Myokines: metabolic regulation in obesity and type 2 diabetes

Abstract

Skeletal muscle plays a vital role in the regulation of systemic metabolism, partly through its secretion of endocrine factors which are collectively known as myokines. Altered myokine levels are associated with metabolic diseases, such as type 2 diabetes (T2D). The significance of interorgan crosstalk, particularly through myokines, has emerged as a fundamental aspect of nutrient and energy homeostasis. However, a comprehensive understanding of myokine biology in the setting of obesity and T2D remains a major challenge. In this review, we discuss the regulation and biological functions of key myokines that have been extensively studied during the past two decades, namely interleukin 6 (IL-6), irisin, myostatin (MSTN), growth differentiation factor 11 (GDF11), fibroblast growth factor 21 (FGF21), apelin, brain-derived neurotrophic factor (BDNF), meteorin-like (Metrnl), secreted protein acidic and rich in cysteine (SPARC), β-aminoisobutyric acid (BAIBA), Musclin, and Dickkopf 3 (Dkk3). Related to these, we detail the role of exercise in myokine expression and secretion together with their contributions to metabolic physiology and disease. Despite significant advancements in myokine research, many myokines remain challenging to measure accurately and investigate thoroughly. Hence, new research techniques and detection methods should be developed and rigorously tested. Therefore, developing a comprehensive perspective on myokine biology is crucial, as this will likely offer new insights into the pathophysiological mechanisms underlying obesity and T2D and may reveal novel targets for therapeutic interventions.

Key words： myokines; skeletal muscle; obesity; type 2 diabetes; metabolism

References

1 Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 2012; 8: 457- 65.

2 Azzu V, Vacca M, Virtue S et al. Adipose tissue-liver cross talk in the control of whole-body metabolism: implications in nonalcoholic fatty liver disease. Gastroenterology 2020; 158: 1899- 912.

3 López-Bermudo L, Luque-Sierra A, Maya-Miles D et al. Contribution of liver and pancreatic islet crosstalk to β-cell function/dysfunction in the presence of fatty liver. Front Endocrinol (Lausanne) 2022; 13: 892672.

4 Yoo ES, Yu J, Sohn JW. Neuroendocrine control of appetite and metabolism. Exp Mol Med 2021; 53: 505- 16.

5 Martinez-Sanchez N, Sweeney O, Sidarta-Oliveira D et al. The sympathetic nervous system in the 21st century: neuroimmune interactions in metabolic homeostasis and obesity. Neuron 2022; 110: 3597- 626.

6 Severinsen MCK, Pedersen BK. Muscle-organ crosstalk: the emerging roles of myokines. Endocr Rev 2020; 41: 594- 609.

7 Ntikoudi E, Kiagia M, Boura P et al. Hormones of adipose tissue and their biologic role in lung cancer. Cancer Treat Rev 2014; 40: 22- 30.

8 Klepac K, Georgiadi A, Tschöp M et al. The role of brown and beige adipose tissue in glycaemic control. Mol Aspects Med 2019; 68: 90- 100.

9 de Oliveira Dos Santos AR et al. Adipokines, myokines, and hepatokines: crosstalk and metabolic repercussions. Int J Mol Sci 2021; 22: 2639.

10 Bondue B, Wittamer V, Parmentier M. Chemerin and its receptors in leukocyte trafficking, inflammation and metabolism. Cytokine Growth Factor Rev 2011; 22: 331- 8.

11 Shabir K, Brown JE, Afzal I et al. Asprosin, a novel pleiotropic adipokine implicated in fasting and obesity-related cardio-metabolic disease: comprehensive review of preclinical and clinical evidence. Cytokine Growth Factor Rev 2021; 60: 120- 32.

12 Stefan N, Häring HU. The role of hepatokines in metabolism. Nat Rev Endocrinol 2013; 9: 144- 52.

13 Watt MJ, Miotto PM, De Nardo W et al. The liver as an endocrine organ-linking NAFLD and insulin resistance. Endocr Rev 2019; 40: 1367- 93.

14 Jensen-Cody SO, Potthoff MJ. Hepatokines and metabolism: deciphering communication from the liver. Mol Metab 2021; 44: 101138.

15 Matafora V, Gorb A, Yang F et al. Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric Aβ. J Neurochem 2023; 166: 346- 66.

16 Zeng W, Yang F, Shen WL et al. Interactions between central nervous system and peripheral metabolic organs. Sci China Life Sci 2022; 65: 1929- 58.

17 Smith JAB, Murach KA, Dyar KA et al. Exercise metabolism and adaptation in skeletal muscle. Nat Rev Mol Cell Biol 2023; 24: 607- 32.

18 Meng ZX, Li S, Wang L et al. Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation. Nat Med 2013; 19: 640- 5.

19 Meng ZX, Gong J, Chen Z et al. Glucose sensing by skeletal myocytes couples nutrient signaling to systemic homeostasis. Mol Cell 2017; 66: 332- 44.e4.

20 Lin J, Wu H, Tarr PT et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 2002; 418: 797- 801.

21 Pedersen , BK , Steensberg A, Fischer C et al. Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil 2003; 24: 113- 9.

22 Roberts LD, Boström P, O'Sullivan JF et al. β-aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab 2014; 19: 96- 108.

23 Larson EA, Dalamaga M, Magkos F. The role of exercise in obesity-related cancers: current evidence and biological mechanisms. Semin Cancer Biol 2023; 91: 16- 26.

24 Chen W, Wang L, You W et al. Myokines mediate the cross talk between skeletal muscle and other organs. J Cell Physiol 2021; 236: 2393- 412.

25 Huh JY. The role of exercise-induced myokines in regulating metabolism. Arch Pharm Res 2018; 41: 14- 29.

26 Pedersen BK. Physical activity and muscle-brain crosstalk. Nat Rev Endocrinol 2019; 15: 383- 92.

27 Lee B, Shin M, Park Y et al. Physical exercise-induced myokines in neurodegenerative diseases. Int J Mol Sci 2021; 22: 5795.

28 Eckel J. Myokines in metabolic homeostasis and diabetes. Diabetologia 2019; 62: 1523- 8.

29 Sharif K, Watad A, Bragazzi NL et al. Physical activity and autoimmune diseases: get moving and manage the disease. Autoimmun Rev 2018; 17: 53- 72.

30 Whitham M, Febbraio MA. The ever-expanding myokinome: discovery challenges and therapeutic implications. Nat Rev Drug Discov 2016; 15: 719- 29.

31 Rai M, Demontis F. Systemic nutrient and stress signaling via myokines and myometabolites. Annu Rev Physiol 2016; 78: 85- 107.

32 Klein S, Gastaldelli A, Yki-Järvinen H et al. Why does obesity cause diabetes? Cell Metab 2022; 34: 11- 20.

33 Roden M, Shulman GI. The integrative biology of type 2 diabetes. Nature 2019; 576: 51- 60.

34 Eizirik DL, Pasquali L, Cnop M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol 2020; 16: 349- 62.

35 Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet 2017; 389: 2239- 51.

36 Steensberg A, van 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 Pt 1: 237- 42.

37 Febbraio MA, Hiscock N, Sacchetti M et al. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 2004; 53: 1643- 8.

38 Pedersen BK. Muscular interleukin-6 and its role as an energy sensor. Med Sci Sports Exerc 2012; 44: 392- 6.

39 Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008; 88: 1379- 406.

40 Febbraio MA, Ott P, Nielsen HB et al. Hepatosplanchnic clearance of interleukin-6 in humans during exercise. Am J Physiol Endocrinol Metab 2003; 285: E397- 402.

41 Keller C, Steensberg A, Hansen AK et al. Effect of exercise, training, and glycogen availability on IL-6 receptor expression in human skeletal muscle. J Appl Physiol (1985) 2005; 99: 2075- 9.

42 Wolf J, Waetzig GH, Chalaris A et al. Different soluble forms of the interleukin-6 family signal transducer gp130 finetune the blockade of interleukin-6 trans-signaling. J Biol Chem 2016; 291: 16186- 96.

