Muscle-Organ Crosstalk: The Emerging Roles of Myokines

Mai Charlotte Krogh Severinsen, Bente Klarlund Pedersen, Mai Charlotte Krogh Severinsen, Bente Klarlund Pedersen

Abstract

Physical activity decreases the risk of a network of diseases, and exercise may be prescribed as medicine for lifestyle-related disorders such as type 2 diabetes, dementia, cardiovascular diseases, and cancer. During the past couple of decades, it has been apparent that skeletal muscle works as an endocrine organ, which can produce and secrete hundreds of myokines that exert their effects in either autocrine, paracrine, or endocrine manners. Recent advances show that skeletal muscle produces myokines in response to exercise, which allow for crosstalk between the muscle and other organs, including brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin, as well as communication within the muscle itself. Although only few myokines have been allocated to a specific function in humans, it has been identified that the biological roles of myokines include effects on, for example, cognition, lipid and glucose metabolism, browning of white fat, bone formation, endothelial cell function, hypertrophy, skin structure, and tumor growth. This suggests that myokines may be useful biomarkers for monitoring exercise prescription for people with, for example, cancer, diabetes, or neurodegenerative diseases.

Keywords: cancer; cytokines; diabetes; exercise; metabolism; physical activity.

© Endocrine Society 2020.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Musclin, LIF, IL-4, IL-6, IL-7, and IL-15 promote muscle hypertrophy. Myostatin inhibits muscle hypertrophy.
Figure 2.
Figure 2.
Cathepsin B and irisin cross the blood–brain barrier and stimulate BDNF production, which leads to hippocampal neurogenesis. IL-6 stimulates appetite. Abbreviations: BDNF, brain-derived neurotrophic factor.
Figure 3.
Figure 3.
IL-6 stimulates lipolysis decreases visceral fat mass. Irisin, meteorin-like, and IL-6 have a role in “browning” of white adipose tissue. IL-6 and BDNF stimulate AMPK activation. Abbreviations: AMPK, 5′-AMP-activated protein kinase; BDNF, brain-derived neurotrophic factor.
Figure 4.
Figure 4.
Decorin, IL-6, IGF-1, and FGF-2 positively regulate bone formation. Abbreviations: FGF-2, fibroblast growth factor 2; IGF-1, insulin-like growth factor I.
Figure 5.
Figure 5.
Angiogenin, osteoprotegerin, and IL-6 possess pancreatic β-cell protective actions against proinflammatory cytokines. IL-6 increases insulin secretion by inducing the expression of GLP-1 by the L cells of the intestine. Abbreviations: GLP-1, glucagon-like peptide 1.
Figure 6.
Figure 6.
IL-6 has anti-inflammatory effects as it inhibits TNF production and stimulates the production of IL-1ra and IL-10. IL-6 stimulates cortisol production and thereby induces neutrocytosis and lymphopenia. Abbreviations: IL-1ra, IL-1 receptor antagonist; TNF, tumor necrosis factor.
Figure 7.
Figure 7.
Cathepsin B and irisin cross the blood–brain barrier and stimulate BDNF production and hippocampal neurogenesis. IL-6 stimulates appetite and lipolysis and decreases visceral fat mass. Irisin, meteorin-like, and IL-6 have a role in “browning” of white adipose tissue. IL-15 improves aging skin. Decorin, IL-6, IGF-1 and FGF-2 positively regulate bone formation. Myostatin negatively regulate bone formation. Musclin, LIF, IL-4, IL-6, IL-7, and IL-15 promote muscle hypertrophy. Myostatin inhibits muscle hypertrophy. BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 enhances insulin-stimulated glucose uptake and stimulates glucose output from the liver, but only during exercise. IL-6 increases insulin secretion by inducing the expression of GLP-1 by the L cells of the intestine. IL-6 has anti-inflammatory effects as it inhibits TNF production and stimulates the production of IL-1ra and IL-10. IL-6 stimulates cortisol production and thereby induces neutrocytosis and lymphopenia. FSTL-1 improves endothelial function and revascularization of ischemic blood vessels. Angiogenin, osteoprotegerin and IL-6 possess pancreatic β-cell protective actions against proinflammatory cytokines. Abbreviations: AMPK, 5′-AMP-activated protein kinase; BDNF, brain-derived neurotrophic factor; FGF-2, fibroblast growth factor 2; FGF-21, fibroblast growth factor 21; FSTL-1, follistatin-related protein 1; GLP-1, glucagon-like peptide 1; IGF-1, insulin-like growth factor I; IL-1ra, IL-1 receptor antagonist; LIF, leukemia inhibitory factor; TGF-β, transforming growth factor β; TNF, tumor necrosis factor.

