Myokines and adipomyokines: inflammatory mediators or unique molecules of targeted therapy for obesity?

Skeletal muscles make up about 25% of the total mass in children and more than 40% in adults. Studies of the last twenty years have shown that along with the main functions, muscle tissue has hormonal activity. It was found that myocytes are able to release signaling molecules-myokines. They act auto-and paracrine within the muscle, and at a high level-through the systemic circulation, carrying out interactions between skeletal muscles and various organs and tissues, such as the liver, bone and adipose tissue, the brain. It is proved that the key factor in the expression of myokines is physical activity, and their level largely depends on physical fitness, the amount of skeletal muscle mass and its composition (the ratio of fast and slow fibers), on the intensity and duration of physical activity. Myokines have a wide range of physiological effects: myostatin suppresses the growth and differentiation of muscle tissue, and decorin, acting as its antagonist, promotes muscle hypertrophy. Interleukin 6 provides an energy substrate for contracting muscle fibers, fibroblast growth factor 21 activates the mechanisms of energy production during fasting and improves tissue sensitivity to insulin; irisin stimulates thermogenesis, glucose uptake by myocytes, and also contributes to an increase in bone mineral density. The study of myokines is one of the key links in understanding the mechanisms underlying obesity and metabolic complications, the consequences of a sedentary lifestyle, as well as the implementation of the action of physical activity. Taking into account the physiological effects of myokines in the body, in the future they can become therapeutic targets for the treatment of these conditions.

1. Steensberg A, Hall G, Osada T, et al. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol. 2000;529(1):237-242. doi: https://doi.org/10.1111/j.1469-7793.2000.00237.x

2. Handschin C, Spiegelman BM. The role of exercise and PGC1α in inflammation and chronic disease. Nature. 2008;454(7203):463-469. doi: https://doi.org/10.1038/nature07206

3. Yudkin J. Inflammation, Obesity, and the Metabolic Syndrome. Horm Metab Res. 2007;39(10):707-709. doi: https://doi.org/10.1055/s-2007-985898.

4. DeFronzo RA, Tripathy D. Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes. Diabetes Care. 2009;32(suppl_2):S157-S163. doi: https://doi.org/10.2337/dc09-S302

5. He Z, Tian Y, Valenzuela PL, et al. Myokine/Adipokine Response to “Aerobic” Exercise: Is It Just a Matter of Exercise Load? Front Physiol. 2019;10(4):1379-1406. doi: https://doi.org/10.3389/fphys.2019.00691

6. Pedersen BK, Febbraio MA. Muscle as an Endocrine Organ: Focus on Muscle-Derived Interleukin-6. Physiol Rev. 2008;88(4):1379-1406. doi: https://doi.org/10.1152/physrev.90100.2007

7. Löffler D, Müller U, Scheuermann K, et al. Serum Irisin Levels Are Regulated by Acute Strenuous Exercise. J Clin Endocrinol Metab. 2015;100(4):1289-1299. doi: https://doi.org/10.1210/jc.2014-2932

8. Laurens C, Bergouignan A, Moro C. Exercise-Released Myokines in the Control of Energy Metabolism. Front Physiol. 2020;11:91. doi: https://doi.org/10.3389/fphys.2020.00091

9. Ahima RS, Park H-K. Connecting Myokines and Metabolism. Endocrinol Metab. 2015;30(3):235. doi: https://doi.org/10.3803/EnM.2015.30.3.235

10. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997;387(6628):83–90.