43 Heink S, Yogev N, Garbers C et al. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T_H17 cells. Nat Immunol 2017; 18: 74- 85.

44 Serrano AL, Baeza-Raja B, Perdiguero E et al. Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab 2008; 7: 33- 44.

45 Begue G, Douillard A, Galbes O et al. Early activation of rat skeletal muscle IL-6/STAT1/STAT3 dependent gene expression in resistance exercise linked to hypertrophy. PLoS One 2013; 8: e57141.

46 van Hall G, Steensberg A, Sacchetti M et al. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 2003; 88: 3005- 10.

47 Saini A, Faulkner SH, Moir H et al. Interleukin-6 in combination with the interleukin-6 receptor stimulates glucose uptake in resting human skeletal muscle independently of insulin action. Diabetes Obes Metab 2014; 16: 931- 6.

48 Holmes AG, Watt MJ, Febbraio MA. Suppressing lipolysis increases interleukin-6 at rest and during prolonged moderate-intensity exercise in humans. J Appl Physiol (1985) 2004; 97: 689- 96.

49 Hirata Y, Nomura K, Kato D et al. A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy. J Clin Invest 2022; 132: e154611.

50 Carey AL, Steinberg GR, Macaulay SL et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMPactivated protein kinase. Diabetes 2006; 55: 2688- 97.

51 Febbraio MA, Steensberg A, Keller C et al. Glucose ingestion attenuates interleukin-6 release from contracting skeletal muscle in humans. J Physiol 2003; 549: 607- 12.

52 Kistner TM, Pedersen BK, Lieberman DE. Interleukin 6 as an energy allocator in muscle tissue. Nat Metab 2022; 4: 170- 9.

53 VanderVeen BN, Fix DK, Montalvo RN et al. The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin-6. Exp Physiol 2019; 104: 385- 97.

54 Tyrrell DJ, Blin MG, Song J et al. Age-associated mitochondrial dysfunction accelerates atherogenesis. Circ Res 2020; 126: 298- 314.

55 Ji C, Chen X, Gao C et al. IL-6 induces lipolysis and mitochondrial dysfunction, but does not affect insulin-mediated glucose transport in 3T3-L1 adipocytes. J Bioenerg Biomembr 2011; 43: 367- 75.

56 Wan Z, Perry CGR, Macdonald T et al. IL-6 is not necessary for the regulation of adipose tissue mitochondrial content. PLoS One 2012; 7: e51233.

57 Xu Y, Zhang Y, Ye J. IL-6: a potential role in cardiac metabolic homeostasis. Int J Mol Sci 2018; 19: 2474.

58 Peng Y, Yang Q, Gao S et al. IL-6 protects cardiomyocytes from oxidative stress at the early stage of LPS-induced sepsis. Biochem Biophys Res Commun 2022; 603: 144- 52.

59 Kumar S, Wang G, Zheng N et al. HIMF (hypoxia-induced mitogenic factor)-IL (interleukin)-6 signaling mediates cardiomyocyte-fibroblast crosstalk to promote cardiac hypertrophy and fibrosis. Hypertension 2019; 73: 1058- 70.

60 Miller CL, Madsen JC. Targeting IL-6 to prevent cardiac allograft rejection. Am J Transplant 2022; 22: 12- 7.

61 Fontes JA, Rose NR, Čiháková D. The varying faces of IL-6: from cardiac protection to cardiac failure. Cytokine 2015; 74: 62- 8.

62 Steensberg A, Fischer CP, Keller C et al. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab 2003; 285: E433- 7.

63 Ellingsgaard H, Hauselmann I, Schuler B et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and α cells. Nat Med 2011; 17: 1481- 9.

64 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: 463- 8.

65 Yu Q, Kou W, Xu X et al. FNDC5/irisin inhibits pathological cardiac hypertrophy. Clin Sci (Lond) 2019; 133: 611- 27.

66 A M, Wales TE, Zhou H et al. Irisin acts through its integrin receptor in a two-step process involving extracellular Hsp90α. Mol Cell 2023; 83: 1903- 20.e12.

67 Trettel CDS, de Avila Pelozin BR, Barros MP et al. Irisin: an anti-inflammatory exerkine in aging and redox-mediated comorbidities. Front Endocrinol (Lausanne) 2023; 14: 1106529.

68 Zhang H, Wu X, Liang J et al. Irisin, an exercise-induced bioactive peptide beneficial for health promotion during aging process. Ageing Res Rev 2022; 80: 101680.

69 Perakakis N, Triantafyllou GA, Fernández-Real JM et al. Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol 2017; 13: 324- 37.

70 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: 1725- 38.

71 Colaianni G, Cuscito C, Mongelli T et al. The myokine irisin increases cortical bone mass. Proc Natl Acad Sci USA 2015; 112: 12157- 62.

72 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: E769- 78.

73 Eckardt K, Görgens SW, Raschke S et al. Myokines in insulin resistance and type 2 diabetes. Diabetologia 2014; 57: 1087- 99.

74 Uysal BA, Kuyumcu MS. Serum irisin and adropin levels may be predictors for coronary artery ectasia. Clin Exp Hypertens 2022; 44: 223- 7.

75 Maak S, Norheim F, Drevon CA et al. Progress and challenges in the biology of FNDC5 and Irisin. Endocr Rev 2021; 42: 436- 56.

76 Pinto AP, Ropelle ER, Quadrilatero J et al. Physical exercise and liver autophagy: potential roles of IL-6 and irisin. Exerc Sport Sci Rev 2022; 50: 89- 96.

77 Kurdiova T, Balaz M, Mayer A et al. Exercise-mimicking treatment fails to increase Fndc5 mRNA & irisin secretion in primary human myotubes. Peptides 2014; 56: 1- 7.

78 Qiu S, Cai X, Sun Z et al. Chronic exercise training and circulating irisin in adults: a meta-analysis. Sports Med 2015; 45: 1577- 88.

79 Bao JF, She QY, Hu PP et al. Irisin, a fascinating field in our times. Trends Endocrinol Metab 2022; 33: 601- 13.

80 Parr EB, Camera DM, Burke LM et al. Circulating microRNA responses between “high” and “low” responders to a 16-wk diet and exercise weight loss intervention. PLoS One 2016; 11: e0152545.

81 McCormick JJ, King KE, Notley SR et al. Exercise in the heat induces similar elevations in serum irisin in young and older men despite lower resting irisin concentrations in older adults. J Therm Biol 2022; 104: 103189.

82 Sesti G, Andreozzi F, Fiorentino TV et al. High circulating irisin levels are associated with insulin resistance and vascular atherosclerosis in a cohort of nondiabetic adult subjects. Acta Diabetol 2014; 51: 705- 13.

83 Park KH, Zaichenko L, Brinkoetter M et al. Circulating irisin in relation to insulin resistance and the metabolic syndrome. J Clin Endocrinol Metab 2013; 98: 4899- 907.

84 Shanaki M, Moradi N, Emamgholipour S et al. Lower circulating irisin is associated with nonalcoholic fatty liver disease and type 2 diabetes. Diabetes Metab Syndr 2017; 11: S467- 72.

85 Mostafa TM, El-Gharbawy NM, Werida RH. Circulating IRAPe, irisin, and IL-34 in relation to insulin resistance in patients with type 2 diabetes. Clin Ther 2021; 43: e230- 40.

86 Huh JY, Mougios V, Kabasakalis A 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: E2154- 61.

87 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: 514- 25.

88 He X, Hua Y, Li Q et al. FNDC5/irisin facilitatesmuscle-adipose-bone connectivity through ubiquitination-dependent activation of runt-related transcriptional factors RUNX1/2. J Biol Chem 2022; 298: 101679.

89 Oguri Y, Shinoda K, Kim H et al. CD81 controls beige fat progenitor cell growth and energy balance via FAK signaling. Cell 2020; 182: 563- 77.e20.

