Journal of Isfahan Medical School

Journal of Isfahan Medical School

The Role of Irisin in Various Organs of the Human Body with Emphasis on the Beneficial Effects on Glucose Homeostasis

Document Type : Review Article

Authors
Farzaneh Yazdanimoghaddam 1
Mahmud Aghaei 2
Fouzieh Zadhoush 3
1 Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
2 Associate Professor, Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
3 Assistant Professor, Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
10.48305/jims.2022.16307
Abstract
Maintaining a normal blood glucose level depends on the proper and coordinated functioning of several systems in the body. Understanding the various molecular mechanisms that regulate blood glucose levels has significant implications for maintaining human health. Insulin resistance can alter the secretion of cytokines or peptides called myokines, which are secreted from skeletal muscle tissue after glucose uptake. Irisin is a recently identified myokine secreted by skeletal muscle. Irisin is a secreted form of fibronectin type 111 domain containing-protein5 (FNDC5) with 112 amino acids and 12 kDa molecular weight. Increasing circulating irisin improves insulin resistance, weight control, cardiovascular and brain health. The secretion of this myokine is regulated by skeletal muscle and to a lesser extent by adipose tissue by various factors. The aim of this review study was to investigate the different pathways of irisin signal transduction pathways that lead to the regulation of carbohydrate and lipid metabolism in different tissues of the body in insulin resistance and type 2 diabetes through in vivo and in vitro experiments. The findings of this review study indicate the important role of irisin in regulating metabolic pathways in the human body. Irisin could be considered as a new therapeutic target in the treatment of metabolic diseases such as insulin resistance and type 2 diabetes.
Keywords
Irisin
FNDC5
Diabetes Mellitus Type 2
Glycemic control
Insulin resistance
  1. Lin EE, Scott-Solomon E, Kuruvilla R. Peripheral innervation in the regulation of glucose homeostasis. Trends Neurosci 2021; 44(3): 189-202.
  2. Suh SH, Paik IY, Jacobs K. Regulation of blood glucose homeostasis during prolonged. Mol cells 2007; 23(3): 272-9.
  3. Hemmingsen B, Gimenez‐Perez G, Mauricio D, I Figuls MR, Metzendorf MI, Richter B. Diet, physical activity or both for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus. Cochrane Database Syst Rev 2017; 12(12): CD003054.
  4. Di Felice V, Coletti D, Seelaender M. Editorial: Myokines, adipokines, cytokines in muscle pathophysiology. Front Physiol 2020; 11: 592856.
  5. Gamas L, Matafome P, Seiça R. Irisin and myonectin regulation in the insulin resistant muscle: implications to adipose tissue: muscle crosstalk. J Diabetes Res 2015; 2015: 359159.
  6. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481(7382): 463-8.
  7. Gizaw M, Anandakumar P, Debela T. A review on the role of irisin in insulin resistance and type 2 diabetes mellitus. J Pharmacopuncture 2017; 20(4): 235-42.
  8. Park K, Ahn CW, Park JS, Kim Y, Nam JS. Circulating myokine levels in different stages of glucose intolerance. Medicine (Baltimore) 2020; 99(8): e19235.
  9. Korta P, Pocheć E, Mazur-Biały A. Irisin as a multifunctional protein: implications for health and certain diseases. Medicina (Kaunas) 2019; 55(8): 485.
  10. Raschke S, Elsen M, Gassenhuber H, Sommerfeld M, Schwahn U, Brockmann B, et al. Evidence against a beneficial effect of irisin in humans. PloS One 2013; 8(9): e73680.
  11. Pardo M, Crujeiras AB, Amil M, Aguera Z, Jimenez-Murcia S, Baños R, et al. Association of irisin with fat mass, resting energy expenditure, and daily activity in conditions of extreme body mass index. Int J Endocrinol 2014; 2014: 857270.