11. Rı́os R, Carneiro I, Arce VM, Devesa J. Myostatin is an inhibitor of myogenic differentiation. Am J Physiol Physiol. 2002;282(5):C993-C999. doi: https://doi.org/10.1152/ajpcell.00372.2001

12. Taylor WE, Bhasin S, Artaza J, et al. Myostatin inhibits cell proliferation and protein synthesis in C 2 C 12 muscle cells. Am J Physiol Metab. 2001;280(2):E221-E228. doi: https://doi.org/10.1152/ajpendo.2001.280.2.E221

13. Braun T, Gautel M. Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis. Nat Rev Mol Cell Biol. 2011;12(6):349-361. doi: https://doi.org/10.1038/nrm3118

14. Han HQ, Zhou X, Mitch WE, Goldberg AL. Myostatin/activin pathway antagonism: Molecular basis and therapeutic potential. Int J Biochem Cell Biol. 2013;45(10):2333-2347. doi: https://doi.org/10.1016/j.biocel.2013.05.019

15. Lee S-J. Sprinting without myostatin: a genetic determinant of athletic prowess. Trends Genet. 2007;23(10):475-477. doi: https://doi.org/10.1016/j.tig.2007.08.008

16. Grobet L, Royo Martin LJ, Poncelet D, et al. A deletion in the bovine myostatin gene causes the double–muscled phenotype in cattle. Nat Genet. 1997;17(1):71-74. doi: https://doi.org/10.1038/ng0997-71

17. Mosher DS, Quignon P, Bustamante CD, et al. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet. 2007;3(5):779-786. doi: https://doi.org/10.1371/journal.pgen.0030079

18. Matsakas A, Friedel A, Hertrampf T, Diel P. Short-term endurance training results in a muscle-specific decrease of myostatin mRNA content in the rat. Acta Physiol Scand. 2005;183(3):299-307. doi: https://doi.org/10.1111/j.1365-201X.2005.01406.x

19. Kainulainen H, Papaioannou KG, Silvennoinen M, et al. Myostatin/ activin blocking combined with exercise reconditions skeletal muscle expression profile of mdx mice. Mol Cell Endocrinol. 2015;399:131-142. doi: https://doi.org/10.1016/j.mce.2014.10.001

20. Ko IG, Jeong JW, Kim YH, et al. Aerobic Exercise Affects Myostatin Expression in Aged Rat Skeletal Muscles: A Possibility of Antiaging Effects of Aerobic Exercise Related With Pelvic Floor Muscle and Urethral Rhabdosphincter. Int Neurourol J. 2014;18(2):77. doi: https://doi.org/10.5213/inj.2014.18.2.77

21. Hittel DS, Axelson M, Sarna N, et al. Myostatin Decreases with Aerobic Exercise and Associates with Insulin Resistance. Med Sci Sport Exerc. 2010;42(11):2023-2029. doi: https://doi.org/10.1249/MSS.0b013e3181e0b9a8.

22. Ryan AS, Li G, Blumenthal JB, Ortmeyer HK. Aerobic exercise + weight loss decreases skeletal muscle myostatin expression and improves insulin sensitivity in older adults. Obesity. 2013;21(7):1350-1356. doi: https://doi.org/10.1002/oby.20216

23. Allen DL, Cleary AS, Speaker KJ, et al. Myostatin, activin receptor IIb, and follistatin-like-3 gene expression are altered in adipose tissue and skeletal muscle of obese mice. Am J Physiol Metab. 2008;294(5):E918-E927. doi: https://doi.org/10.1152/ajpendo.00798.2007

24. Li F, Yang H, Duan Y, Yin Y. Myostatin regulates preadipocyte differentiation and lipid metabolism of adipocyte via ERK1/2. Cell Biol Int. 2011;35(11):1141-1146. doi: https://doi.org/10.1042/CBI20110112

25. Guo T, Jou W, Chanturiya T, et al. Myostatin Inhibition in Muscle, but Not Adipose Tissue, Decreases Fat Mass and Improves Insulin Sensitivity. Calbet JAL, ed. PLoS One. 2009;4(3):e4937. doi: https://doi.org/10.1371/journal.pone.0004937

26. Bond ND, Guo J, Hall KD, McPherron AC. Modeling Energy Dynamics in Mice with Skeletal Muscle Hypertrophy Fed High Calorie Diets. Int J Biol Sci. 2016;12(5):617-630. doi: https://doi.org/10.7150/ijbs.13525