90 Raschke S, Elsen M, Gassenhuber H et al. Evidence against a beneficial effect of irisin in humans. PLoS One 2013; 8: e73680.

91 Elsen M, Raschke S, Eckel J. Browning of white fat: does irisin play a role in humans? J Endocrinol 2014; 222: R25- 38.

92 Shaw A, Tóth BB, Király R et al. Irisin stimulates the release of CXCL1 from differentiating human subcutaneous and deepneck derived adipocytes via upregulation of NFκB pathway. Front Cell Dev Biol 2021; 9: 737872.

93 Basini G, Bussolati S, Grolli S et al. Effects of the myokine irisin on stromal cells from swine adipose tissue. Biomolecules 2022; 12: 1895.

94 Huh JY, Dincer F, Mesfum E et al. Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans. Int J Obes (Lond) 2014; 38: 1538- 44.

95 Ye X, Shen YM, Ni C et al. Irisin reverses insulin resistance in C2C12 cells via the p38-MAPK-PGC-1α pathway. Peptides 2019; 119: 170120.

96 Yano N, Zhang L, Wei D et al. Irisin counteracts high glucose and fatty acid-induced cytotoxicity by preserving the AMPK-insulin receptor signaling axis in C2C12 myoblasts. Am J Physiol Endocrinol Metab 2020; 318: E791- 805.

97 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 (Lond) 2016; 40: 443- 51.

98 Natalicchio A, Marrano N, Biondi G 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: 2849- 56.

99 Wang L, Song J, Wang C et al. Circulating levels of betatrophin and irisin are not associated with pancreatic β-cell function in previously diagnosed type 2 diabetes mellitus patients. J Diabetes Res 2016; 2016: 2616539.

100 Norman D, Drott CJ, Carlsson PO et al. Irisin—A pancreatic islet hormone. Biomedicines 2022; 10: 258.

101 Tang H, Yu R, Liu S et al. Irisin inhibits hepatic cholesterol synthesis via AMPK-SREBP2 signaling. EBioMedicine 2016; 6: 139- 48.

102 Zhu W, Sahar NE, Javaid HMA et al. Exercise-induced irisin decreases inflammation and improves NAFLD by competitive binding with MD2. Cells 2021; 10: 3306.

103 Bi J, Zhang J, Ren Y et al. Irisin alleviates liver ischemia-reperfusion injury by inhibiting excessive mitochondrial fission, promoting mitochondrial biogenesis and decreasing oxidative stress. Redox Biol 2019; 20: 296- 306.

104 So WY, Leung PS. Irisin ameliorates hepatic glucose/lipid metabolism and enhances cell survival in insulin-resistant human HepG2 cells through adenosine monophosphate-activated protein kinase signaling. Int J Biochem Cell Biol 2016; 78: 237- 47.

105 McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 1997; 387: 83- 90.

106 Lee SJ. Targeting the myostatin signaling pathway to treat muscle loss and metabolic dysfunction. J Clin Invest 2021; 131: e148372.

107 McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA 1997; 94: 12457- 61.

108 Kim HS, Liang L, Dean RG et al. Inhibition of preadipocyte differentiation by myostatin treatment in 3T3-L1 cultures. Biochem Biophys Res Commun 2001; 281: 902- 6.

109 Fakhfakh R, Michaud A, Tremblay JP. Blocking the myostatin signal with a dominant negative receptor improves the success of human myoblast transplantation in dystrophic mice. Mol Ther 2011; 19: 204- 10.

110 Ricaud S, Vernus B, Duclos M et al. Inhibition of autocrine secretion of myostatin enhances terminal differentiation in human rhabdomyosarcoma cells. Oncogene 2003; 22: 8221- 32.

111 Thomas M, Langley B, Berry C et al. Myostatin, a negative regulator of muscle growth, functions by inhibiting myoblast proliferation. J Biol Chem 2000; 275: 40235- 43.

112 Liu Y, Cheng H, Zhou Y et al. Myostatin induces mitochondrial metabolic alteration and typical apoptosis in cancer cells. Cell Death Dis 2013; 4: e494.

113 Hittel DS, Berggren JR, Shearer J et al. Increased secretion and expression of myostatin in skeletal muscle from extremely obese women. Diabetes 2009; 58: 30- 8.

114 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 Endocrinol Metab 2008; 294: E918- 27.

115 Hjorth M, Pourteymour S, Görgens SW et al. Myostatin in relation to physical activity and dysglycaemia and its effect on energy metabolism in human skeletal muscle cells. Acta Physiol (Oxf) 2016; 217: 45- 60.

116 Camporez JP, Petersen MC, Abudukadier A et al. Antimyostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice. Proc Natl Acad Sci USA 2016; 113: 2212- 7.

117 Braga M, Pervin S, Norris K et al. Inhibition of in vitro and in vivo brown fat differentiation program by myostatin. Obesity (Silver Spring) 2013; 21: 1180- 8.

118 Fournier B, Murray B, Gutzwiller S et al. Blockade of the activin receptor IIb activates functional brown adipogenesis and thermogenesis by inducing mitochondrial oxidative metabolism. Mol Cell Biol 2012; 32: 2871- 9.

119 Zhang C, McFarlane C, Lokireddy S et al. Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice. Diabetologia 2012; 55: 183- 93.

120 LeBrasseur NK, Schelhorn TM, Bernardo BL et al. Myostatin inhibition enhances the effects of exercise on performance and metabolic outcomes in aged mice. J Gerontol A Biol Sci Med Sci 2009; 64: 940- 8.

121 Feldman BJ, Streeper RS, Farese RV et al. Myostatin modulates adipogenesis to generate adipocytes with favorable metabolic effects. Proc Natl Acad Sci USA 2006; 103: 15675- 80.

122 McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest 2002; 109: 595- 601.

123 Gu M, Wei Z, Wang X et al. Myostatin knockout affects mitochondrial function by inhibiting the AMPK/SIRT1/PGC1α Pathway in skeletal muscle. Int J Mol Sci 2022; 23: 13703.

124 Ren H, Xiao W, Qin X et al. Myostatin regulates fatty acid desaturation and fat deposition through MEF2C/miR222/SCD5 cascade in pigs. Commun Biol 2020; 3: 612.

125 Zhu HJ, Pan H, Zhang XZ et al. The effect of myostatin on proliferation and lipid accumulation in 3T3-L1 preadipocytes. J Mol Endocrinol 2015; 54: 217- 26.

126 Chen Y, Ye J, Cao L et al. Myostatin regulates glucose metabolism via the AMP-activated protein kinase pathway in skeletal muscle cells. Int J Biochem Cell Biol 2010; 42: 2072- 81.

127 Eilers W, Chambers D, Cleasby M et al. Local myostatin inhibition improves skeletal muscle glucose uptake in insulin-resistant high-fat diet-fed mice. Am J Physiol Endocrinol Metab 2020; 319: E163- 74.

128 Hittel DS, Axelson M, Sarna N et al. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med Sci Sports Exerc 2010; 42: 2023- 9.

129 Wang X, Wei Z, Gu M et al. Loss of myostatin alters mitochondrial oxidative phosphorylation, TCA cycle activity, and ATP production in skeletal muscle. Int J Mol Sci 2022; 23: 15707.

130 Rovira Gonzalez YI, Moyer AL, LeTexier NJ et al. Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice. JCI Insight 2019; 4: e122247.

131 Ge X, Sathiakumar D, Lua BJG et al. Myostatin signals through miR-34a to regulate Fndc5 expression and browning of white adipocytes. Int J Obes (Lond) 2017; 41: 137- 48.

132 Tao R, Stöhr O, Wang C et al. Hepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance. Mol Metab 2023; 71: 101703.

133 Zarfeshani A, Ngo S, Sheppard AM. Leucine alters hepatic glucose/lipid homeostasis via the myostatin-AMP-activated protein kinase pathway—potential implications for nonalcoholic fatty liver disease. Clin Epigenetics 2014; 6: 27.

