Fibroblast growth factor 21: a novel link in the development and treatment of metabolic disorders
https://doi.org/10.18705/1607-419X-2024-2455
EDN: AEKLUB
Abstract
In recent years, fibroblast growth factor 21 (FGF21) has garnered increasing attention as a metabolic regulator. It plays a role in the development of tissue insulin sensitivity, exerts beneficial effects on carbohydrate and lipid metabolism, and exhibits antihyperglycemic and antilipidemic properties. Elevated FGF21 levels have been observed in patients with type 2 diabetes, obesity, non-alcoholic fatty liver disease, and a range of other conditions. This may indicate either resistance to FGF21 or a compensatory response to metabolic stress. Evidence suggests that FGF21 can be considered both a marker of several metabolic disorders and a potential therapeutic agent for the treatment of significant societal health issues. Objective. The objective of this review is to summarize the data published to date in the literature, including meta-analyses, reviews, and original studies, focusing on the diagnostic and potential therapeutic role of FGF21 in metabolic disorders.
Keywords
About the Authors
A. A. MikhailovaRussian Federation
Arina A. Mikhailova, MD, Endocrinologist, Junior Researcher, Research Laboratory of new Coronavirus Infection and Postcovid Syndrome, World-Class Research “Centre for Personalized Medicine”, Postgraduate Student, Department of Endocrinology
2 Akkuratov str., St Petersburg, 197341
M. V. Sharypova
Russian Federation
Marina V. Sharypova, MD, Laboratory Assistant Researcher, Research Laboratory of new Coronavirus Infection and Postcovid Syndrome, World-Class Research “Centre for Personalized Medicine”
2 Akkuratov str., St Petersburg, 197341
A. V. Simanenkova
Russian Federation
Anna V. Simanenkova, MD, PhD, Senior Researcher, Research Laboratory of Clinical Endocrinology of the Institute of Endocrinology, Assistant, Department of Faculty Therapy at the Institute of Medical Education
2 Akkuratov str., St Petersburg, 197341
Yu. V. Cheburkin
Russian Federation
Yuri V. Cheburkin, MD, PhD, Researcher, Research Laboratory of Neurogenesis and Neurodegenerative Diseases, Head, Research Laboratory of Infectious Pathogens and Biomolecular Nanostructures, World-Class Research “Centre for Personalized Medicine”
2 Akkuratov str., St Petersburg, 197341
O. S. Fuks
Russian Federation
Oksana S. Fuks, MD, Research Assistant, Laboratory of Novel Coronavirus Infection and Post-COVID Syndrome, World-Class Research Centre for Personalized Medicine
2 Akkuratov str., St Petersburg, 197341
N. V. Timkina
Russian Federation
Natalya V. Timkina, MD, Junior Researcher, Laboratory of Clinical Endocrinology
2 Akkuratov str., St Petersburg, 197341
V. A. Dyachuk
Russian Federation
Vyacheslav A. Dyachuk, Candidate of Biological Sciences, Leading Researcher, Head, Research Laboratory of Neurogenesis and Neurodegenerative Diseases, World-Class Research “Centre for Personalized Medicine”
2 Akkuratov str., St Petersburg, 197341
T. L. Karonova
Russian Federation
Tatiana L. Karonova, MD, PhD, DSc, Head, Research Laboratory of New Coronavirus infection and Postcovid syndrome, World-Class Research “Centre for Personalized Medicine”, Chief Researcher, Research Laboratory of Clinical Endocrinology, Institute of Endocrinology, Professor, Department of Endocrinology, Institute of Medical Education
