Effect of Exercise Training on Serum FGF21 Level in Adults with Metabolic Disorders, A Meta-Analysis

Ravasi, Ali Asghar; Khalafi, Mousa; Azali Alamdari, Karim

Volume 19, Issue 22 (12-2021) RSMT 2021, 19(22): 130-151 | Back to browse issues page

‎ 20.1001.1.22520708.1400.19.22.11.5

Mendeley

Zotero

RefWorks

Ravasi A A, Khalafi M, Azali Alamdari K. Effect of Exercise Training on Serum FGF21 Level in Adults with Metabolic Disorders, A Meta-Analysis. RSMT 2021; 19 (22) :130-151
URL: http://jsmt.khu.ac.ir/article-1-495-en.html

Effect of Exercise Training on Serum FGF21 Level in Adults with Metabolic Disorders, A Meta-Analysis

Ali Asghar Ravasi

, Mousa Khalafi

, Karim Azali Alamdari

Azarbaijan Shahid Madani University , k.azali@azaruniv.ac.ir

Abstract: (3167 Views)

Background and objective: Effects of exercise training on metabolic disorders through modifications in fibroblast growth factor -21 (FGF-21) level are controversial. Therefore, the aim of study was to determine the quantitative effect of exercise training protocols on serum FGF-21 level in adults with metabolic disorders. Methods: A systematic search of the published Persian or English-language studies from PubMed and Google Scholar databases up to march 2021 was done and standardized mean differences (SMDs) were calculated using random-effects models. Results: a total of 14 studies (aerobic training=3, resistance training=3, HIIT=4, concurrent training=4) including on 19 interventions conducted on 503 subjects (with overweight, obesity, type 2 diabetes, metabolic syndrome and or fatty liver disease) were eligible to include in the meta-analysis. However, because of the heterogeneity, the final quantitative impact of 16 interventions was calculated as a declining serum FGF21 level after training [SMD=-0.44(CI: -0.65 to -0.22) p=0.001] which had no correlation with subjects age(p=0.10) or BMI(p=0.50) level. Conclusion: exercise training protocols are efficient tools for a remarkable decrease in serum FGF-21 in patients with metabolic disorders which seems to lead to more beneficial effects on metabolic disturbances. However, more clinical trials are still warranted in this area considering the role of exercise components such as exercise intensity and type

Keywords: Exercise Training, Fgf-21, Obesity, Diabetes, Fatty Liver Diseases

Full-Text [PDF 1066 kb] (1040 Downloads)

Type of Study: Applicable | Subject: sport physiology
Received: 2021/06/20 | Accepted: 2021/11/18 | Published: 2021/12/22

References

1. رفرنس های متنی مثل خروجی کراس رف را در اینجا وارد کرده و تایید کنید --------1. Lara-Castro C, Garvey WT. Intracellular lipid accumulation in liver and muscle and the insulin resistance syndrome. Endocrinol Metab Clin North Am. 2008;37(4):841-56. [DOI:10.1016/j.ecl.2008.09.002]

2. Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cellular and molecular life sciences : CMLS. 2018;75(18):3313-27. [DOI:10.1007/s00018-018-2860-6]

3. Oikonomou D, Georgiopoulos G, Katsi V, Kourek C, Tsioufis C, Alexopoulou A, et al. Non-alcoholic fatty liver disease and hypertension: coprevalent or correlated? European journal of gastroenterology & hepatology. 2018;30(9):979-85. [DOI:10.1097/MEG.0000000000001191]

4. Oh K-J, Lee DS, Kim WK, Han BS, Lee SC, Bae K-H. Metabolic adaptation in obesity and type II diabetes: myokines, adipokines and hepatokines. International journal of molecular sciences. 2017;18(1):8. [DOI:10.3390/ijms18010008]

5. Ritchie M, Hanouneh IA, Noureddin M, Rolph T, Alkhouri N. Fibroblast growth factor (FGF)-21 based therapies: A magic bullet for nonalcoholic fatty liver disease (NAFLD)? Expert opinion on investigational drugs. 2020;29(2):197-204. [DOI:10.1080/13543784.2020.1718104]

6. Lee Y, Lim S, Hong ES, Kim JH, Moon MK, Chun EJ, et al. Serum FGF 21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status. Clinical endocrinology. 2014;80(1):57-64. [DOI:10.1111/cen.12134]

7. Zhu S, Ren G, Zhang Z, Wang W, Ye X, Han M, et al. Therapeutic effect of fibroblast growth factor 21 on hypertension induced by insulin resistance. Yao xue xue bao= Acta pharmaceutica Sinica. 2013;48(9):1409-14.