27. Zhang C, McFarlane C, Lokireddy S, et al. Myostatindeficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway. Diabetologia. 2011;54(6):1491-1501. doi: https://doi.org/10.1007/s00125-011-2079-7

28. Qin Y, Peng Y, Zhao W, et al. Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: A novel mechanism in muscle-bone communication. J Biol Chem. 2017;292(26):11021-11033. doi: https://doi.org/10.1074/jbc.M116.770941

29. Droguett R, Cabello-Verrugio C, Riquelme C, Brandan E. Extracellular proteoglycans modify TGF-β bio-availability attenuating its signaling during skeletal muscle differentiation. Matrix Biol. 2006;25(6):332-341. doi: https://doi.org/10.1016/j.matbio.2006.04.004

30. Kanzleiter T, Rath M, Görgens SW, et al. The myokine decorin is regulated by contraction and involved in muscle hypertrophy. Biochem Biophys Res Commun. 2014;450(2):1089-1094. doi: https://doi.org/10.1016/j.bbrc.2014.06.123

31. Amthor H, Nicholas G, McKinnell I, et al. Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis. Dev Biol. 2004. doi: https://doi.org/10.1016/j.ydbio.2004.01.046

32. Zhu J, Li Y, Shen W, et al. Relationships between Transforming Growth Factor-β1, Myostatin, and Decorin. J Biol Chem. 2007;282(35):25852-25863. doi: https://doi.org/10.1074/jbc.M704146200

33. Kharitonenkov A, Adams AC. Inventing new medicines: The FGF21 story. Mol Metab. 2014;3(3):221-229. doi: https://doi.org/10.1016/j.molmet.2013.12.003

34. Martínez-Garza Ú, Torres-Oteros D, et al. Fibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges. Int J Mol Sci. 2019;20(19):4692. doi: https://doi.org/10.3390/ijms20194692

35. Inagaki T, Dutchak P, Zhao G, et al. Endocrine Regulation of the Fasting Response by PPARα-Mediated Induction of Fibroblast Growth Factor 21. Cell Metab. 2007;5(6):415-425. doi: https://doi.org/10.1016/j.cmet.2007.05.003

36. Izumiya Y, Bina HA, Ouchi N, et al. FGF21 is an Aktregulated myokine. FEBS Lett. 2008;582(27):3805-3810. doi: https://doi.org/10.1016/j.febslet.2008.10.021

37. Fazeli PK, Lun M, Kim SM, et al. FGF21 and the late adaptive response to starvation in humans. J Clin Invest. 2015;125(12):4601-4611. doi: https://doi.org/10.1172/JCI83349

38. Jimenez V, Jambrina C, Casana E, et al. FGF21 gene therapy as treatment for obesity and insulin resistance. EMBO Mol Med. 2018;10(8). doi: https://doi.org/10.15252/emmm.201708791

39. Ritchie M, Hanouneh IA, Noureddin M, et al. Fibroblast growth factor (FGF)-21 based therapies: A magic bullet for nonalcoholic fatty liver disease (NAFLD)? Expert Opin Investig Drugs. 2020;29(2):197-204. doi: https://doi.org/10.1080/13543784.2020.1718104

40. Zarei M, Barroso E, Palomer X, et al. Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates nonalcoholic fatty liver disease. Mol Metab. 2018;8:117-131. doi: https://doi.org/10.1016/j.molmet.2017.12.008

41. Hojman P, Pedersen M, Nielsen AR, et al. Fibroblast Growth Factor-21 Is Induced in Human Skeletal Muscles by Hyperinsulinemia. Diabetes. 2009;58(12):2797-2801. doi: https://doi.org/10.2337/db09-0713

42. Samms RJ, Lewis JE, Norton L, et al. FGF21 Is an Insulin-Dependent Postprandial Hormone in Adult Humans. J Clin Endocrinol Metab. 2017;102(10):3806-3813. doi: https://doi.org/10.1210/jc.2017-01257