134 Nakashima M, Toyono T, Akamine A et al. Expression of growth/differentiation factor 11, a new member of the BMP/TGFβ super-family during mouse embryogenesis. Mech Dev 1999; 80: 185- 9.

135 Zhang Y, Wei Y, Liu D et al. Role of growth differentiation factor 11 in development, physiology and disease. Oncotarget 2017; 8: 81604- 16.

136 Sinha M, Jang YC, Oh J et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 2014; 344: 649- 52.

137 Bagheri R, Moghadam BH, Church DD et al. The effects of concurrent training order on body composition and serum concentrations of follistatin, myostatin and GDF11 in sarcopenic elderly men. Exp Gerontol 2020; 133: 110869.

138 Katsimpardi L, Kuperwasser N, Camus C et al. Systemic GDF11 stimulates the secretion of adiponectin and induces a calorie restriction-like phenotype in aged mice. Aging Cell 2020; 19: e13038.

139 Frohlich J, Kovacovicova K, Raffaele M et al. GDF11 inhibits adipogenesis and improves mature adipocytes metabolic function via WNT/β-catenin and ALK5/SMAD2/3 pathways. Cell Prolif 2022; 55: e13310.

140 Lu B, Zhong J, Pan J et al. Gdf11 gene transfer prevents high fat diet-induced obesity and improves metabolic homeostasis in obese and STZ-induced diabetic mice. J Transl Med 2019; 17: 422.

141 Walker RG, Barrandon O, Poggioli T et al. Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice. Sci Rep 2020; 10: 4561.

142 Lee M, Oikawa S, Ushida T et al. Effects of exercise training on growth and differentiation factor 11 expression in aged mice. Front Physiol 2019; 10: 970.

143 Li H, Li Y, Xiang L et al. GDF11 attenuates development of type 2 diabetes via improvement of islet β-cell function and survival. Diabetes 2017; 66: 1914- 27.

144 Jing YY, Li D, Wu F et al. GDF11 does not improve the palmitate induced insulin resistance in C2C12. Eur Rev Med Pharmacol Sci 2017; 21: 1795- 802.

145 Añón-Hidalgo J, Catalán V, Rodríguez A et al. Circulating GDF11 levels are decreased with age but are unchanged with obesity and type 2 diabetes. Aging (Albany NY) 2019; 11: 1733- 44.

146 Schafer MJ, Atkinson EJ, Vanderboom PM et al. Quantification of GDF11 and myostatin in human aging and cardiovascular disease. Cell Metab 2016; 23: 1207- 15.

147 Fadini GP, Menegazzo L, Bonora BM et al. Effects of age, diabetes, and vascular disease on growth differentiation factor 11: first-in-human study. Diabetes Care 2015; 38: e118- 9.

148 Luo H, Guo Y, Liu Y et al. Growth differentiation factor 11 inhibits adipogenic differentiation by activating TGF-β/Smad signalling pathway. Cell Prolif 2019; 52: e12631.

149 Lin S, Zhong L, Chen J et al. GDF11 inhibits adipogenesis of human adipose-derived stromal cells through ALK5/KLF15/β-catenin/PPARγ cascade. Heliyon 2023; 9: e13088.

150 Pham HG, Park JP, Yun JW. BMP11 negatively regulates lipid metabolism in C2C12 muscle cells. Biotechnol Bioprocess Eng 2020; 25: 670- 80.

151 Chen Y, Guo Q, Zhang M et al. Relationship of serum GDF11 levels with bone mineral density and bone turnover markers in postmenopausal Chinese women. Bone Res 2016; 4: 16012.

152 Liu W, Zhou L, Zhou C et al. GDF11 decreases bone mass by stimulating osteoclastogenesis and inhibiting osteoblast differentiation. Nat Commun 2016; 7: 12794.

153 Shen GS, Zhou HB, Zhang H et al. The GDF11-FTO-PPARγ axis controls the shift of osteoporotic MSC fate to adipocyte and inhibits bone formation during osteoporosis. Biochim Biophys Acta Mol Basis Dis 2018; 1864: 3644- 54.

154 Suh J, Kim NK, Lee SH et al. GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone. Proc Natl Acad Sci USA 2020; 117: 4910- 20.

155 Tezze C, Romanello V, Sandri M. FGF21 as modulator of metabolism in health and disease. Front Physiol 2019; 10: 419.

156 Yie J, Wang W, Deng L et al. Understanding the physical interactions in the FGF21/FGFR/β-Klotho complex: structural requirements and implications in FGF21 signaling. Chem Biol Drug Des 2012; 79: 398- 410.

157 Itoh N. FGF21 as a hepatokine, adipokine, and myokine in metabolism and diseases. Front Endocrinol (Lausanne) 2014; 5: 107.

158 Murata Y, Konishi M, Itoh N. FGF21 as an endocrine regulator in lipid metabolism: from molecular evolution to physiology and pathophysiology. J Nutr Metab 2011; 2011: 981315.

159 Lee P, Linderman JD, Smith S et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014; 19: 302- 9.

160 Yano K, Yamaguchi K, Seko Y et al. Hepatocyte-specific fibroblast growth factor 21 overexpression ameliorates high-fat diet-induced obesity and liver steatosis in mice. Lab Invest 2022; 102: 281- 9.

161 Luo Y, McKeehan WL. Stressed liver and muscle call on adipocytes with FGF21. Front Endocrinol (Lausanne) 2013; 4: 194.

162 Fisher FM, Maratos-Flier E. Understanding the physiology of FGF21. Annu Rev Physiol 2016; 78: 223- 41.

163 Izumiya Y, Bina HA, Ouchi N et al. FGF21 is an Akt-regulated myokine. FEBS Lett 2008; 582: 3805- 10.

164 Oost LJ, Kustermann M, Armani A et al. Fibroblast growth factor 21 controls mitophagy and muscle mass. J Cachexia Sarcopenia Muscle 2019; 10: 630- 42.

165 Ost M, Coleman V, Voigt A et al. Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action. Mol Metab 2016; 5: 79- 90.

166 Pereira RO, Tadinada SM, Zasadny FM et al. OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance. EMBO J 2017; 36: 2126- 45.

167 Romanello V, Scalabrin M, Albiero M et al. Inhibition of the fission machinery mitigates OPA1 impairment in adult skeletal muscles. Cells 2019; 8: 597.

168 Keipert S, Ost M, Johann K et al. Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. Am J Physiol Endocrinol Metab 2014; 306: E469- 82.

169 Lin Z, Tian H, Lam KSL et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 2013; 17: 779- 89.

170 Hotta Y, Nakamura H, Konishi M et al. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology 2009; 150: 4625- 33.

171 Sheikh AY, Chun HJ, Glassford AJ et al. In vivo genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial-centered pathway activated in ischemic heart failure. Am J Physiol Heart Circ Physiol 2008; 294: H88- 98.

172 Fasshauer M, Blüher M. Adipokines in health and disease. Trends Pharmacol Sci 2015; 36: 461- 70.

173 Tatemoto K, Hosoya M, Habata Y et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 1998; 251: 471- 6.

174 Besse-Patin A, Montastier E, Vinel C et al. Effect of endurance training on skeletal muscle myokine expression in obese men: identification of apelin as a novel myokine. Int J Obes (Lond) 2014; 38: 707- 13.

175 Vinel C, Lukjanenko L, Batut A et al. The exerkine apelin reverses age-associated sarcopenia. Nat Med 2018; 24: 1360- 71.

176 Yue P, Jin H, Aillaud M et al. Apelin is necessary for the maintenance of insulin sensitivity. Am J Physiol Endocrinol Metab 2010; 298: E59- 67.

177 Dray C, Knauf C, Daviaud D et al. Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metab 2008; 8: 437- 45.

178 Attane C, Foussal C, Le Gonidec S et al. Apelin treatment increases complete fatty acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice. Diabetes 2012; 61: 310- 20.