8. Gao R-Y, Hsu B-G, Wu D-A, Hou J-S, Chen M-C. Serum fibroblast growth factor 21 levels are positively associated with metabolic syndrome in patients with type 2 diabetes. International journal of endocrinology. 2019;2019. [DOI:10.1155/2019/5163245]

9. Tezze C, Romanello V, Sandri M. FGF21 as Modulator of Metabolism in Health and Disease. Frontiers in physiology. 2019;10:419. [DOI:10.3389/fphys.2019.00419]

10. Flippo KH, Potthoff MJ. Metabolic Messengers: FGF21. Nature Metabolism. 2021;3(3):309-17. [DOI:10.1038/s42255-021-00354-2]

11. Lu W, Li X, Luo Y. FGF21 in obesity and cancer: New insights. Cancer letters. 2021;499:5-13. [DOI:10.1016/j.canlet.2020.11.026]

12. Battista F, Ermolao A, van Baak MA, Beaulieu K, Blundell JE, Busetto L, et al. Effect of exercise on cardiometabolic health of adults with overweight or obesity: Focus on blood pressure, insulin resistance, and intrahepatic fat-A systematic review and meta‐analysis. Obesity Reviews. 2021:e13269. [DOI:10.1111/obr.13269]

13. Yang W, Liu L, Wei Y, Fang C, Zhou F, Chen J, et al. Exercise ameliorates the FGF21-adiponectin axis impairment in diet-induced obese mice. Endocrine connections. 2019;8(5):596-604. [DOI:10.1530/EC-19-0034]

14. Shabkhiz F, Khalafi M, Rosenkranz S, Karimi P, Moghadami K. Resistance training attenuates circulating FGF-21 and myostatin and improves insulin resistance in elderly men with and without type 2 diabetes mellitus: A randomised controlled clinical trial. European journal of sport science. 2020:1-10. [DOI:10.1080/17461391.2020.1762755]

15. Geng L, Liao B, Jin L, Huang Z, Triggle CR, Ding H, et al. Exercise alleviates obesity-induced metabolic dysfunction via enhancing FGF21 sensitivity in adipose tissues. Cell reports. 2019;26(10):2738-52. e4. [DOI:10.1016/j.celrep.2019.02.014]

16. Azali Alamdari K, Khalafi M. THE EFFECTS OF HIGH INTENSITY INTERVAL TRAINING ON SERUM LEVELS OF FGF21 AND INSULIN RESISTANCE IN OBESE MEN. Iranian Journal of Diabetes and Lipid Disorders. 2019;18(1):41-8.

17. Taniguchi H, Tanisawa K, Sun X, Kubo T, Higuchi M. Endurance Exercise Reduces Hepatic Fat Content and Serum Fibroblast Growth Factor 21 Levels in Elderly Men. The Journal of clinical endocrinology and metabolism. 2016;101(1):191-8. [DOI:10.1210/jc.2015-3308]

18. Takahashi A, Abe K, Fujita M, Hayashi M, Okai K, Ohira H. Simple resistance exercise decreases cytokeratin 18 and fibroblast growth factor 21 levels in patients with nonalcoholic fatty liver disease: A retrospective clinical study. Medicine. 2020;99(22):e20399. [DOI:10.1097/MD.0000000000020399]

19. Yang SJ, Hong HC, Choi HY, Yoo HJ, Cho GJ, Hwang TG, et al. Effects of a three‐month combined exercise programme on fibroblast growth factor 21 and fetuin‐A levels and arterial stiffness in obese women. Clinical endocrinology. 2011;75(4):464-9. [DOI:10.1111/j.1365-2265.2011.04078.x]

20. Vizvari E, Farzanegi P, Abbas Zade Sourati H. Effect of Vigorous Aerobic Exercise on Serum Levels of SIRT1, FGF21 and Fetuin A in Women with Type II Diabetes. Medical Laboratory Journal. 2018;12(2):1-6. [DOI:10.29252/mlj.12.2.1]

21. Tofighi A, Alizadeh R, Tolouei Azar J. THE EFFECT OF EIGHT WEEKS HIGH INTENSITY INTERVAL TRAINING (HIIT) ON SERUM AMOUNTS OF FGF21 AND IRISIN IN SEDENTARY OBESE WOMEN. Studies in Medical Sciences. 2017;28(7):453-66.