43. Khalafi M, Alamdari KA, Symonds ME, et al. Impact of acute exercise on immediate and following early postexercise FGF-21 concentration in adults: systematic review and meta-analysis. Hormones. 2021;20(1):23-33. doi: https://doi.org/10.1007/s42000-020-00245-3

44. Hansen JS, Pedersen BK, Xu G, et al. Exercise-Induced Secretion of FGF21 and Follistatin Are Blocked by Pancreatic Clamp and Impaired in Type 2 Diabetes. J Clin Endocrinol Metab. 2016;101(7):2816-2825. doi: https://doi.org/10.1210/jc.2016-1681

45. Boström P, Wu J, Jedrychowski MP, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-468. doi: https://doi.org/10.1038/nature10777

46. Raschke S, Elsen M, Gassenhuber H, et al. Evidence against a Beneficial Effect of Irisin in Humans. López-Lluch G, ed. PLoS One. 2013;8(9):e73680. doi: https://doi.org/10.1371/journal.pone.0073680

47. Gerhard GS, Styer AM, Strodel WE, et al. Gene expression profiling in subcutaneous, visceral and epigastric adipose tissues of patients with extreme obesity. Int J Obes. 2014;38(3):371-378. doi: https://doi.org/10.1038/ijo.2013.152

48. Kim H, Wrann CD, Jedrychowski M, et al. Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Cell. 2018;175(7):1756-1768. doi: https://doi.org/10.1016/j.cell.2018.10.025

49. Conde J, Scotece M, Gómez R, et al. Adipokines: Biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity. BioFactors. 2011;37(6):413-420. doi: https://doi.org/10.1002/biof.185

50. Moreno-Navarrete JM, Ortega F, Serrano M, et al. Irisin Is Expressed and Produced by Human Muscle and Adipose Tissue in Association With Obesity and Insulin Resistance. J Clin Endocrinol Metab. 2013;98(4):E769-E778. doi: https://doi.org/10.1210/jc.2012-2749

51. Huh JY, Panagiotou G, Mougios V, et al. FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise. Metabolism. 2012;61(12):1725-1738. doi: https://doi.org/10.1016/j.metabol.2012.09.002

52. Perakakis N, Triantafyllou GA, Fernández-Real JM, et al. Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol. 2017;13(6):324-337. doi: https://doi.org/10.1038/nrendo.2016.221

53. Xin C, Liu J, Zhang J, et al. Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway. Int J Obes. 2016;40(3):443-451. doi: https://doi.org/10.1038/ijo.2015.199

54. Zhang Y, Li R, Meng Y, et al. Irisin Stimulates Browning of White Adipocytes Through Mitogen-Activated Protein Kinase p38 MAP Kinase and ERK MAP Kinase Signaling. Diabetes. 2014;63(2):514-525. doi: https://doi.org/10.2337/db13-1106

55. Xiong X-Q, Chen D, Sun H-J, et al. FNDC5 overexpression and irisin ameliorate glucose/lipid metabolic derangements and enhance lipolysis in obesity. Biochim Biophys Acta - Mol Basis Dis. 2015;1852(9):1867-1875. doi: https://doi.org/10.1016/j.bbadis.2015.06.017

56. Miyamoto-Mikami E, Sato K, Kurihara T, et al. Endurance TrainingInduced Increase in Circulating Irisin Levels Is Associated with Reduction of Abdominal Visceral Fat in Middle-Aged and Older Adults. Kaser S, ed. PLoS One. 2015;10(3):e0120354. doi: https://doi.org/10.1371/journal.pone.0120354

57. Park M-J, Kim D-I, Choi J-H, et al. New role of irisin in hepatocytes: The protective effect of hepatic steatosis in vitro. Cell Signal. 2015;27(9):1831-1839. doi: https://doi.org/10.1016/j.cellsig.2015.04.010