179 Enoki Y, Nagai T, Hamamura Y et al. The G protein-coupled receptor ligand apelin-13 ameliorates skeletal muscle atrophy induced by chronic kidney disease. J Cachexia Sarcopenia Muscle 2023; 14: 553- 64.

180 Lee U, Stuelsatz P, Karaz S et al. A Tead1-apelin axis directs paracrine communication from myogenic to endothelial cells in skeletal muscle. Iscience 2022; 25: 104589.

181 Ashley EA, Powers J, Chen M et al. The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc Res 2005; 65: 73- 82.

182 Nordvall G, Forsell P, Sandin J. Neurotrophin-targeted therapeutics: a gateway to cognition and more? Drug Discov Today 2022; 27: 103318.

183 Delezie J, Weihrauch M, Maier G et al. BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle. Proc Natl Acad Sci USA 2019; 116: 16111- 20.

184 Iu ECY, Chan CB. Is brain-derived neurotrophic factor a metabolic hormone in peripheral tissues? Biology (Basel) 2022; 11: 1063.

185 Yang X, Brobst D, Chan WS et al. Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility. Sci Signal 2019; 12: eaau1468.

186 Matthews VB, Aström MB, Chan MHS et al. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia 2009; 52: 1409- 18.

187 Ahuja P, Ng CF, Pang BPS et al. Muscle-generated BDNF (brain derived neurotrophic factor) maintains mitochondrial quality control in female mice. Autophagy 2022; 18: 1367- 84.

188 Martín-González C, Romero-Acevedo L, Fernández-Rodríguez CM et al. Brain-derived neurotrophic factor among patients with alcoholism. CNS Spectr 2021; 26: 400- 5.

189 Shu HC, Hu J, Jiang XB et al. BDNF gene polymorphism and serum level correlate with liver function in patients with hepatitis B-induced cirrhosis. Int J Clin Exp Pathol 2019; 12: 2368- 80.

190 Xiong J, Liu T, Mi L et al. hnRNPU/TrkB defines a chromatin accessibility checkpoint for liver injury and nonalcoholic steatohepatitis pathogenesis. Hepatology 2020; 71: 1228- 46.

191 Cırrık S, Hacioglu G, Abidin I et al. Endoplasmic reticulum stress in the livers of BDNF heterozygous knockout mice. Arch Physiol Biochem 2019; 125: 378- 86.

192 Li Z, Gao Z, Sun T et al. Meteorin-like/Metrnl, a novel secreted protein implicated in inflammation, immunology, and metabolism: a comprehensive review of preclinical and clinical studies. Front Immunol 2023; 14: 1098570.

193 Rao RR, Long JZ, White JP et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 2014; 157: 1279- 91.

194 Du Y, Ye X, Lu A et al. Inverse relationship between serum Metrnl levels and visceral fat obesity (VFO) in patients with type 2 diabetes. Diabetes Res Clin Pract 2020; 161: 108068.

195 Dadmanesh M, Aghajani H, Fadaei R et al. Lower serum levels of Meteorin-like/Subfatin in patients with coronary artery disease and type 2 diabetes mellitus are negatively associated with insulin resistance and inflammatory cytokines. PLoS One 2018; 13: e0204180.

196 Ding X, Chang X, Wang J et al. Serum Metrnl levels are decreased in subjects with overweight or obesity and are independently associated with adverse lipid profile. Front Endocrinol (Lausanne) 2022; 13: 938341.

197 Schmid A, Karrasch T, Schäffler A. Meteorin-like protein (Metrnl) in obesity, during weight loss and in adipocyte differentiation. J Clin Med 2021; 10: 4338.

198 El-Ashmawy HM, Selim FO, Hosny TAM et al. Association of low serum Meteorin like (Metrnl) concentrations with worsening of glucose tolerance, impaired endothelial function and atherosclerosis. Diabetes Res Clin Pract 2019; 150: 57- 63.

199 Wu Q, Dan YL, He YS et al. Circulating Meteorin-like levels in patients with type 2 diabetes mellitus: a meta-analysis. Curr Pharm Des 2020; 26: 5732- 8.

200 AlKhairi I, Cherian P, Abu-Farha M et al. Increased expression of Meteorin-LIKE HORMONE in type 2 diabetes and obesity and its association with irisin. Cells 2019; 8: 1283.

201 Lee JH, Kang YE, Kim JM et al. Serum Meteorin-like protein levels decreased in patients newly diagnosed with type 2 diabetes. Diabetes Res Clin Pract 2018; 135: 7- 10.

202 Bae JY. Aerobic exercise increases Meteorin-like protein in muscle and adipose tissue of chronic high-fat diet-induced obese mice. Biomed Res Int 2018; 2018: 6283932.

203 Eaton M, Granata C, Barry J et al. Impact of a single bout of high-intensity interval exercise and short-term interval training on interleukin-6, FNDC5, and METRNL mRNA expression in human skeletal muscle. J Sport Health Sci 2018; 7: 191- 6.

204 Pellitero S, Piquer-Garcia I, Ferrer-Curriu G et al. Opposite changes in meteorin-like and oncostatin m levels are associated with metabolic improvements after bariatric surgery. Int J Obes (Lond) 2018; 42: 919- 22.

205 Jamal MH, AlOtaibi F, Dsouza C et al. Changes in the expression of meteorin-like (METRNL), irisin (FNDC5), and uncoupling proteins (UCPs) after bariatric surgery. Obesity (Silver Spring) 2022; 30: 1629- 38.

206 Zhou Y, Liu L, Jin B et al. Metrnl alleviates lipid accumulation by modulating mitochondrial homeostasis in diabetic nephropathy. Diabetes 2023; 72: 611- 26.

207 Zheng SL, Li ZY, Song J et al. Metrnl: a secreted protein with new emerging functions. Acta Pharmacol Sin 2016; 37: 571- 9.

208 Löffler D, Landgraf K, Rockstroh D et al. METRNL decreases during adipogenesis and inhibits adipocyte differentiation leading to adipocyte hypertrophy in humans. Int J Obes (Lond) 2017; 41: 112- 9.

209 Li ZY, Song J, Zheng SL et al. Adipocyte Metrnl antagonizes insulin resistance through PPARγ signaling. Diabetes 2015; 64: 4011- 22.

210 Zuo L, Ge S, Ge Y et al. The Adipokine Metrnl ameliorates chronic colitis in Il-10-/- mice by attenuating mesenteric adipose tissue lesions during spontaneous colitis. J Crohns Colitis 2019; 13: 931- 41.

211 Lee JO, Byun WS, Kang MJ et al. The myokine meteorin-like (metrnl) improves glucose tolerance in both skeletal muscle cells and mice by targeting AMPKα2. FEBS J 2020; 287: 2087- 104.

212 Jung TW, Lee SH, Kim HC et al. METRNL attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARδ-dependent pathways in skeletal muscle of mice. Exp Mol Med 2018; 50: 1- 11.

213 Hu W, Wang R, Sun B. Meteorin-like ameliorates β cell function by inhibiting β cell apoptosis of and promoting β cell proliferation via activating the WNT/β-catenin pathway. Front Pharmacol 2021; 12: 627147.

214 Gries KJ, Zysik VS, Jobe TK et al. Muscle-derived factors influencing bone metabolism. Semin Cell Dev Biol 2022; 123: 57- 63.

215 Huang R, Balu AR, Molitoris KH et al. The role of meteorin-like in skeletal development and bone fracture healing. J Orthop Res 2022; 40: 2510- 21.

216 Kos K, Wilding JP. SPARC: a key player in the pathologies associated with obesity and diabetes. Nat Rev Endocrinol 2010; 6: 225- 35.

217 Kos K, Wong S, Tan B et al. Regulation of the fibrosis and angiogenesis promoter SPARC/osteonectin in human adipose tissue by weight change, leptin, insulin, and glucose. Diabetes 2009; 58: 1780- 8.