22. Kruse R, Vienberg SG, Vind BF, Andersen B, Højlund K. Effects of insulin and exercise training on FGF21, its receptors and target genes in obesity and type 2 diabetes. Diabetologia. 2017;60(10):2042-51. [DOI:10.1007/s00125-017-4373-5]

23. Henkel J, Buchheim-Dieckow K, Castro JP, Laeger T, Wardelmann K, Kleinridders A, et al. Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH. Nutrients. 2019;11(11):2709. [DOI:10.3390/nu11112709]

24. Zhang Y, Wang D, Liu Y, Zhang Y, Liu Y, Su Z, et al. Impacts of chronic exercise on human blood fibroblast growth factor 21 levels in normal people: a meta-analysis. 2017.

25. Khalafi M, Alamdari KA, Symonds ME, Nobari H, Carlos-Vivas J. Impact of acute exercise on immediate and following early post-exercise FGF-21 concentration in adults: systematic review and meta-analysis. Hormones. 2020:1-11. [DOI:10.1007/s42000-020-00245-3]

26. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC medical research methodology. 2014;14(1):135. [DOI:10.1186/1471-2288-14-135]

27. Gordon BR, McDowell CP, Hallgren M, Meyer JD, Lyons M, Herring MP. Association of efficacy of resistance exercise training with depressive symptoms: meta-analysis and meta-regression analysis of randomized clinical trials. JAMA psychiatry. 2018;75(6):566-76. [DOI:10.1001/jamapsychiatry.2018.0572]

28. Wen H, Wang L. Reducing effect of aerobic exercise on blood pressure of essential hypertensive patients: A meta-analysis. Medicine. 2017;96(11). [DOI:10.1097/MD.0000000000006150]

29. toloueiazar j, Tofighi A, alizadeh r. The Effect of High Intensity Interval Training on Serum Levels of FGF21, Insulin Resistance and Lipid Profile in Sedentary Obese Women. Journal of Sport Biosciences. 2019;10(4):449-64.

30. Saeidi A, Jabbour G, Ahmadian M, Abbassi-Daloii A, Malekian F, Hackney AC, et al. Independent and Combined Effects of Antioxidant Supplementation and Circuit Resistance Training on Selected Adipokines in Postmenopausal Women. Frontiers in physiology. 2019;10:484. [DOI:10.3389/fphys.2019.00484]

31. abbasi-daloii A, ., Abdi A, Ghasemi M. The effects of eight weeks of resistance training on serum levels of FGF21, LCAT and LDL-C to HDL-C ratio in obese women. Journal of Applied Exercise Physiology. 2017;13(25):15-24.

32. Keihanian A, Arazi H, Kargarfard M. Effects of aerobic versus resistance training on serum fetuin-A, fetuin-B, and fibroblast growth factor-21 levels in male diabetic patients. Physiology International. 2019;106:1-11. [DOI:10.1556/2060.106.2019.01]

33. Banitalebi E, Kazemi A, Faramarzi M, Nasiri S, Haghighi MM. Effects of sprint interval or combined aerobic and resistance training on myokines in overweight women with type 2 diabetes: A randomized controlled trial. Life sciences. 2019;217:101-9. [DOI:10.1016/j.lfs.2018.11.062]

34. Taniguchi H, Tanisawa K, Sun X, Cao Z-B, Oshima S, Ise R, et al. Cardiorespiratory Fitness and Visceral Fat Are Key Determinants of Serum Fibroblast Growth Factor 21 Concentration in Japanese Men. The Journal of Clinical Endocrinology & Metabolism. 2014;99(10):E1877-E84. [DOI:10.1210/jc.2014-1877]

35. Hamedinia MR, Firozeh Z, Haghighi AH, Ramezani S. Effect of 12 weeks of light and heavy interval training on the level of irisin and fibroblast growth factor 21 in obese and overweight women: A clinical trial study. Journal of Gorgan University of Medical Sciences. 2019;21(1):7-14.

36. Alizadeh L, Tofighi A, Tolouei Azar J. The Effect of 8 Weeks of High Intensity Interval Training (HIIT) On Serum Irisin, FGF21 and Glycemic Indices in Type 2 Diabetic Women. Journal of Applied Health Studies in Sport Physiology. 2019;6(2):17-24.

37. Fereidoonfar K, Monazzami A, Razimi Z, Rahimi M. Effects of eight-week resistance training on serum level of βKlotho and FGF21 in diabetic women with non-alcoholic fatty liver disease. Iranian Journal of Physiology and Pharmacology. 2020;4(1):48-39.

38. Astinchap A, Monazzami A, Rahimi Z, Rahimi M. The effect of moderate intensity endurance training on some fatty liver and metabolic indices in diabetic women with non-alcoholic fatty liver. Iranian Journal of Physiology and Pharmacology. 2020;4(1):58-49.