  12. Provatopoulou X, Georgiou GP, Kalogera E, Kalles V, Matiatou MA, Papapanagiotou I, et al. Serum irisin levels are lower in patients with breast cancer: association with disease diagnosis and tumor characteristics. BMC Cancer 2015; 15(1): 898.
  13. Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, et al. Irisin mediates effects on bone and fat via αV integrin receptors. Cell 2018; 175(7): 1756-68.
  14. Askari H, Rajani SF, Poorebrahim M, Haghi-Aminjan H, Raeis-Abdollahi E, Abdollahi M. A glance at the therapeutic potential of irisin against diseases involving inflammation, oxidative stress, and apoptosis: an introductory review. Pharmacol Res 2018; 129: 44-55.
  15. Kurdiova T, Balaz M, Mayer A, Maderova D, Belan V, Wolfrum C, et al. Exercise-mimicking treatment fails to increase Fndc5 mRNA & irisin secretion in primary human myotubes. Peptides 2014; 56: 1-7.
  16. Uysal N, Yuksel O, Kizildag S, Yuce Z, Gumus H, Karakilic A, et al. Regular aerobic exercise correlates with reduced anxiety and incresed levels of irisin in brain and white adipose tissue. Neurosci Lett 2018; 676: 92-7.
  17. Huh JY, Siopi A, Mougios V, Park KH, Mantzoros CS. Irisin in response to exercise in humans with and without metabolic syndrome. J Clin Endocrinol Metab 2015; 100(3): E453-E7.
  18. Al‐Daghri NM, Alokail MS, Rahman S, Amer OE, Al‐Attas OS, Alfawaz H, et al. Habitual physical activity is associated with circulating irisin in healthy controls but not in subjects with diabetes mellitus type 2. Eur J Clin Invest 2015; 45(8): 775-81.
  19. Huh JY, Mougios V, Kabasakalis A, Fatouros I, Siopi A, Douroudos II, et al. Exercise-induced irisin secretion is independent of age or fitness level and increased irisin may directly modulate muscle metabolism through AMPK activation. J Clin Endocrinol Metab 2014; 99(11): E2154-61.
  20. Belviranlı M, Okudan N. Exercise training increases cardiac, hepatic and circulating levels of brain-derived neurotrophic factor and irisin in young and aged rats. Horm Mol Biol Clin Investig 2018; 36(3).
  21. Amengual J, García-Carrizo FJ, Arreguín A, Mušinović H, Granados N, Palou A, et al. Retinoic acid increases fatty acid oxidation and irisin expression in skeletal muscle cells and impacts irisin in vivo. Cell Physiol Biochem 2018; 46(1): 187-202.
  22. Safarpour P, Daneshi-Maskooni M, Vafa M, Nourbakhsh M, Janani L, Maddah M, et al. Vitamin D supplementation improves SIRT1, Irisin, and glucose indices in overweight or obese type 2 diabetic patients: a double-blind randomized placebo-controlled clinical trial. BMC Fam Pract 2020; 21(1): 26.
  23. Tung YT, Chiang PC, Chen YL, Chien YW. Effects of melatonin on lipid metabolism and circulating irisin in sprague-dawley rats with diet-induced obesity. Molecules 2020; 25(15): 3329.
  24. Li L, Rampersad S, Wang X, Cheng X, Qu S. Serum irisin concentrations were increased after transient continuous subcutaneous insulin infusion in type 2 diabetes mellitus patients. Diabetes Res Clin Pract 2016; 113: 44-7.
  25. Varela-Rodríguez BM, Pena-Bello L, Juiz-Valiña P, Vidal-Bretal B, Cordido F, Sangiao-Alvarellos S. FNDC5 expression and circulating irisin levels are modified by diet and hormonal conditions in hypothalamus, adipose tissue and muscle. Sci Rep 2016; 6(1): 29898.