218 Termine JD, Kleinman HK, Whitson SW et al. Osteonectin, a bone-specific protein linking mineral to collagen. Cell 1981; 26: 99- 105.

219 Bradshaw AD. Diverse biological functions of the SPARC family of proteins. Int J Biochem Cell Biol 2012; 44: 480- 8.

220 Aoi W, Naito Y, Takagi T et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut 2013; 62: 882- 9.

221 Pourteymour S, Eckardt K, Holen T et al. Global mRNA sequencing of human skeletal muscle: search for novel exercise-regulated myokines. Mol Metab 2017; 6: 352- 65.

222 Atorrasagasti C, Onorato A, Gimeno ML et al. SPARC is required for the maintenance of glucose homeostasis and insulin secretion in mice. Clin Sci (Lond) 2019; 133: 351- 65.

223 Cherian P, Al-Khairi I, Jamal M et al. Association between factors involved in bone remodeling (Osteoactivin and OPG) with plasma levels of irisin and meteorin-like protein in people with T2D and obesity. Front Endocrinol (Lausanne) 2021; 12: 752892.

224 Garneau L, Parsons SA, Smith SR et al. Plasma myokine concentrations after acute exercise in non-obese and obese sedentary women. Front Physiol 2020; 11: 18.

225 Nishida Y, Hara M, Higaki Y et al. Sedentary time, physical activity, and serum SPARC in a middle-aged population. Eur J Sport Sci 2022; 22: 1786- 94.

226 Rovira M, Arrey G, Planas JV. Exercise-induced hypertrophic and oxidative signaling pathways and myokine expression in fast muscle of adult Zebrafish. Front Physiol 2017; 8: 1063.

227 Aoi W, Hirano N, Lassiter DG et al. Secreted protein acidic and rich in cysteine (SPARC) improves glucose tolerance via AMP-activated protein kinase activation. FASEB J 2019; 33: 10551- 62.

228 Jäger S, Handschin C, St-Pierre J et al. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc Natl Acad Sci USA 2007; 104: 12017- 22.

229 Melouane A, Yoshioka M, Kanzaki M et al. Sparc, an EPS-induced gene, modulates the extracellular matrix and mitochondrial function via ILK/AMPK pathways in C2C12 cells. Life Sci 2019; 229: 277- 87.

230 Boettcher M, Machann J, Stefan N et al. Intermuscular adipose tissue (IMAT): association with other adipose tissue compartments and insulin sensitivity. J Magn Reson Imaging 2009; 29: 1340- 5.

231 Mathes S, Fahrner A, Ghoshdastider U et al. FGF-2-dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis. Proc Natl Acad Sci USA 2021; 118: e2021013118.

232 Galimov A, Hartung A, Trepp R et al. Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance. J Mol Med (Berl) 2015; 93: 1369- 79.

233 Mathes S, Fahrner A, Luca E et al. Growth hormone/IGF-I-dependent signaling restores decreased expression of the myokine SPARC in aged skeletal muscle. J Mol Med (Berl) 2022; 100: 1647- 58.

234 Nie J, Sage EH. SPARC inhibits adipogenesis by its enhancement of β-catenin signaling. J Biol Chem 2009; 284: 1279- 90.

235 Nie J, Sage EH. SPARC functions as an inhibitor of adipogenesis. J Cell Commun Signal 2009; 3: 247- 54.

236 Naïmi M, Van Obberghen E. Inflammation: where is the SPARC in adipose-tissue inflammation? Nat Rev Endocrinol 2009; 5: 648- 9.

237 Ryu S, Spadaro O, Sidorov S et al. Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity. J Clin Invest 2023; 133: e169173.

238 Onorato AM, Fiore E, Bayo J et al. SPARC inhibition accelerates NAFLD-associated hepatocellular carcinoma development by dysregulating hepatic lipid metabolism. Liver Int 2021; 41: 1677- 93.

239 Yi X, Yang Y, Li T et al. Signaling metabolite β-aminoisobutyric acid as a metabolic regulator, biomarker, and potential exercise pill. Front Endocrinol (Lausanne) 2023; 14: 1192458.

240 Crumpler HR, Dent CE, Harris H et al. β-aminoisobutyric acid (α-methyl-β-alanine): a new amino-acid obtained from human urine. Nature 1951; 167: 307- 8.

241 Lyssikatos C, Wang Z, Liu Z et al. L-β-aminoisobutyric acid, L-BAIBA, a marker of bone mineral density and body mass index, and D-BAIBA of physical performance and age. Sci Rep 2023; 13: 17212.

242 Tanianskii DA, Jarzebska N, Birkenfeld AL et al. β-aminoisobutyric acid as a novel regulator of carbohydrate and lipid metabolism. Nutrients 2019; 11: 524.

243 Stautemas J, Van Kuilenburg ABP, Stroomer L et al. Acute aerobic exercise leads to increased plasma levels of R- and S-β-aminoisobutyric acid in humans. Front Physiol 2019; 10: 1240.

244 Solem E, Jellum E, Eldjarn L. The absolute configuration of β-aminoisobutyric acid in human serum and urine. Clin Chim Acta 1974; 50: 393- 403.

245 Morales FE, Forsse JS, Andre TL et al. BAIBA does not regulate UCP-3 expression in human skeletal muscle as a response to aerobic exercise. J Am Coll Nutr 2017; 36: 200- 9.

246 Simon J, Nuñez-García M, Fernández-Tussy P et al. Targeting hepatic glutaminase 1 ameliorates non-alcoholic steatohepatitis by restoring very-low-density lipoprotein triglyceride assembly. Cell Metab 2020; 31: 605- 22.e10.

247 Vergès B. Abnormal hepatic apolipoprotein B metabolism in type 2 diabetes. Atherosclerosis 2010; 211: 353- 60.

248 Begriche K, Massart J, Abbey-Toby A et al. β-aminoisobutyric acid prevents diet-induced obesity in mice with partial leptin deficiency. Obesity (Silver Spring) 2008; 16: 2053- 67.

249 Shi CX, Zhao MX, Shu XD et al. β-aminoisobutyric acid attenuates hepatic endoplasmic reticulum stress and glucose/lipid metabolic disturbance in mice with type 2 diabetes. Sci Rep 2016; 6: 21924.

250 Kitase Y, Vallejo JA, Gutheil W et al. β-aminoisobutyric acid, l-BAIBA, is a muscle-derived osteocyte survival factor. Cell Rep 2018; 22: 1531- 44.

251 Prideaux M, Smargiassi A, Peng G et al. L-BAIBA synergizes with sub-optimal mechanical loading to promote new bone formation. Jbmr Plus 2023; 7: e10746.

252 Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev 2006; 27: 47- 72.

253 Jin L, Han S, Lv X et al. The muscle-enriched myokine musclin impairs beige fat thermogenesis and systemic energy homeostasis via Tfr1/PKA signaling in male mice. Nat Commun 2023; 14: 4257.

254 Thomas G, Moffatt P, Salois P et al. Osteocrin, a novel bone-specific secreted protein that modulates the osteoblast phenotype. J Biol Chem 2003; 278: 50563- 71.

255 Moffatt P, Thomas G, Sellin K et al. Osteocrin is a specific ligand of the natriuretic peptide clearance receptor that modulates bone growth. J Biol Chem 2007; 282: 36454- 62.

256 Wang JS, Kamath T, Mazur CM et al. Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin. Nat Commun 2021; 12: 6271.

257 Nishizawa H, Matsuda M, Yamada Y et al. Musclin, a novel skeletal muscle-derived secretory factor.J Biol Chem 2004; 279: 19391- 5.

258 Subbotina E, Sierra A, Zhu Z et al. Musclin is anactivity-stimulated myokine that enhances physical endurance. Proc Natl Acad Sci USA 2015; 112: 16042- 7.