39. Motahari Rad M, Bijeh N, Attarzadeh Hosseini SR, Raouf Saeb A. The effect of two concurrent exercise modalities on serum concentrations of FGF21, irisin, follistatin, and myostatin in men with type 2 diabetes mellitus. Archives of Physiology and Biochemistry. 2020:1-10. [DOI:10.1080/13813455.2020.1829649]

40. Chang JS, Namkung J. Effects of Exercise Intervention on Mitochondrial Stress Biomarkers in Metabolic Syndrome Patients: A Randomized Controlled Trial. International journal of environmental research and public health. 2021;18(5):2242. [DOI:10.3390/ijerph18052242]

41. Pérez-López A, Gonzalo-Encabo P, Pérez-Köhler B, García-Honduvilla N, Valadés D. Circulating myokines IL-6, IL-15 and FGF21 response to training is altered by exercise type but not by menopause in women with obesity. European Journal of Sport Science. 2021:1-22. [DOI:10.1080/17461391.2021.1939430]

42. Pérez-López A, Gonzalo-Encabo P, Pérez-Köhler B, García-Honduvilla N, Valadés D. Circulating myokines IL-6, IL-15 and FGF21 response to training is altered by exercise type but not by menopause in women with obesity. European Journal of Sport Science. 2021(just-accepted):1-22. [DOI:10.1080/17461391.2021.1939430]

43. Hanks LJ, Gutiérrez OM, Bamman MM, Ashraf A, McCormick KL, Casazza K. Circulating levels of fibroblast growth factor-21 increase with age independently of body composition indices among healthy individuals. Journal of clinical & translational endocrinology. 2015;2(2):77-82. [DOI:10.1016/j.jcte.2015.02.001]

44. Villarroya J, Gallego‐Escuredo JM, Delgado‐Anglés A, Cairó M, Moure R, Gracia Mateo M, et al. Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue. Aging cell. 2018;17(5):e12822. [DOI:10.1111/acel.12822]

45. Thaane T, Motala AA, Mckune AJ. Lifestyle modification in the management of insulin resistance states in overweight/obesity: the role of exercise training. Journal of Endocrinology, Metabolism and Diabetes of South Africa. 2019;24(2):65-9. [DOI:10.1080/16089677.2019.1608054]

46. Gimeno RE, Moller DE. FGF21-based pharmacotherapy - potential utility for metabolic disorders. Trends in Endocrinology & Metabolism. 2014;25(6):303-11. [DOI:10.1016/j.tem.2014.03.001]

47. Estall JL, Ruas JL, Choi CS, Laznik D, Badman M, Maratos-Flier E, et al. PGC-1α negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erbα axis. Proceedings of the National Academy of Sciences. 2009;106(52):22510-5. [DOI:10.1073/pnas.0912533106]

48. Saydi A, Sheikholeslami-Vatani D. The Effect of Resistance Training with High and Moderate Intensities on Lipid Profile, Glycemic Index and FGF21 in Type 2 Diabetic Patients. Sport Physiology & Management Investigations. 2019;11(3):89-103.

49. Recinella L, Leone S, Ferrante C, Chiavaroli A, Di Nisio C, Martinotti S, et al. Effects of central fibroblast growth factor 21 (FGF21) in energy balance. Journal of biological regulators and homeostatic agents. 2017;31(3):603-13.

50. Markan KR. Defining "FGF21 Resistance" during obesity: Controversy, criteria and unresolved questions. F1000Research. 2018;7. [DOI:10.12688/f1000research.14117.1]

51. Lewis JE, Samms RJ, Cooper S, Luckett JC, Perkins AC, Adams AC, et al. Reduced adiposity attenuates FGF21 mediated metabolic improvements in the Siberian hamster. Scientific Reports. 2017;7(1):4238. [DOI:10.1038/s41598-017-03607-x]

52. Matsui M, Kosaki K, Akazawa N, Tanahashi K, Kuro-o M, Maeda S. Association between circulating fibroblast growth factor 21, aerobic fitness, and aortic blood pressure in middle-aged and older women. The Journal of Physical Fitness and Sports Medicine. 2019;8(5):195-201. [DOI:10.7600/jpfsm.8.195]

53. Geng L, Lam KSL, Xu A. The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nature Reviews Endocrinology. 2020;16(11):654-67. [DOI:10.1038/s41574-020-0386-0]