2 Akkuratov str., St Petersburg, 197341
References
1. Cuevas-Ramos D, Aguilar-Salinas CA, Gómez-Pérez FJ. Metabolic actions of fibroblast growth factor 21. Curr Opin Pediatr. 2012;24(4):523–529. doi:10.1097/MOP.0b013e3283557d22
2. Chen Z, Yang L, Liu Y, Huang P, Song H, ZhengP.The potential function and clinical application of FGF21 in metabolic diseases. Front Pharmacol. 2022;13:1089214. doi:10.3389/fphar.2022.1089214
3. Nishimura T, Nakatake Y, Konishi M, ItohN.Identification of a novel FGF, FGF21, preferentially expressed in the liver. Biochim Biophys Acta. 2000;1492(1):203–206. doi:10.1016/s0167-4781(00)00067-1
4. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-FlierE.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
5. Berglund ED, Kang L, Lee-Young RS, Hasenour CM, Lustig DG, Lynes SE et al. Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARα and FGF21 transcripts in vivo. Am J Physiol Endocrinol Metab. 2010;299(4):E607–E614. doi:10.1152/ajpendo.00263.2010
6. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ et al. FGF21 as a novel metabolic regulator. J Clin Invest. 2005;115(6):1627–1635. doi:10.1172/JCI23606
7. Spann RA, Morrison CD, den Hartigh LJ. The nuanced metabolic functions of endogenous FGF21 depend on the nature of the stimulus, tissue source, and experimental model. Front Endocrinol (Lausanne). 2022;12:802541. doi:10.3389/fendo.2021.802541
8. Tezze C, Romanello V, SandriM. FGF21 as modulator of metabolism in health and disease. Front Physiol. 2019;10:419. doi:10.3389/fphys.2019.00419
9. Li S, Chen J, Wei P, Zou T, YouJ.Fibroblast growth factor 21: a fascinating perspective on the regulation of muscle metabolism. Int J Mol Sci. 2023;24(23):16951. doi:10.3390/ijms242316951
10. Kaur N, Gare SR, Shen J, Raja R, Fonseka O, LiuW.Multiorgan FGF21-FGFR1 signaling in metabolic health and disease. Front Cardiovasc Med. 2022;9:962561. doi:10.3389/fcvm.2022.962561
11. Pan Y, Wang B, Zheng J, Xiong R, Fan Z, Ye Y et al. Pancreatic fibroblast growth factor 21 protects against type 2 diabetes in mice by promoting insulin expression and secretion in a PI3K/Akt signaling-dependent manner. J Cell Mol Med. 2019;23(2):1059–1071. doi:10.1111/jcmm.14007
12. Klein Hazebroek M, KeipertS.Adapting to the cold: a role for endogenous fibroblast growth factor 21 in thermoregulation? Front Endocrinol (Lausanne). 2020;11:389. doi:10.3389/fendo.2020.00389
13. BonDurant LD, Ameka M, Naber MC, Markan KR, Idiga SO, Acevedo MR et al. FGF21 Regulates metabolism through adipose-dependent and independent mechanisms. Cell Metab. 2017;25(4):935–44.e4. doi:10.1016/j.cmet.2017.03.005
14. Suzuki M, Uehara Y, Motomura-Matsuzaka K, Oki J, Koyama Y, Kimura M et al. betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol Endocrinol. 2008;22(4):1006–1014. doi:10.1210/me.2007-0313
15. Geng L, Liao B, Jin L, Yu J, Zhao X, Zhao Y et al. β-Klotho promotes glycolysis and glucose-stimulated insulin secretion via GP130. Nat Metab. 2022;4(5):608–626. doi:10.1038/s42255-022-00572-2
16. Villarroya F, Cereijo R, Villarroya J, Giralt M.Brown adipose tissue as a secretory organ. Nat Rev Endocrinol. 2017;13(1):26–35. doi:10.1038/nrendo.2016.136
17. Flippo KH, Potthoff MJ. Metabolic messengers: FGF21. Nat Metab. 2021;3(3):309–317. doi:10.1038/s42255-021-00354-2