References

    1. Kjaer M, Secher NH, Bangsbo J, et al. Hormonal and metabolic responses to electrically induced cycling during epidural anesthesia in humans. J Appl Physiol (1985). 1996;80(6):2156-2162.
    1. Mohr T, Andersen JL, Biering-Sørensen F, et al. Long-term adaptation to electrically induced cycle training in severe spinal cord injured individuals. Spinal Cord. 1997;35(1):1-16.
    1. Goldstein M. Humoral nature of hypoglycemia in muscular activity. Am J Physiol. 1961;200:67-70.
    1. 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(2-3):113-119.
    1. Steensberg A, van Hall G, Osada T, Sacchetti M, Saltin B, Klarlund Pedersen B. 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):237-242.
    1. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2008;88(4):1379-1406.
    1. Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012;8(8):457-465.
    1. Safdar A, Tarnopolsky MA. Exosomes as mediators of the systemic adaptations to endurance exercise. Cold Spring Harb Perspect Med. 2018;8(3):a029827.
    1. Safdar A, Saleem A, Tarnopolsky MA. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat Rev Endocrinol. 2016;12(9):504-517.
    1. Whitham M, Parker BL, Friedrichsen M, et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 2018;27(1):237-251.e4.
    1. Das DK, Graham ZA, Cardozo CP. Myokines in skeletal muscle physiology and metabolism: recent advances and future perspectives. Acta Physiol (Oxf). 2020;228(2):e13367.
    1. Eckel J. Myokines in metabolic homeostasis and diabetes. Diabetologia. 2019;62(9):1523-1528.
    1. Garneau L, Aguer C. Role of myokines in the development of skeletal muscle insulin resistance and related metabolic defects in type 2 diabetes. Diabetes Metab. 2019;45(6):505-516.
    1. Lee JH, Jun HS. Role of myokines in regulating skeletal muscle mass and function. Front Physiol. 2019;10:42.
    1. Díaz BB, González DA, Gannar F, Pérez MCR, de León AC. Myokines, physical activity, insulin resistance and autoimmune diseases. Immunol Lett. 2018;203:1-5.
    1. Hoffmann C, Weigert C. Skeletal muscle as an endocrine organ: the role of myokines in exercise adaptations. Cold Spring Harb Perspect Med. 2017;7(11):a029793.
    1. Rodríguez A, Becerril S, Ezquerro S, Méndez-Giménez L, Frühbeck G. Crosstalk between adipokines and myokines in fat browning. Acta Physiol (Oxf). 2017;219(2):362-381.
    1. Schnyder S, Handschin C. Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise. Bone. 2015;80:115-125.
    1. Ahima RS, Park HK. Connecting myokines and metabolism. Endocrinol Metab (Seoul). 2015;30(3):235-245.
    1. Raschke S, Eckel J. Adipo-myokines: two sides of the same coin–mediators of inflammation and mediators of exercise. Mediators Inflamm. 2013;2013:320724.
    1. Pedersen BK. Exercise-induced myokines and their role in chronic diseases. Brain Behav Immun. 2011;25(5):811-816.
    1. Trayhurn P, Drevon CA, Eckel J. Secreted proteins from adipose tissue and skeletal muscle - adipokines, myokines and adipose/muscle cross-talk. Arch Physiol Biochem. 2011;117(2):47-56.
    1. Hamrick MW. A role for myokines in muscle-bone interactions. Exerc Sport Sci Rev. 2011;39(1):43-47.
    1. Brandt C, Pedersen BK. The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases. J Biomed Biotechnol. 2010;2010:520258.
    1. Arnold AS, Egger A, Handschin C. PGC-1α and myokines in the aging muscle - a mini-review. Gerontology. 2011;57(1):37-43.
    1. Pedersen BK. The diseasome of physical inactivity- and the role of myokines in muscle-fat cross talk. J Physiol. 2009;587(Pt 23):5559-5568.