259 Kita S, Nishizawa H, Okuno Y et al. Competitive binding of Musclin to natriuretic peptide receptor 3 with atrial natriuretic peptide. J Endocrinol 2009; 201: 287- 95.

260 Ajay A, Rasoul D, Abdullah A et al. Augmentation of natriuretic peptide (NP) receptor A and B (NPR-A and NPR-B) and cyclic guanosine monophosphate (cGMP) signalling as a therapeutic strategy in heart failure. Expert Opin Investig Drugs 2023; 32: 1157- 70.

261 Mitsuishi M, Miyashita K, Itoh H. cGMP rescues mitochondrial dysfunction induced by glucose and insulin in myocytes. Biochem Biophys Res Commun 2008; 367: 840- 5.

262 Miyazaki T, Otani K, Chiba A et al. A new secretory peptide of natriuretic peptide family, osteocrin, suppresses the progression of congestive heart failure after myocardial infarction. Circ Res 2018; 122: 742- 51.

263 Szaroszyk M, Kattih B, Martin-Garrido A et al. Skeletal muscle derived Musclin protects the heart during pathological overload. Nat Commun 2022; 13: 149.

264 Watanabe-Takano H, Ochi H, Chiba A et al. Mechanical load regulates bone growth via periosteal Osteocrin. Cell Rep 2021; 36: 109380.

265 Re Cecconi AD, Forti M, Chiappa M et al. Musclin, a myokine induced by aerobic exercise, retards muscle atrophy during cancer cachexia in mice. Cancers (Basel) 2019; 11: 1541.

266 Schafer C, Moore V, Dasgupta N et al. The effects of PPAR stimulation on cardiac metabolic pathways in barth syndrome mice. Front Pharmacol 2018; 9: 318.

267 Sierra A, Subbotina E, Zhu Z et al. Disruption of ATP-sensitive potassium channel function in skeletal muscles promotes production and secretion of musclin. Biochem Biophys Res Commun 2016; 471: 129- 34.

268 Kang X, Qian J, Shi YX et al. Exercise-induced Musclin determines the fate of fibro-adipogenic progenitors to control muscle homeostasis. Cell Stem Cell 2024; 31: 212- 26.e7.

269 Mendez-Gutierrez A, Aguilera CM, Osuna-Prieto FJ et al. Exercise-induced changes on exerkines that might influence brown adipose tissue metabolism in young sedentary adults. Eur J Sport Sci 2023; 23: 625- 36.

270 Yu J, Zheng J, Liu XF et al. Exercise improved lipid metabolism and insulin sensitivity in rats fed a high-fat diet by regulating glucose transporter 4 (GLUT4) and musclin expression. Braz J Med Biol Res 2016; 49: e5129.

271 Sánchez YL, Yepes-Calderón M, Valbuena L et al. Musclin is related to insulin resistance and body composition, but not to body mass index or cardiorespiratory capacity in adults. Endocrinol Metab (Seoul) 2021; 36: 1055- 68.

272 Li J, Pan X, Pan G et al. Transferrin receptor 1 regulates thermogenic capacity and cell fate in brown/beige adipocytes. Adv Sci (Weinh) 2020; 7: 1903366.

273 Niehrs C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 2006; 25: 7469- 81.

274 Jin T. The WNT signalling pathway and diabetes mellitus. Diabetologia 2008; 51: 1771- 80.

275 Lattanzio S, Santilli F, Liani R et al. Circulating Dickkopf-1 in diabetes mellitus: association with platelet activation and effects of improved metabolic control and low-dose aspirin. J Am Heart Assoc 2014; 3: e001000.

276 Baetta R, Banfi C. Dkk (Dickkopf) proteins. Arterioscler Thromb Vasc Biol 2019; 39: 1330- 42.

277 Gustafson B, Eliasson B, Smith U. Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis. Diabetologia 2010; 53: 536- 40.

278 Li X, Shan J, Chang W et al. Chemical and genetic evidence for the involvement of Wnt antagonist Dickkopf2 in regulation of glucose metabolism. Proc Natl Acad Sci USA 2012; 109: 11402- 7.

279 Lou X, Meng Y, Hou Y. A literature review on function and regulation mechanism of DKK4. J Cell Mol Med 2021; 25: 2786- 94.

280 Kohn MJ, Sztein J, Yagi R et al. The acrosomal protein Dickkopf-like 1 (DKKL1) facilitates sperm penetration of the zona pellucida. Fertil Steril 2010; 93: 1533- 7.

281 Kaneko KJ, Kohn MJ, Liu C et al. The acrosomal protein Dickkopf-like 1 (DKKL1) is not essential for fertility. Fertil Steril 2010; 93: 1526- 32.

282 Yan Q, Wu X, Chen C et al. Developmental expression and function of DKKL1/Dkkl1 in humans and mice. Reprod Biol Endocrinol 2012; 10: 51.

283 Han L, Wu S, Hu P. The functions of sarcopenia related myokines. Trans Med Aging 2018; 2: 38- 41.

284 Yin J, Yang L, Xie Y et al. Dkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy. Nat Commun 2018; 9: 1752.

285 Tsuji T, Miyazaki M, Sakaguchi M et al. A REIC gene shows down-regulation in human immortalized cells and human tumor-derived cell lines. Biochem Biophys Res Commun 2000; 268: 20- 4.

286 Zenzmaier C, Marksteiner J, Kiefer A et al. Dkk-3 is elevated in CSF and plasma of Alzheimer’s disease patients. J Neurochem 2009; 110: 653- 61.

287 Piek A, Smit L, Suthahar N et al. The emerging plasma biomarker Dickkopf-3 (DKK3) and its association with renal and cardiovascular disease in the general population. Sci Rep 2021; 11: 8642.

288 Zhao C, Gu Y, Wang Y et al. miR-129-5p promotes osteogenic differentiation of BMSCs and bone regeneration via repressing Dkk3. Stem Cells Int 2021; 2021: 7435605.

289 Zenzmaier C, Sklepos L, Berger P. Increase of Dkk-3 blood plasma levels in the elderly. Exp Gerontol 2008; 43: 867- 70.

290 D’Souza DM, Al-Sajee D, Hawke TJ. Diabetic myopathy: impact of diabetes mellitus on skeletal muscle progenitor cells. Front Physiol 2013; 4: 379.

291 Akhmedov D, Berdeaux R. The effects of obesity on skeletal muscle regeneration. Front Physiol 2013; 4: 371.

292 Yin H, Price F, Rudnicki MA. Satellite cells and the muscle stem cell niche. Physiol Rev 2013; 93: 23- 67.

293 Ling C, Rönn T. Epigenetics in human obesity and type 2 diabetes. Cell Metab 2019; 29: 1028- 44.

294 Milagro FI, Mansego ML, De Miguel C et al. Dietary factors, epigenetic modifications and obesity outcomes: progresses and perspectives. Mol Aspects Med 2013; 34: 782- 812.

295 Wang RR, Pan R, Zhang W et al. The SWI/SNF chromatin-remodeling factors BAF60a, b, and c in nutrient signaling and metabolic control. Protein Cell 2018; 9: 207- 15.

296 Xu J, Li X, Chen W et al. Myofiber Baf60c controls muscle regeneration by modulating Dkk3-mediated paracrine signaling. J Exp Med 2023; 220: e20221123.

297 Meng ZX, Wang L, Xiao Y et al. The Baf60c/Deptor pathway links skeletal muscle inflammation to glucose homeostasis in obesity. Diabetes 2014; 63: 1533- 45.

298 Goldstein MS. Humoral nature of the hypoglycemic factor of muscular work. Diabetes 1961; 10: 232- 4.

299 Febbraio MA, Pedersen BK. Who would have thought—myokines two decades on. Nat Rev Endocrinol 2020; 16: 619- 20.

300 Chow LS, Gerszten RE, Taylor JM et al. Exerkines in health, resilience and disease. Nat Rev Endocrinol 2022; 18: 273- 89.