54. Lara-Castro, C., Garvey, WT. (2008). Intracellular lipid accumulation in liver and muscle and the insulin resistance syndrome. Endocrinology and Metabolism Clinics of North America. 37(4):841-56. [DOI:10.1016/j.ecl.2008.09.002]

55. Ipsen, DH., Lykkesfeldt, J., Tveden-Nyborg, P. (2018). Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cellular and Molecular Life Sciences: CMLS. 75(18):3313-27. [DOI:10.1007/s00018-018-2860-6]

56. Oikonomou, D., Georgiopoulos, G., Katsi, V., Kourek, C., Tsioufis, C., Alexopoulou, A., Koutli, E., Tousoulis, D. (2018). Non-alcoholic fatty liver disease and hypertension: coprevalent or correlated? European Journal of Gastroenterology & Hepatology. 30(9):979-85. [DOI:10.1097/MEG.0000000000001191]

57. Oh, K-J., Lee, DS., Kim, WK., Han, BS., Lee, SC., Bae, K-H. (2017). Metabolic adaptation in obesity and type II diabetes: myokines, adipokines and hepatokines. International Journal of Molecular Sciences. 18(1):8-17. [DOI:10.3390/ijms18010008]

58. Ritchie, M., Hanouneh, IA., Noureddin, M., Rolph, T., Alkhouri, N. (2020). Fibroblast growth factor (FGF)-21 based therapies: A magic bullet for nonalcoholic fatty liver disease (NAFLD)? Expert Opinion on Investigational Drugs. 29(2):197-204. [DOI:10.1080/13543784.2020.1718104]

59. Lee, Y., Lim, S., Hong, ES., Kim, JH., Moon, MK., Chun, EJ., Choi, SI., Kim, YB., Park, YJ, Park, KS. (2014). Serum FGF 21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status. Clinical Endocrinology. 80(1):57-64. [DOI:10.1111/cen.12134]

60. 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. Yao xue xue bao= Acta Pharmaceutica Sinica. 48(9):1409-14.

61. Gao, R-Y., Hsu, B-G., Wu, D-A., Hou, J-S, Chen, M-C. (2019). Serum fibroblast growth factor 21 levels are positively associated with metabolic syndrome in patients with type 2 diabetes. International Journal of Endocrinology. 2019(2019)::5163245. [DOI:10.1155/2019/5163245]

62. Tezze, C., Romanello, V., Sandri, M. (2019). FGF21 as Modulator of Metabolism in Health and Disease. Frontiers in Physiology. 10:419-427. [DOI:10.3389/fphys.2019.00419]

63. Flippo, KH., Potthoff, MJ. (2021). Metabolic Messengers: FGF21. Nature Metabolism. 3(3):309-17. [DOI:10.1038/s42255-021-00354-2]

64. Lu, W., Li, X., Luo, Y. (2021). FGF21 in obesity and cancer: New insights. Cancer Letters. 499:5-13. [DOI:10.1016/j.canlet.2020.11.026]

65. Chui, PC., Antonellis, PJ., Bina, HA., Kharitonenkov, A., Flier, JS., Maratos-Flier, E. (2010). Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes. 59(11):2781-9. [DOI:10.2337/db10-0193]

66. Battista, F., Ermolao, A., van Baak, MA., Beaulieu, K., Blundell, JE., Busetto, L., Carraça, EV., Encantado, J., Dicker, D., Farpour‐Lambert, N. (2021). Effect of exercise on cardiometabolic health of adults with overweight or obesity: Focus on blood pressure, insulin resistance, and intrahepatic fat-A systematic review and meta‐analysis. Obesity Reviews.e13269. [DOI:10.1111/obr.13269]

67. Azali Alamdari, K., Khalafi, M., Ghorbanian, B. (2017). Effect of aerobic training on serum adiponectin and Ctrp-3 in males with metabolic syndrome. Iranian Journal of Endocrinology and Metabolism. 18(5):368-79.

68. Yang, W., Liu, L., Wei, Y., Fang, C., Zhou, F., Chen, J., Han, Q., Huang, M., Tan, X., Liu, Q. (2019). Exercise ameliorates the FGF21-adiponectin axis impairment in diet-induced obese mice. Endocrine Connections. 8(5):596-604. [DOI:10.1530/EC-19-0034]

69. Shabkhiz, F., Khalafi, M., Rosenkranz, S., Karimi, P., Moghadami, K. (2020). Resistance training attenuates circulating FGF-21 and myostatin and improves insulin resistance in elderly men with and without type 2 diabetes mellitus: A randomised controlled clinical trial. European Journal of Sport Science.1-10. [DOI:10.1080/17461391.2020.1762755]