18. Liu Y, Liu Y, Deng J, Li W, Nie X. Fibroblast growth factor in diabetic foot ulcer: progress and therapeutic prospects. Front Endocrinol (Lausanne). 2021;12:744868. doi:10.3389/fendo.2021.744868
19. Yie J, Hecht R, Patel J, Stevens J, Wang W, Hawkins N et al. FGF21 N- and C-termini play different roles in receptor interaction and activation. FEBS Lett. 2009;583(1):19–24. doi:10.1016/j.febslet.2008.11.023
20. Ye M, Lu W, Wang X, Wang C, Abbruzzese JL, Liang G et al. FGF21-FGFR1 coordinates phospholipid homeostasis, lipid droplet function, and ER stress in obesity. Endocrinology. 2016;157(12):4754–4769. doi:10.1210/en.2016-1710
21. Raptis DD, Mantzoros CS, Polyzos SA. Fibroblast growth factor21 as a potential therapeutic target of nonalcoholic fatty liver disease. Ther Clin Risk Manag. 2023;19:77–96. doi:10.2147/TCRM.S352008
22. Wente W, Efanov AM, Brenner M, Kharitonenkov A, Köster A, Sandusky GE et al. Fibroblast growth factor21 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
23. Al-Kuraishy HM, Al-Gareeb AI, Saad HM, Batiha GE. The potential effect of metformin on fibroblast growth factor 21 in type 2 diabetes mellitus (T2DM). Inflammopharmacology. 2023;31(4):1751–1760. doi:10.1007/s10787-023-01255-4
24. Qian Z, Zhang Y, Yang N, Nie H, Yang Z, Luo P et al. Close association between lifestyle and circulating FGF21 levels: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2022;13:984828. doi:10.3389/fendo.2022.984828
25. Wang WF, Li SM, Ren GP, Zheng W, Lu YJ, Yu YH et al. Recombinant murine fibroblast growth factor 21 ameliorates obesity-related inflammation in monosodium glutamate-induced obesity rats. Endocrine. 2015;49(1):119–129. doi:10.1007/s12020-014-0433-5
26. Tanajak P, Sa-Nguanmoo P, Wang X, Liang G, Li X, Jiang C et al. Fibroblast growth factor 21 (FGF21) therapy attenuates left ventricular dysfunction and metabolic disturbance by improving FGF21 sensitivity, cardiac mitochondrial redox homoeostasis and structural changes in pre-diabetic rats. Acta Physiol (Oxf). 2016;217(4):287–299. doi:10.1111/apha.12698
27. He JL, Zhao M, Xia JJ, Guan J, Liu Y, Wang LQ et al. FGF21 ameliorates the neurocontrol of blood pressure in the high fructose-drinking rats. Sci Rep. 2016;6:29582.
28. Guo Q, Xu L, Liu J, Li H, Sun H, Wu S et al. Fibroblast growth factor 21 reverses suppression of adiponectin expression via inhibiting endoplasmic reticulum stress in adipose tissue of obese mice. Exp Biol Med (Maywood). 2017;242(4):441–447. doi:10.1177/1535370216677354
29. Laeger T, Baumeier C, Wilhelmi I, Würfel J, Kamitz A, SchürmannA. FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes. Diabetologia. 2017;60(11):2274–2284. doi:10.1007/s00125-017-4389-x
30. Pan X, Shao Y, Wu F, Wang Y, Xiong R, Zheng J et al. FGF21 Prevents Angiotensin II-Induced Hypertension and Vascular Dysfunction by Activation of ACE2/Angiotensin-(1-7) Axis in Mice. Cell Metab. 2018;27(6):1323–1337.e5. doi:10.1016/j.cmet.2018.04.002
31. Chen P, Xu B, Feng Y, Li KX, Liu Z, Sun X et al. FGF21 ameliorates essential hypertension of SHR via baroreflex afferent function. Brain Res Bull. 2020;154:9–20. doi:10.1016/j. brainresbull.2019.10.003
32. Makarova E, Kazantseva A, Dubinina A, Denisova E, Jakovleva T, Balybina N et al. Fibroblast Growth Factor 21 (FGF21) administration sex-specifically affects blood insulin levels and liver steatosis in obese Ay Mice. Cells. 2021;10(12):3440. doi:10.3390/cells10123440
