM, Wang Y, Lam KS, Xu A (2014) Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice. Hepatology 60(3):977–989CrossRefPubMedGoogle Scholar
  123. Ye X, Qi J, Ren G, Xu P, Wu Y, Zhu S, Yu D, Li S, Wu Q, Muhi RL (2015) Long-lasting anti-diabetic efficacy of PEGylated FGF-21 and liraglutide in treatment of type 2 diabetic mice. Endocrine 49(3):683–692CrossRefPubMedGoogle Scholar
  124. Youm Y-H, Horvath TL, Mangelsdorf DJ, Kliewer SA, Dixit VD (2016) Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc Natl Acad Sci USA 113(4): 1026–1031CrossRefPubMedGoogle Scholar
  125. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798CrossRefPubMedPubMedCentralGoogle Scholar
  126. Yu Y, Bai F, Wang W, Liu Y, Yuan Q, Qu S, Zhang T, Tian G, Li S, Li D (2015a) Fibroblast growth factor 21 protects mouse brain against D-galactose induced aging via suppression of oxidative stress response and advanced glycation end products formation. Pharmacol Biochem Behav 133:122–131CrossRefPubMedGoogle Scholar
  127. Yu Y, Li S, Liu Y, Tian G, Yuan Q, Bai F, Wang W, Zhang Z, Ren G, Zhang Y (2015b) Fibroblast growth factor 21 (FGF21) ameliorates collagen-induced arthritis through modulating oxidative stress and suppressing nuclear factor-kappa B pathway. Int Immunopharmacol 25(1):74–82CrossRefPubMedGoogle Scholar
  128. Yu Y, He J, Li S, Song L, Guo X, Yao W, Zou D, Gao X, Liu Y, Bai F (2016) Fibroblast growth factor 21 (FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-κB signaling pathway. Int Immunopharmacol 38:144–152CrossRefPubMedGoogle Scholar
  129. Yu D, Ye X, Che R, Wu Q, Qi J, Song L, Guo X, Zhang S, Wu H, Ren G (2017) FGF21 exerts comparable pharmacological efficacy with Adalimumab in ameliorating collagen-induced rheumatoid arthritis by regulating systematic inflammatory response. Biomed Pharmacother 89:751–760CrossRefPubMedGoogle Scholar
  130. Zhang J, Li Y (2014) Fibroblast growth factor 21, the endocrine FGF pathway and novel treatments for metabolic syndrome. Drug Discov Today 19(5):579–589CrossRefPubMedGoogle Scholar
  131. Zhang J, Li Y (2015) Fibroblast growth factor 21 analogs for treating metabolic disorders. Front Endocrinol (Lausanne) 6:168Google Scholar
  132. Zhang Y, Xie Y, Berglund ED, Coate KC, He TT, Katafuchi T, Xiao G, Potthoff MJ, Wei W, Wan Y (2012) The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. Elife 1:e00065CrossRefPubMedPubMedCentralGoogle Scholar
  133. Zhang C, Shao M, Yang H, Chen L, Yu L, Cong W, Tian H, Zhang F, Cheng P, Jin L (2013) Attenuation of hyperlipidemia-and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation. PLoS ONE 8(12):e82275CrossRefPubMedPubMedCentralGoogle Scholar
  134. Zhang X, Hu Y, Zeng H, Li L, Zhao J, Zhao J, Liu F, Bao Y, Jia W (2015a) Serum fibroblast growth factor 21 levels is associated with lower extremity atherosclerotic disease in Chinese female diabetic patients. Cardiovasc Diabetol 14(1):32CrossRefPubMedPubMedCentralGoogle Scholar
  135. Zhang F, Yu L, Lin X, Cheng P, He L, Li X, Lu X, Tan Y, Yang H, Cai L (2015b) Minireview: roles of fibroblast growth factors 19 and 21 in metabolic regulation and chronic diseases. Mol Endocrinol 29(10):1400–1413CrossRefPubMedPubMedCentralGoogle Scholar
  136. Zhang W, Chu S, Ding W, Wang F (2015c) Serum level of fibroblast growth factor 21 is independently associated with acute myocardial infarction. PLoS ONE 10(6):e0129791CrossRefPubMedPubMedCentralGoogle Scholar
  137. Zhang S, Yu D, Wang M, Huang T, Wu H, Zhang Y, Zhang T, Wang W, Yin J, Ren G (2018) FGF21 attenuates pulmonary fibrogenesis through ameliorating oxidative stress in vivo and in vitro. Biomed Pharmacother 103:1516–1525CrossRefPubMedGoogle Scholar
  138. Zhao Y, Dunbar JD, Kharitonenkov A (2012) FGF21 as a therapeutic reagent. Adv Exp Med Biol 728:214–228CrossRefPubMedGoogle Scholar
  139. Zhu S, Ren G, Zhang Z, Wang W, Ye X, Han M, Zhao J, Xu T, Liu M, Li D (2013) Therapeutic effect of fibroblast growth factor 21 on hypertension induced by insulin resistance. Acta Pharm Sin 48(9):1409–1414Google Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Yeboah Kwaku Opoku
    • 1
  • Zhihang Liu
    • 1
  • Justice Afrifa
    • 2
  • Mir Hassan Khoso
    • 1
  • Guiping Ren
    • 1
    • 3
    • 4
    Email author
  • Deshan Li
    • 1
    • 3
    • 4
    Email author
  1. 1.Bio-pharmaceutical Laboratory, College of Life SciencesNortheast Agricultural UniversityHarbinChina
  2. 2.Scientific Research Center of the Second Affiliated HospitalHarbin Medical UniversityHarbinChina
  3. 3.Key Laboratory of Agricultural Biological Functional GeneHarbinChina
  4. 4.Biopharmaceutical Teaching and Research Section, College of Life SciencesNortheast Agricultural UniversityHarbinChina

Personalised recommendations