70. Geng, L., Liao, B., Jin, L., Huang, Z., Triggle, CR., Ding, H., Zhang, J., Huang, Y., Lin, Z., Xu, A. (2019). Exercise alleviates obesity-induced metabolic dysfunction via enhancing FGF21 sensitivity in adipose tissues. Cell Reports. 26(10):2738-52. e4. [DOI:10.1016/j.celrep.2019.02.014]

71. Khalafi, M., Mohebbi, H., Symonds, ME., Karimi, P., Akbari, A., Tabari, E., Faridnia, M, Moghaddami, K. (2020). The impact of moderate-intensity continuous or high-intensity interval training on adipogenesis and browning of subcutaneous adipose tissue in obese male rats. Nutrients. 12(4):925-33. [DOI:10.3390/nu12040925]

72. Azali Alamdari, K., Khalafi, M. (2019). The effects of high intensity interval training on serum levels of fgf21 and insulin resistance in obese men. Iranian Journal of Diabetes and Lipid Disorders. 18(1):41-8.

73. Taniguchi, H., Tanisawa, K., Sun, X., Kubo, T., Higuchi, M. (2016). Endurance Exercise Reduces Hepatic Fat Content and Serum Fibroblast Growth Factor 21 Levels in Elderly Men. The Journal of Clinical Endocrinology and Metabolism. 101(1):191-8. [DOI:10.1210/jc.2015-3308]

74. Takahashi, A., Abe, K., Fujita, M., Hayashi, M., Okai, K., Ohira, H. (2020). Simple resistance exercise decreases cytokeratin 18 and fibroblast growth factor 21 levels in patients with nonalcoholic fatty liver disease: A retrospective clinical study. Medicine. 99(22):e20399. [DOI:10.1097/MD.0000000000020399]

75. Yang, SJ., Hong, HC., Choi, HY., Yoo, HJ., Cho, GJ., Hwang, TG., Baik, SH., Choi, DS., Kim, SM., Choi, KM. (2011). Effects of a three‐month combined exercise programme on fibroblast growth factor 21 and fetuin‐A levels and arterial stiffness in obese women. Clinical Endocrinology. 75(4):464-9. [DOI:10.1111/j.1365-2265.2011.04078.x]

76. Vizvari, E., Farzanegi, P., Abbas Zade Sourati, H. (2018). Effect of Vigorous Aerobic Exercise on Serum Levels of SIRT1, FGF21 and Fetuin A in Women with Type II Diabetes. Medical Laboratory Journal. 12(2):1-6. [DOI:10.29252/mlj.12.2.1]

77. Tofighi, A., Alizadeh, R., Tolouei Azar, J. (2017). The effect of eight weeks high intensity interval training (hiit) on serum amounts of fgf21 and irisin in sedentary obese women. Studies in Medical Sciences. 28(7):453-66.

78. Kruse, R., Vienberg, SG., Vind, BF., Andersen, B., Højlund, K. (2017). Effects of insulin and exercise training on FGF21, its receptors and target genes in obesity and type 2 diabetes. Diabetologia. 60(10):2042-51. [DOI:10.1007/s00125-017-4373-5]

79. Henkel, J., Buchheim-Dieckow, K., Castro, JP., Laeger, T., Wardelmann, K., Kleinridders, A., Jöhrens, K., Püschel, GP. (2019). Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH. Nutrients. 11(11):2709-15. [DOI:10.3390/nu11112709]

80. Zhang, Y., Wang, D., Liu, Y., Zhang, Y., Liu, Y., Su, Z., Luo, T. (2017). Impacts of chronic exercise on human blood fibroblast growth factor 21 levels in normal people: a meta-analysis. Biomedical Research. 2017; 28(13): 5726-7532.

81. Khalafi, M., Alamdari, KA., Symonds, ME., Nobari, H., Carlos-Vivas, J. (2020). Impact of acute exercise on immediate and following early post-exercise FGF-21 concentration in adults: systematic review and meta-analysis. Hormones. 20(1): 23-33. [DOI:10.1007/s42000-020-00245-3]

82. Khalafi, M., Symonds, ME. (2020). The impact of high‐intensity interval training on inflammatory markers in metabolic disorders: A meta‐analysis. Scandinavian Journal of Medicine & Science in Sports. 30(11):2020-36. [DOI:10.1111/sms.13754]

83. Wan, X., Wang, W., Liu, J., Tong, T. (2014). Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Medical Research Methodology. 14(1):135-43. [DOI:10.1186/1471-2288-14-135]