58. Crujeiras AB, Pardo M, Arturo R-R, et al. Longitudinal variation of circulating irisin after an energy restriction-induced weight loss and following weight regain in obese men and women. Am J Hum Biol. 2014;26(2):198-207. doi: https://doi.org/10.1002/ajhb.22493

59. Gutierrez-Repiso C, Garcia-Serrano S, Rodriguez-Pacheco F, et al. FNDC5 could be regulated by leptin in adipose tissue. Eur J Clin Invest. 2014;44(10):918-925. doi: https://doi.org/10.1111/eci.12324

60. Pardo M, Crujeiras AB, Amil M, 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;2014:1-9. doi: https://doi.org/10.1155/2014/857270

61. Stengel A, Hofmann T, Goebel-Stengel M, et al. Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity – Correlation with body mass index. Peptides. 2013;39:125-130. doi: https://doi.org/10.1016/j.peptides.2012.11.014

62. Crujeiras AB, Zulet MA, Lopez-Legarrea P, et al. Association between circulating irisin levels and the promotion of insulin resistance during the weight maintenance period after a dietary weightlowering program in obese patients. Metabolism. 2014;63(4):520-531. doi: https://doi.org/10.1016/j.metabol.2013.12.007

63. Huerta AE, Prieto-Hontoria PL, Fernández-Galilea M, et al. Circulating irisin and glucose metabolism in overweight/obese women: effects of α-lipoic acid and eicosapentaenoic acid. J Physiol Biochem. 2015;71(3):547-558. doi: https://doi.org/10.1007/s13105-015-0400-5

64. Liu J-J, Wong MDS, Toy WC, et al. Lower circulating irisin is associated with type 2 diabetes mellitus. J Diabetes Complications. 2013;27(4):365-369. doi: https://doi.org/10.1016/j.jdiacomp.2013.03.002

65. Qiu S, Cai X, Yin H, et al. Association between circulating irisin and insulin resistance in non-diabetic adults: A meta-analysis. Metabolism. 2016;65(6):825-834. doi: https://doi.org/10.1016/j.metabol.2016.02.006

66. Polyzos SA, Kountouras J, Shields K, Mantzoros CS. Irisin: A renaissance in metabolism? Metabolism. 2013;62(8):1037-1044. doi: https://doi.org/10.1016/j.metabol.2013.04.008

67. Espes D, Lau J, Carlsson PO. Increased levels of irisin in people with long-standing Type 1 diabetes. Diabet Med. 2015;32(9):1172-1176. doi: https://doi.org/10.1111/dme.12731

68. Ates I, Arikan MF, Erdogan K, et al. Factors associated with increased irisin levels in the type 1 diabetes mellitus. Endocr Regul. 2017;51(1):1-7. doi: https://doi.org/10.1515/enr-2017-0001

69. Zhang C, Ding Z, Lv G, et al. Lower irisin level in patients with type 2 diabetes mellitus: A case-control study and meta-analysis. J Diabetes. 2016;8(1):56-62. doi: https://doi.org/10.1111/1753-0407.12256

70. Shoukry A, Shalaby SM, El-Arabi Bdeer S, et al. Circulating serum irisin levels in obesity and type 2 diabetes mellitus. IUBMB Life. 2016;68(7):544-556. doi: https://doi.org/10.1002/iub.1511

71. Du X, Jiang W, Lv Z. Lower Circulating Irisin Level in Patients with Diabetes Mellitus: A Systematic Review and Meta-Analysis. Horm Metab Res. 2016;48(10):644-652. doi: https://doi.org/10.1055/s-0042-108730

72. Akour A, Kasabri V, Boulatova N, et al. Levels of metabolic markers in drug-naive prediabetic and type 2 diabetic patients. Acta Diabetol. 2017;54(2):163-170. doi: https://doi.org/10.1007/s00592-016-0926-1

73. Soyal S, Krempler F, Oberkofler H, Patsch W. PGC-1α: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes. Diabetologia. 2006;49(7):1477-1488. doi: https://doi.org/10.1007/s00125-006-0268-6

74. Lu Y, Li H, Shen S-W, et al. Swimming exercise increases serum irisin level and reduces body fat mass in highfat-diet fed Wistar rats. Lipids Health Dis. 2016;15(1):93. doi: https://doi.org/10.1186/s12944-016-0263-y

75. Yang X-Q, Yuan H, Li J, et al. Swimming intervention mitigates HFDinduced obesity of rats through PGC-1α-irisin pathway. Eur Rev Med Pharmacol Sci. 2016;20(10):2123-2130.