    1. Walsh K. Adipokines, myokines and cardiovascular disease. Circ J. 2009;73(1):13-18.
    1. Pedersen BK, Akerström TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol (1985). 2007;103(3):1093-1098.
    1. Benatti FB, Pedersen BK. Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation. Nat Rev Rheumatol. 2015;11(2):86-97.
    1. Pedersen BK. Physical activity and muscle-brain crosstalk. Nat Rev Endocrinol. 2019;15(7):383-392.
    1. Whitham M, Febbraio MA. The ever-expanding myokinome: discovery challenges and therapeutic implications. Nat Rev Drug Discov. 2016;15(10):719-729.
    1. Pal M, Febbraio MA, Whitham M. From cytokine to myokine: the emerging role of interleukin-6 in metabolic regulation. Immunol Cell Biol. 2014;92(4):331-339.
    1. Ruiz-Casado A, Martín-Ruiz A, Pérez LM, Provencio M, Fiuza-Luces C, Lucia A. Exercise and the hallmarks of cancer. Trends Cancer. 2017;3(6):423-441.
    1. Fiuza-Luces C, Santos-Lozano A, Joyner M, et al. Exercise benefits in cardiovascular disease: beyond attenuation of traditional risk factors. Nat Rev Cardiol. 2018;15(12):731-743.
    1. Indrakusuma I, Sell H, Eckel J. Novel mediators of adipose tissue and muscle crosstalk. Curr Obes Rep. 2015;4(4):411-417.
    1. Graf C, Ferrari N. Metabolic health-the role of adipo-myokines. Int J Mol Sci. 2019;20(24):6159.
    1. Coelho-Junior HJ, Picca A, Calvani R, Uchida MC, Marzetti E. If my muscle could talk: myokines as a biomarker of frailty. Exp Gerontol. 2019;127:110715.
    1. Khan SU, Ghafoor S. Myokines: discovery challenges and therapeutic impediments. J Pak Med Assoc. 2019;69(7):1014-1017.
    1. Henningsen J, Pedersen BK, Kratchmarova I. Quantitative analysis of the secretion of the MCP family of chemokines by muscle cells. Mol Biosyst. 2011;7(2):311-321.
    1. Henningsen J, Rigbolt KT, Blagoev B, Pedersen BK, Kratchmarova I. Dynamics of the skeletal muscle secretome during myoblast differentiation. Mol Cell Proteomics. 2010;9(11):2482-2496.
    1. Hojman P, Gehl J, Christensen JF, Pedersen BK. Molecular mechanisms linking exercise to cancer prevention and treatment. Cell Metab. 2018;27(1):10-21.
    1. Pedersen L, Idorn M, Olofsson GH, et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 2016;23(3):554-562.
    1. 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.
    1. 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):e79.
    1. Grobet L, 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.
    1. 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.
    1. Saremi A, Gharakhanloo R, Sharghi S, Gharaati MR, Larijani B, Omidfar K. Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol. 2010;317(1-2):25-30.
    1. Hittel DS, Axelson M, Sarna N, Shearer J, Huffman KM, Kraus WE. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med Sci Sports Exerc. 2010;42(11):2023-2029.
    1. Serrano AL, Baeza-Raja B, Perdiguero E, Jardí M, Muñoz-Cánoves P. Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab. 2008;7(1):33-44.
    1. Broholm C, Mortensen OH, Nielsen S, et al. Exercise induces expression of leukaemia inhibitory factor in human skeletal muscle. J Physiol. 2008;586(8):2195-2201.
    1. Broholm C, Pedersen BK. Leukaemia inhibitory factor–an exercise-induced myokine. Exerc Immunol Rev. 2010;16:77-85.
    1. Gao S, Durstine JL, Koh HJ, Carver WE, Frizzell N, Carson JA. Acute myotube protein synthesis regulation by IL-6-related cytokines. Am J Physiol Cell Physiol. 2017;313(5):C487-C500.
    1. Nielsen AR, Mounier R, Plomgaard P, et al. Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J Physiol. 2007;584(Pt 1):305-312.