84. Khalafi, M., Malandish, A., Rosenkranz, SK., Ravasi, AA. (2021). Effect of resistance training with and without caloric restriction on visceral fat: A systemic review and meta‐analysis. Obesity Reviews.e13275. [DOI:10.1111/obr.13275]

85. Gordon, BR., McDowell, CP., Hallgren, M., Meyer, JD., Lyons, M., Herring, MP. (2018). Association of efficacy of resistance exercise training with depressive symptoms: meta-analysis and meta-regression analysis of randomized clinical trials. JAMA Psychiatry. 75(6):566-76. [DOI:10.1001/jamapsychiatry.2018.0572]

86. Wen, H., Wang, L. (2017). Reducing effect of aerobic exercise on blood pressure of essential hypertensive patients: A meta-analysis. Medicine. 96(11):e6150. [DOI:10.1097/MD.0000000000006150]

87. Toloueiazar, j., Tofighi, A., Alizadeh, R. (2019). The effect of high intensity interval training on serum levels of fgf21, insulin resistance and lipid profile in sedentary obese women. Journal of Sport Biosciences. 10(4):449-64.

88. Saeidi, A., Jabbour, G., Ahmadian, M., Abbassi-Daloii, A., Malekian, F., Hackney, AC., Saedmocheshi, S., Basati, G., Ben Abderrahman, A., Zouhal, H. (2019). Independent and Combined Effects of Antioxidant Supplementation and Circuit Resistance Training on Selected Adipokines in Postmenopausal Women. Frontiers in Physiology. 10:484-91. [DOI:10.3389/fphys.2019.00484]

89. Abbasi-Daloii, A., Abdi, A., Ghasemi, M. (2017). The effects of eight weeks of resistance training on serum levels of FGF21, LCAT and LDL-C to HDL-C ratio in obese women. Journal of Applied Exercise Physiology. 13(25):15-24.

90. Keihanian, A., Arazi, H., Kargarfard, M. (2019). Effects of aerobic versus resistance training on serum fetuin-A, fetuin-B, and fibroblast growth factor-21 levels in male diabetic patients. Physiology International. 106:1-11. [DOI:10.1556/2060.106.2019.01]

91. Banitalebi, E., Kazemi, A., Faramarzi, M., Nasiri, S., Haghighi, MM. (2019). Effects of sprint interval or combined aerobic and resistance training on myokines in overweight women with type 2 diabetes: A randomized controlled trial. Life Sciences. 217:101-9. [DOI:10.1016/j.lfs.2018.11.062]

92. Taniguchi, H., Tanisawa, K., Sun, X., Cao, Z-B., Oshima, S., Ise, R., Sakamoto, S., Higuchi, M. (2014). Cardiorespiratory Fitness and Visceral Fat Are Key Determinants of Serum Fibroblast Growth Factor 21 Concentration in Japanese Men. The Journal of Clinical Endocrinology & Metabolism. 99(10):E1877-E84. [DOI:10.1210/jc.2014-1877]

93. Hamedinia, MR., Firozeh, Z., Haghighi, AH., Ramezani, S. (2019). Effect of 12 weeks of light and heavy interval training on the level of irisin and fibroblast growth factor 21 in obese and overweight women: A clinical trial study. Journal of Gorgan University of Medical Sciences. 21(1):7-14.

94. Alizadeh, L., Tofighi, A., Tolouei Azar, J. (2019). The Effect of 8 Weeks of High Intensity Interval Training (HIIT) On Serum Irisin, FGF21 and Glycemic Indices in Type 2 Diabetic Women. Journal of Applied Health Studies in Sport Physiology. 6(2):17-24.

95. Fereidoonfar, K., Monazzami, A., Razimi, Z., Rahimi, M. (2020). Effects of eight-week resistance training on serum level of βKlotho and FGF21 in diabetic women with non-alcoholic fatty liver disease. Iranian Journal of Physiology and Pharmacology. 4(1):48-39.

96. Astinchap, A., Monazzami, A., Rahimi, Z., Rahimi, M. (2020). The effect of moderate intensity endurance training on some fatty liver and metabolic indices in diabetic women with non-alcoholic fatty liver. Iranian Journal of Physiology and Pharmacology. 4(1):58-49.