  26. Rodríguez A, Becerril S, Méndez-Giménez L, Ramírez B, Sáinz N, Catalán V, et al. Leptin administration activates irisin-induced myogenesis via nitric oxide-dependent mechanisms, but reduces its effect on subcutaneous fat browning in mice. Int J Obes (Lond) 2015; 39(3): 397-407.
  27. Seo DY, Lee SR, Heo JW, No MH, Rhee BD, Ko KS, et al. Ursolic acid in health and disease. Korean J Physiol Pharmacol 2018; 22(3): 235-48.
  28. Sun A, Hu X, Chen H, Ma Y, Yan X, Peng D, et al. Ursolic acid induces white adipose tissue beiging in high-fat-diet obese male mice. Food Funct 2021; 12(14): 6490-501.
  29. Chen SQ, Ding LN, Zeng NX, Liu HM, Zheng SH, Xu JW, et al. Icariin induces irisin/FNDC5 expression in C2C12 cells via the AMPK pathway. Biomed Pharmacother 2019; 115: 108930.
  30. Lanzi CR, Perdicaro DJ, Tudela JG, Muscia V, Fontana AR, Oteiza PI, et al. Grape pomace extract supplementation activates FNDC5/irisin in muscle and promotes white adipose browning in rats fed a high-fat diet. Food Funct 2020; 11(2): 1537-46.
  31. Perakakis N, Triantafyllou GA, Fernández-Real JM, Huh JY, Park KH, Seufert J, et al. Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol 2017; 13(6): 324-37.
  32. Li Q, Jia S, Xu L, Li B, Chen N. Metformin‐induced autophagy and irisin improves INS‐1 cell function and survival in high‐glucose environment via AMPK/SIRT1/PGC‐1α signal pathway. Food Sci Nutr 2019; 7(5): 1695-703.
  33. Deshmukh AS. Insulin-stimulated glucose uptake in healthy and insulin-resistant skeletal muscle. Horm Mol Biol Clin Investig 2016; 26(1): 13-24.
  34. Lee HJ, Lee JO, Kim N, Kim JK, Kim HI, Lee YW, et al. Irisin, a novel myokine, regulates glucose uptake in skeletal muscle cells via AMPK. Mol Endocrinol 2015; 29(6): 873-81.
  35. Xin C, Liu J, Zhang J, Zhu D, Wang H, Xiong L, et al. Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway. Int J Obes (Lond) 2016; 40(3): 443-51.
  36. Vaughan RA, Gannon NP, Barberena MA, Garcia‐Smith R, Bisoffi M, Mermier CM, et al. Characterization of the metabolic effects of irisin on skeletal muscle in vitro. Diabetes Obes Metab 2014; 16(8): 711-8.
  37. Guo Q, Wei X, Hu H, Yang D, Zhang B, Fan X, et al. The saturated fatty acid palmitate induces insulin resistance through Smad3-mediated down-regulation of FNDC5 in myotubes. Biochem Biophys Res Commun 2019; 520(3): 619-26.
  38. Chait A, den Hartigh LJ. Adipose tissue distribution, inflammation and its metabolic consequences, including diabetes and cardiovascular disease. Front Cardiovasc Med 2020; 7: 22.
  39. White JD, Dewal RS, Stanford KI. The beneficial effects of brown adipose tissue transplantation. Mol Aspects Med 2019; 68: 74-81.
  40. Bartelt A, Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol 2014; 10(1): 24-36.
  41. Cui XB, Chen SY. White adipose tissue browning and obesity. J Biomed Res 2017; 31(1): 1-2.
  42. Zhang Y, Xie C, Wang H, Foss RM, Clare M, George EV, et al. Irisin exerts dual effects on browning and adipogenesis of human white adipocytes. Am J Physiol Endocrinol Metab 2016; 311(2): E530-E41.
  43. Purwana I, Zheng J, Li X, Deurloo M, Son DO, Zhang Z, et al. GABA promotes human β-cell proliferation and modulates glucose homeostasis.