76. Morton TL, Galior K, McGrath C, et al. Exercise Increases and Browns Muscle Lipid in High-Fat Diet-Fed Mice. Front Endocrinol (Lausanne). 2016;7:80. doi: https://doi.org/10.3389/fendo.2016.00080

77. Blüher S, Panagiotou G, Petroff D, et al. Effects of a 1-year exercise and lifestyle intervention on irisin, adipokines, and inflammatory markers in obese children. Obesity. 2014;22(7):1701-1708. doi: https://doi.org/10.1002/oby.20739

78. Rodríguez A, Becerril S, Méndez-Giménez L, 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. 2015;39(3):397-407. doi: https://doi.org/10.1038/ijo.2014.166

79. Reinehr T, Elfers C, Lass N, Roth CL. Irisin and Its Relation to Insulin Resistance and Puberty in Obese Children: A Longitudinal Analysis. J Clin Endocrinol Metab. 2015;100(5):2123-2130. doi: https://doi.org/10.1210/jc.2015-1208

80. Soininen S, Sidoroff V, Lindi V, Mahonen A, Kröger L, Kröger H, et al. Body fat mass, lean body mass and associated biomarkers as determinants of bone mineral density in children 6–8years of age — The Physical Activity and Nutrition in Children (PANIC) study. Bone. 2018 Mar;108:106–14.

81. Singhal V, Lawson EA, Ackerman KE, et al. Irisin levels are lower in young amenorrheic athletes compared with eumenorrheic athletes and non-athletes and are associated with bone density and strength estimates. PLoS One. 2014;9(6):e100218. doi: https://doi.org/10.1016/j.bone.2018.01.003

82. Kaji H. Effects of myokines on bone. Bonekey Rep. 2016;5:826. doi: https://doi.org/10.1038/bonekey.2016.48

83. Qiao X, Nie Y, Ma Y, et al. Irisin promotes osteoblast proliferation and differentiation via activating the MAP kinase signaling pathways. Sci Rep. 2016;6(1):18732. doi: https://doi.org/10.1038/srep18732

84. Sopasakis VR, Sandqvist M, Gustafson B, et al. High Local Concentrations and Effects on Differentiation Implicate Interleukin-6 as a Paracrine Regulator. Obes Res. 2004;12(3):454-460. doi: https://doi.org/10.1038/oby.2004.51

85. Carey AL, Bruce CR, Sacchetti M, et al. Interleukin-6 and tumor necrosis factor-? are not increased in patients with Type 2 diabetes: evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness. Diabetologia. 2004;47(6):2084-2089. doi: https://doi.org/10.1007/s00125-004-1403-x

86. Bastard JP, Maachi M, Van Nhieu JT, et al. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab. 2002. doi: https://doi.org/10.1210/jcem.87.5.8450

87. Lyngsø D, Simonsen L, Bülow J. Metabolic effects of interleukin-6 in human splanchnic and adipose tissue. J Physiol. 2002;543(1):379-386. doi: https://doi.org/10.1113/jphysiol.2002.021022

88. Trujillo ME, Sullivan S, Harten I, et al. Interleukin-6 Regulates Human Adipose Tissue Lipid Metabolism and Leptin Production in Vitro. J Clin Endocrinol Metab. 2004;89(11):5577-5582. doi: https://doi.org/10.1210/jc.2004-0603

89. Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) Induces Insulin Resistance in 3T3-L1 Adipocytes and Is, Like IL-8 and Tumor Necrosis Factor-α, Overexpressed in Human Fat Cells from Insulin-resistant Subjects. J Biol Chem. 2003;278(46):45777-45784. doi: https://doi.org/10.1074/jbc.M301977200

90. Tsigos C, Papanicolaou DA, Kyrou I, Defensor R, Mitsiadis CS, Chrousos GP. Dose-Dependent Effects of Recombinant Human Interleukin-6 on Glucose Regulation. J Clin Endocrinol Metab. 1997;82(12):4167-4170. doi: https://doi.org/10.1210/jcem.82.12.4422

91. Stouthard JML, Oude Elferink RPJ, Sauerwein HP. Interleukin-6 Enhances Glucose Transport in 3T3-L1 Adipocytes. Biochem Biophys Res Commun. 1996;220(2):241-245. doi: https://doi.org/10.1006/bbrc.1996.0389

92. Kanemaki T, Kitade H, Kaibori M, et al. Interleukin-1 and interleukin 6, but not tumor necrosis factor, inhibit insulin-stimulated glycogen synthesis in rat hepatocytes. Hepatology. 1998;27(5):1296-1303. doi: https://doi.org/10.1002/hep.510270515

93. Starr R, Willson TA, Viney EM, et al. A family of cytokine-inducible inhibitors of signalling. Nature. 1997;387(6636):917-921. doi: https://doi.org/10.1038/43206

94. Febbraio MA, Hiscock N, Sacchetti M, et al. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes. 2004;53(7):1643-1648. doi: https://doi.org/10.2337/diabetes.53.7.1643

95. Hiscock N, Chan MHS, Bisucci T, Darby IA, Febbraio MA. Skeletal myocytes are a source of interleukin-6 mRNA expression and protein release during contraction: evidence of fiber type specificity. FASEB J. 2004;18(9):992-994. doi: https://doi.org/10.1096/fj.03-1259fje

96. Steensberg A, Febbraio MA, Osada T, et al. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol. 2001;537(2):633-639. doi: https://doi.org/10.1111/j.1469-7793.2001.00633.x

97. van Hall G, Steensberg A, Sacchetti M, et al. Interleukin-6 Stimulates Lipolysis and Fat Oxidation in Humans. J Clin Endocrinol Metab. 2003;88(7):3005-3010. doi: https://doi.org/10.1210/jc.2002-021687

98. Lee NK, Sowa H, Hinoi E, et al. Endocrine Regulation of Energy Metabolism by the Skeleton. Cell. 2007;130(3):456-469. doi: https://doi.org/10.1016/j.cell.2007.05.047

99. Lin C-F, Huang T, Tu K-C, et al. Acute effects of plyometric jumping and intermittent running on serum bone markers in young males. Eur J Appl Physiol. 2012;112(4):1475-1484. doi: https://doi.org/10.1007/s00421-011-2108-8

100. Ahn N, Kim K. Effects of 12-week exercise training on osteocalcin, high-sensitivity C-reactive protein concentrations, and insulin resistance in elderly females with osteoporosis. J Phys Ther Sci. 2016;28(8):2227-2231. doi: https://doi.org/10.1589/jpts.28.2227

101. Kim Y-S, Nam JS, Yeo D-W, et al. The effects of aerobic exercise training on serum osteocalcin, adipocytokines and insulin resistance on obese young males. Clin Endocrinol (Oxf ). 2015;82(5):686-694. doi: https://doi.org/10.1111/cen.12601

102. Mera P, Laue K, Wei J, et al. Osteocalcin is necessary and sufficient to maintain muscle mass in older mice. Mol Metab. 2016;5(10):1042-1047. doi: https://doi.org/10.1016/j.molmet.2016.07.002

103. Chowdhury S, Schulz L, Palmisano B, et al. Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts. J Clin Invest. 2020;130(6):2888-2902. doi: https://doi.org/10.1172/JCI133572