97. Motahari Rad, M., Bijeh, N., Attarzadeh Hosseini, SR., Raouf Saeb, A. (2020). The effect of two concurrent exercise modalities on serum concentrations of FGF21, irisin, follistatin, and myostatin in men with type 2 diabetes mellitus. Archives of Physiology and Biochemistry.1-10. [DOI:10.1080/13813455.2020.1829649]

98. Chang, JS., Namkung, J. (2021). Effects of Exercise Intervention on Mitochondrial Stress Biomarkers in Metabolic Syndrome Patients: A Randomized Controlled Trial. International Journal of Environmental Research and Public Health. 18(5):2242-49. [DOI:10.3390/ijerph18052242]

99. Pérez-López, A., Gonzalo-Encabo, P., Pérez-Köhler, B., García-Honduvilla, N., Valadés, D. (2021). Circulating myokines IL-6, IL-15 and FGF21 response to training is altered by exercise type but not by menopause in women with obesity. European Journal of Sport Science.1-22. [DOI:10.1080/17461391.2021.1939430]

100. 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. Journal of Clinical & Translational Endocrinology. 2(2):77-82. [DOI:10.1016/j.jcte.2015.02.001]

101. Villarroya, J., Gallego‐Escuredo, JM., Delgado‐Anglés, A., Cairó, M., Moure, R., Gracia Mateo, M., Domingo, JC., Domingo, P., Giralt, M., Villarroya, F. (2018). Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue. Aging Cell. 17(5):e12822. [DOI:10.1111/acel.12822]

102. Thaane, T., Motala, AA., Mckune, AJ. (2019). Lifestyle modification in the management of insulin resistance states in overweight/obesity: the role of exercise training. Journal of Endocrinology, Metabolism and Diabetes of South Africa. 24(2):65-9. [DOI:10.1080/16089677.2019.1608054]

103. Gimeno, RE., Moller, DE. (2014). FGF21-based pharmacotherapy - potential utility for metabolic disorders. Trends in Endocrinology & Metabolism. 25(6):303-11. [DOI:10.1016/j.tem.2014.03.001]

104. Estall, JL., Ruas, JL., Choi, CS., Laznik, D., Badman, M., Maratos-Flier, E., Shulman, GI., Spiegelman, BM. (2009). PGC-1α negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erbα axis. Proceedings of the National Academy of Sciences. 106(52):22510-5. [DOI:10.1073/pnas.0912533106]

105. Saydi, A., Sheikholeslami-Vatani, D. (2019). The Effect of Resistance Training with High and Moderate Intensities on Lipid Profile, Glycemic Index and FGF21 in Type 2 Diabetic Patients. Sport Physiology & Management Investigations. 11(3):89-103.

106. Recinella, L., Leone, S., Ferrante, C., Chiavaroli, A., Di Nisio, C., Martinotti, S., Vacca, M., Brunetti, L., Orlando, G. (2017). Effects of central fibroblast growth factor 21 (FGF21) in energy balance. Journal of Biological Regulators and Homeostatic Agents. 31(3):603-13.

107. Markan, KR. (2018). Defining "FGF21 Resistance" during obesity: Controversy, criteria and unresolved questions. F1000Research. 7(289): 1-9. [DOI:10.12688/f1000research.14117.1]

108. Lewis, JE., Samms, RJ., Cooper, S., Luckett, JC., Perkins, AC., Adams, AC., Tsintzas, K., Ebling, FJP. (2017). Reduced adiposity attenuates FGF21 mediated metabolic improvements in the Siberian hamster. Scientific Reports. 7(1):4238-46. [DOI:10.1038/s41598-017-03607-x]

109. Taniguchi, H., Tanisawa, K., Sun, X., Kubo, T, Higuchi, M. (2016). Endurance Exercise Reduces Hepatic Fat Content and Serum Fibroblast Growth Factor 21 Levels in Elderly Men. The Journal of Clinical Endocrinology & Metabolism. 101(1):191-8. [DOI:10.1210/jc.2015-3308]

110. Cho, J., Lee, I., Kim, D., Koh, Y., Kong, J., Lee, S., Kang, H. (2014). Effect of aerobic exercise training on non-alcoholic fatty liver disease induced by a high fat diet in C57BL/6 mice. Journal of Exercise Nutrition & Biochemistry. 18(4):339-46. [DOI:10.5717/jenb.2014.18.4.339]

111. Matsui, M., Kosaki, K., Akazawa, N., Tanahashi, K., Kuro-o, M., Maeda, S. (2019). Association between circulating fibroblast growth factor 21, aerobic fitness, and aortic blood pressure in middle-aged and older women. The Journal of Physical Fitness and Sports Medicine. 8(5):195-201. [DOI:10.7600/jpfsm.8.195]

112. Geng, L., Lam, KSL., Xu, A. (2020). The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nature Reviews Endocrinology. 16(11):654-67. [DOI:10.1038/s41574-020-0386-0]