    Diabetes 2014; 63(12): 4197-205.
  44. Ma EB, Sahar NE, Jeong M, Huh JY. Irisin exerts inhibitory effect on adipogenesis through regulation of Wnt signaling. Front Physiol 2019; 10: 1085.
  45. Xiong XQ, Chen D, Sun HJ, Ding L, Wang JJ, Chen Q, et al. FNDC5 overexpression and irisin ameliorate glucose/lipid metabolic derangements and enhance lipolysis in obesity. Biochim Biophys Acta 2015; 1852(9): 1867-75.
  46. Gao S, Li F, Li H, Huang Y, Liu Y, Chen Y. Effects and molecular mechanism of GST-irisin on lipolysis and autocrine function in 3T3-L1 adipocytes. PloS One 2016; 11(1): e0147480.
  47. Hashimoto S. Glucose metabolism and liver. In: Ohira H, editor. The liver in systemic diseases. New York, NY: Springer; 2016. p. 77-103.
  48. Rines AK, Sharabi K, Tavares CD, Puigserver P. Targeting hepatic glucose metabolism in the treatment of type 2 diabetes. Nat Rev Drug Discov 2016; 15(11): 786-804.
  49. Liu TY, Shi CX, Gao R, Sun HJ, Xiong XQ, Ding L, et al. Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K/Akt pathway in type 2 diabetic mice and hepatocytes. Clin Sci (Lond) 2015; 129(10): 839-50.
  50. Mo L, Shen J, Liu Q, Zhang Y, Kuang J, Pu S, et al. Irisin is regulated by CAR in liver and is a mediator of hepatic glucose and lipid metabolism. Mol Endocrinol 2016; 30(5): 533-42.
  51. Yu L, Wang Z, Huang M, Li Y, Zeng K, Lei J, et al. Evodia alkaloids suppress gluconeogenesis and lipogenesis by activating the constitutive androstane receptor. Biochim Biophys Acta 2016; 1859(9): 1100-11.
  52. Jiao Y, Lu Y, Li XY. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis. Acta Pharmacol Sin 2015; 36(1): 44-50.
  53. Hayatmoghadam B, Zadhoush F, Amirkhani F, Pourfarzam M. Cholesterol synthesis and absorption markers in type 2 diabetes mellitus. J Isfahan Med Sch 2019; 37(519): 214-21. [In Persian].
  54. Park MJ, Kim DI, Choi JH, Heo YR, Park SH. New role of irisin in hepatocytes: The protective effect of hepatic steatosis in vitro. Cell Signal 2015; 27(9): 1831-9.
  55. Kim DI, Park MJ, Lim SK, Park JI, Yoon KC, Han HJ, et al. PRMT3 regulates hepatic lipogenesis through direct interaction with LXRα. Diabetes 2015; 64(1): 60-71.
  56. Remedi MS, Emfinger C. Pancreatic β‐cell identity in diabetes. Diabetes Obes Metab 2016; 18(Suppl 1): 110-6.
  57. Zhong F, Jiang Y. Endogenous pancreatic β cell regeneration: a potential strategy for the recovery of β cell deficiency in diabetes. Front Endocrinol (Lausanne) 2019; 10: 101.
  58. Natalicchio A, Marrano N, Biondi G, Spagnuolo R, Labarbuta R, Porreca I, et al. The myokine irisin is released in response to saturated fatty acids and promotes pancreatic β-cell survival and insulin secretion. Diabetes 2017; 66(11): 2849-56.
  59. Zhang D, Xie T, Leung PS. Irisin ameliorates glucolipotoxicity-Associated β-Cell dysfunction and apoptosis via AMPK signaling and anti-inflammatory actions. Cell Physiol Biochem 2018; 51(2): 924-37.
  60. Liu S, Du F, Li X, Wang M, Duan R, Zhang J, et al. Effects and underlying mechanisms of irisin on the proliferation and apoptosis of pancreatic β cells. PloS One 2017; 12(4): e0175498.