33. Diener JL, Mowbray S, Huang WJ, Yowe D, Xu J, Caplan S et al. FGF21 normalizes plasma glucose in mouse models of type 1 diabetes and insulin receptor dysfunction. Endocrinology. 2021;162(9): bqab092. doi:10.1210/endocr/bqab092
34. Pan Q, Lin S, Li Y, Liu L, Li X, Gao X et al. Anovel GLP1 and FGF21 dual agonist has therapeutic potential for diabetes and non-alcoholic steatohepatitis. EBioMedicine. 2021;63:103202. doi:10.1016/j.ebiom.2020.103202
35. Tanbek K, Yılmaz U, Gul M, Koç A, SandalS.Effects of central FGF21 infusion on the glucose homeostasis in rats (brainpancreas axis). Arch Physiol Biochem. 2023;130(5):515–522. doi :10.1080/13813455.2023.2166964
36. Bartesaghi S, Wallenius K, Hovdal D, Liljeblad M, Wallin S, Dekker N et al. Subcutaneous delivery of FGF21 mRNA therapy reverses obesity, insulin resistance, and hepatic steatosis in diet-induced obese mice. Mol Ther Nucleic Acids. 2022;28:500– 513. doi:10.1016/j.omtn.2022.04.010
37. Tillman EJ, Brock WJ, RolphT.Efruxifermin, a long-acting Fc-fusion FGF21 analogue, reduces body weight gain but does not increase sympathetic tone or urine volume in Sprague Dawley rats. British J Pharm. 2022;179(7):1384–1394. doi:10.1111/bph.15725
38. Xu W, Gao X, Luo H, ChenY. FGF21 attenuates saltsensitive hypertension via regulating HNF4α/ACE2 axis in the hypothalamic paraventricular nucleus of mice. Clin Exp Hypertens. 2024;46(1):2361671. doi:10.1080/10641963.2024.2361671
39. Stanic S, Bardova K, Janovska P, Rossmeisl M, Kopecky J, ZouharP.Prolonged FGF21 treatment increases energy expenditure and induces weight loss in obese mice independently of UCP1 and adrenergic signaling. Biochem Pharmacol. 2024;221:116042. doi:10.1016/j.bcp.2024.116042
40. Geng L, Lam KSL, XuA.The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nat Rev Endocrinol. 2020;16(11):654–667. doi:10.1038/s41574-020-0386-0
41. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013;18(3):333– 340. doi:10.1016/j.cmet.2013.08.005
42. Charles ED, Neuschwander-Tetri BA, Pablo Frias J, Kundu S, Luo Y, Tirucherai GS et al. Pegbelfermin (BMS986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: results from a randomized phase 2 study. Obesity (Silver Spring). 2019;27(1):41–49. doi:10.1002/oby.22344
43. Filtz A, Parihar S, Greenberg GS, Park CM, Scotti A, Lorenzatti D et al. New approaches to triglyceride reduction: Is there any hope left? Am J Prev Cardiol. 2024;18:100648. doi:10.1016/j.ajpc.2024.100648
44. Research study on whether a combination of 2 medicines (NNC0194 0499 and Semaglutide) works in people with NonAlcoholic SteatoHepatitis (NASH); ClinicalTrials.gov ID NCT05016882. https://clinicaltrials.gov/study/NCT05016882
45. Zhu L, Zhao H, Liu J, Cai H, Wu B, Liu Z et al. Dynamic folding modulation generates FGF21 variant against diabetes. EMBO Rep. 2021;22(1): e51352. doi:10.15252/embr.202051352
46. Talukdar S, KharitonenkovA. FGF19 and FGF21: in NASH we trust. Mol Metab. 2021;46:101152. doi:10.1016/j.molmet.2020.101152
Review
For citations:
Mikhailova A.A., Sharypova M.V., Simanenkova A.V., Cheburkin Yu.V., Fuks O.S., Timkina N.V., Dyachuk V.A., Karonova T.L. Fibroblast growth factor 21: a novel link in the development and treatment of metabolic disorders. "Arterial’naya Gipertenziya" ("Arterial Hypertension"). 2024;30(5):441-450. (In Russ.) https://doi.org/10.18705/1607-419X-2024-2455. EDN: AEKLUB