301 Kirk B, Feehan J, Lombardi G et al. Muscle, bone, and fat crosstalk: the biological role of myokines, osteokines, and adipokines. Curr Osteoporos Rep 2020; 18: 388- 400.

302 Whitham M, Parker BL, Friedrichsen M et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab 2018; 27: 237- 51.e4.

303 Bortoluzzi S, Scannapieco P, Cestaro A et al. Computational reconstruction of the human skeletal muscle secretome. Proteins 2006; 62: 776- 92.

304 Yoon JH, Yea K, Kim J et al. Comparative proteomic analysis of the insulin-induced L6 myotube secretome. Proteomics 2009; 9: 51- 60.

305 Henningsen J, Rigbolt KTG, Blagoev B et al. Dynamics of the skeletal muscle secretome during myoblast differentiation. Mol Cell Proteomics 2010; 9: 2482- 96.

306 Li J, Fang J, Jiang X et al. RNAkines are secreted messengers shaping health and disease. Trends Endocrinol Metab 2023; 35: 201- 18.

307 Guilherme A, Rowland LA, Wang H et al. The adipocyte supersystem of insulin and cAMP signaling. Trends Cell Biol 2023; 33: 340- 54.

308 Hu X, Sun M, Chen Q et al. Skeletal muscle-secreted DLPC orchestrates systemic energy homeostasis by enhancing adipose browning. Nat Commun 2023; 14: 7916.

309 Brooks GA, Osmond AD, Arevalo JA et al. Lactate as a major myokine and exerkine. Nat Rev Endocrinol 2022; 18: 712.

310 He Y, Hakvoort TBM, Köhler SE et al. Glutamine synthetase in muscle is required for glutamine production during fasting and extrahepatic ammonia detoxification. J Biol Chem 2010; 285: 9516- 24.

311 Abdelkader Y, Perez-Davalos L, LeDuc R et al. Omics approaches for the assessment of biological responses to nanoparticles. Adv Drug Deliv Rev 2023; 200: 114992.

312 Artigues A, Nadeau OW, Rimmer MA et al. Protein structural analysis via mass spectrometry-based proteomics. Adv Exp Med Biol 2016; 919: 397- 431.

313 Blume JE, Manning WC, Troiano G et al. Rapid, deep and precise profiling of the plasma proteome with multi-nanoparticle protein corona. Nat Commun 2020; 11: 3662.

314 Weigert C, Lehmann R, Hartwig S et al. The secretome of the working human skeletal muscle—A promising opportunity to combat the metabolic disaster? Proteomics Clin Appl 2014; 8: 5- 18.

315 Seldin MM, Koplev S, Rajbhandari P et al. A strategy for discovery of endocrine interactions with application to whole-body metabolism. Cell Metab 2018; 27: 1138- 1155.e6.

316 Alexovic M, Sabo J, Longuespee R. Microproteomic sample preparation. Proteomics 2021; 21: e2000318.

317 Li L, Sun C, Sun Y et al. Spatially resolved proteomics via tissue expansion. Nat Commun 2022; 13: 7242.

318 Milwid JM, Elman JS, Li M et al. Enriched protein screening of human bone marrow mesenchymal stromal cell secretions reveals MFAP5 and PENK as novel IL-10 modulators. Mol Ther 2014; 22: 999- 1007.

319 Gavaldà-Navarro A, Villarroya J, Cereijo R et al. The endocrine role of brown adipose tissue: an update on actors and actions. Rev Endocr Metab Disord 2022; 23: 31- 41.

320 Erta M, Quintana A, Hidalgo J. Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 2012; 8: 1254- 66.

321 Arhire LI, Mihalache L, Covasa M. Irisin: a hope in understanding and managing obesity and metabolic syndrome. Front Endocrinol (Lausanne) 2019; 10: 524.

322 Schöbitz B, de Kloet ER, Sutanto W et al. Cellular localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain. Eur J Neurosci 1993; 5: 1426- 35.

323 Kong X, Yao T, Zhou P et al. Brown adipose tissue controls skeletal muscle function via the secretion of myostatin. Cell Metab 2018; 28: 631- 643.e3.

324 Egerman MA, Cadena SM, Gilbert JA et al. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab 2015; 22: 164- 74.

325 Dai Z, Song G, Balakrishnan A et al. Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells. Gut 2020; 69: 1104- 15.

326 Ren Y, Zhao H, Yin C et al. Adipokines, hepatokines and myokines: focus on their role and molecular mechanisms in adipose tissue inflammation. Front Endocrinol (Lausanne) 2022; 13: 873699.

327 Dray C, Debard C, Jager J et al. Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans. Am J Physiol Endocrinol Metab 2010; 298: E1161- 9.

328 Yan J, Wang A, Cao J et al. Apelin/APJ system: an emerging therapeutic target for respiratory diseases. Cell Mol Life Sci 2020; 77: 2919- 30.

329 Liu Q, Zhou S, Wang X et al. Apelin alleviated neuroinflammation and promoted endogenous neural stem cell proliferation and differentiation after spinal cord injury in rats. J Neuroinflammation 2022; 19: 160.

330 Jin YJ, Cao PJ, Bian WH et al. BDNF levels in adipose tissue and hypothalamus were reduced in mice with MSG-induced obesity. Nutr Neurosci 2015; 18: 376- 82.

331 Cassiman D, Denef C, Desmet VJ et al. Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. Hepatology 2001; 33: 148- 58.

332 Wang P, Loh KH, Wu M et al. A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue. Nature 2020; 583: 839- 44.

333 Rupérez C, Ferrer-Curriu G, Cervera-Barea A et al. Meteorin-like/Meteorin-β protects heart against cardiac dysfunction. J Exp Med 2021; 218: e20201206.

334 Li ZY, Fan MB, Zhang SL et al. Intestinal Metrnl released into the gut lumen acts as a local regulator for gut antimicrobial peptides. Acta Pharmacol Sin 2016; 37: 1458- 66.

335 Atorrasagasti C, Onorato AM, Mazzolini G. The role of SPARC (secreted protein acidic and rich in cysteine) in the pathogenesis of obesity, type 2 diabetes, and nonalcoholic fatty liver disease. J Physiol Biochem 2023; 79: 815- 31.

336 López-Murcia FJ, Terni B, Llobet A. SPARC triggers a cell-autonomous program of synapse elimination. Proc Natl Acad Sci U S A 2015; 112: 13366- 71.

337 Xie L, Wang PX, Zhang P et al. DKK3 expression in hepatocytes defines susceptibility to liver steatosis and obesity. J Hepatol 2016; 65: 113- 24.

338 Pollen AA, Kriegstein AR. Primate neurons flex their musclin. Neuron 2016; 92: 681- 3.

339 Ollewagen T, Myburgh KH, van de Vyver M et al. Rheumatoid cachexia: the underappreciated role of myoblast, macrophage and fibroblast interplay in the skeletal muscle niche. J Biomed Sci 2021; 28: 15.

340 Wei W, Riley NM, Yang AC et al. Cell type-selective secretome profiling in vivo. Nat Chem Biol 2021; 17: 326- 34.

341 Hui S, Cowan AJ, Zeng X et al. Quantitative fluxomics of circulating metabolites. Cell Metab 2020; 32: 676- 88.e4.

342 Sung BH, von Lersner A, Guerrero J et al. A live cell reporter of exosome secretion and uptake reveals pathfinding behavior of migrating cells. Nat Commun 2020; 11: 2092.

343 Kim KE, Park I, Kim J et al. Dynamic tracking and identification of tissue-specific secretory proteins in the circulation of live mice. Nat Commun 2021; 12: 5204.

344 Kontermann RE. Antibody-cytokine fusion proteins. Arch Biochem Biophys 2012; 526: 194- 205.

345 Roux KJ, Kim DI, Burke B et al. BioID: a screen for protein-protein interactions. Curr Protoc Protein Sci 2018; 91: 19.23.1- 15.