  61. Kenny HC, Abel ED. Heart failure in type 2 diabetes mellitus: impact of glucose-lowering agents, heart failure therapies, and novel therapeutic strategies. Circ Res 2019; 124(1): 121-41.
  62. Pourfarzam M, Zadhoush F, Sadeghi M. The difference in correlation between insulin resistance index and chronic inflammation in type 2 diabetes with and without metabolic syndrome. Adv Biomed Res 2016; 5: 153.
  63. Zadhoush F, Sadeghi M, Pourfarzam M. Biochemical changes in blood of type 2 diabetes with and without metabolic syndrome and their association with metabolic syndrome components. J Res Med Sci 2015; 20(8): 763-70.
  64. Najafi A, Pourfarzam M, Zadhoush F. Oxidant/antioxidant status in Type-2 diabetes mellitus patients with metabolic syndrome. J Res Med Sci 2021; 26: 6.
  65. Wang Z, Chen K, Han Y, Zhu H, Zhou X, Tan T, et al. Irisin protects heart against ischemia-reperfusion injury through a SOD2-dependent mitochondria mechanism. J Cardiovasc Pharmacol 2018; 72(6): 259-69.
  66. Zhang Y, Mu Q, Zhou Z, Song H, Zhang Y, Wu F, et al. Protective effect of irisin on atherosclerosis via suppressing oxidized low density lipoprotein induced vascular inflammation and endothelial dysfunction. PloS One 2016; 11(6): e0158038.
  67. Xin C, Zhang Z, Gao G, Ding L, Yang C, Wang C, et al. Irisin attenuates myocardial ischemia/reperfusion injury and improves mitochondrial function through AMPK pathway in diabetic mice. Front Pharmacol 2020; 11: 565160.
  68. Wang J, Zhao YT, Zhang L, Dubielecka PM, Zhuang S, Qin G, et al. Irisin improves myocardial performance and attenuates insulin resistance in spontaneous mutation (Leprdb) mice. Front Pharmacol 2020; 11: 769.
  69. Song R, Zhao X, Cao R, Liang Y, Zhang DQ, Wang R. Irisin improves insulin resistance by inhibiting autophagy through the PI3K/Akt pathway in H9c2 cells. Gene 2021; 769: 145209.
  70. Deng J, Zhang N, Chen F, Yang C, Ning H, Xiao C, et al. Irisin ameliorates high glucose‐induced cardiomyocytes injury via AMPK/mTOR signal pathway. Cell Biol Int 2020; 44(11): 2315-25.
  71. Munoz IYM, Romero EdS, de Jesus Garduno Garcia J. Irisin a novel metabolic biomarker: present knowledge and future directions. Int J Endocrinol 2018; 2018: 7816806.
  72. Huang L, Yan S, Luo L, Yang L. Irisin regulates the expression of BDNF and glycometabolism in diabetic rats. Mol Med Rep 2019; 19(2): 1074-82.
  73. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab 2013; 18(5): 649-59.
  74. Li DJ, Li YH, Yuan HB, Qu LF, Wang P. The novel exercise-induced hormone irisin protects against neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotection of physical exercise in cerebral ischemia. Metabolism 2017; 68: 31-42.
  75. Wang K, Song F, Xu K, Liu Z, Han S, Li F, et al. Irisin attenuates neuroinflammation and prevents the memory and cognitive deterioration in streptozotocin-induced diabetic mice. Mediators Inflamm 2019; 2019: 1567179.
  76. Li H, Wang F, Yang M, Sun J, Zhao Y, Tang D. The effect of irisin as a metabolic regulator and its therapeutic potential for obesity. Int J Endocrinol 2021; 2021: 6572342.
Journal of Isfahan Medical School
Volume 40, Issue 660
4th Week, April
March and April 2022
Pages 84-94

  • Receive Date 23 April 2022