    1. Haugen F, Norheim F, Lian H, et al. IL-7 is expressed and secreted by human skeletal muscle cells. Am J Physiol Cell Physiol. 2010;298(4):C807-C816.
    1. Fischer CP. Interleukin-6 in acute exercise and training: what is the biological relevance? Exerc Immunol Rev. 2006;12:6-33.
    1. Fischer CP, Plomgaard P, Hansen AK, Pilegaard H, Saltin B, Pedersen BK. Endurance training reduces the contraction-induced interleukin-6 mRNA expression in human skeletal muscle. Am J Physiol Endocrinol Metab. 2004;287(6):E1189-E1194.
    1. Keller C, Steensberg A, Hansen AK, Fischer CP, Plomgaard P, Pedersen BK. Effect of exercise, training, and glycogen availability on IL-6 receptor expression in human skeletal muscle. J Appl Physiol (1985). 2005;99(6):2075-2079.
    1. 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 AMP-activated protein kinase. Diabetes. 2006;55(10):2688-2697.
    1. Bruce CR, Dyck DJ. Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-alpha. Am J Physiol Endocrinol Metab. 2004;287(4):E616-E621.
    1. Petersen EW, Carey AL, Sacchetti M, et al.. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro: evidence that IL-6 acts independently of lipolytic hormones. Am J Physiol. 2005;288(1):E155-E162.
    1. 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.
    1. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1(1):15-25.
    1. Matthews VB, Aström MB, Chan MH, 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(7):1409-1418.
    1. Nishizawa H, Matsuda M, Yamada Y, et al. Musclin, a novel skeletal muscle-derived secretory factor. J Biol Chem. 2004;279(19):19391-19395.
    1. Subbotina E, Sierra A, Zhu Z, et al. Musclin is an activity-stimulated myokine that enhances physical endurance. Proc Natl Acad Sci U S A. 2015;112(52):16042-16047.
    1. Re Cecconi AD, Forti M, Chiappa M, et al. Myokine induced by aerobic exercise, retards muscle atrophy during cancer cachexia in mice. Cancers. 2019;11(10):1541.
    1. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30(9):464-472.
    1. Mattson MP. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab. 2012;16(6): 706-722.
    1. Aarsland D, Sardahaee FS, Anderssen S, Ballard C; Alzheimer’s Society Systematic Review group . Is physical activity a potential preventive factor for vascular dementia? A systematic review. Aging Ment Health. 2010;14(4):386-395.
    1. Williams JW, Plassman BL, Burke J, Benjamin S. Preventing Alzheimer’s disease and cognitive decline. Evid Rep Technol Assess (Full Rep). 2010;(193):1-727.
    1. Santos-Lozano A, Pareja-Galeano H, Sanchis-Gomar F, et al. Physical activity and Alzheimer disease: a protective association. Mayo Clin Proc. 2016;91(8):999-1020.
    1. Pedersen BK, Saltin B. Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports. 2015;25 Suppl(3):1-72.
    1. Voss MW, Nagamatsu LS, Liu-Ambrose T, Kramer AF. Exercise, brain, and cognition across the life span. J Appl Physiol (1985). 2011;111(5):1505-1513.
    1. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25(6):295-301.
    1. Smith PJ, Blumenthal JA, Hoffman BM, et al. Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med. 2010;72(3):239-252.
    1. Snowden M, Steinman L, Mochan K, et al. Effect of exercise on cognitive performance in community-dwelling older adults: review of intervention trials and recommendations for public health practice and research. J Am Geriatr Soc. 2011;59(4):704-716.
    1. Aberg MA, Pedersen NL, Torén K, et al. Cardiovascular fitness is associated with cognition in young adulthood. Proc Natl Acad Sci U S A. 2009;106(49):20906-20911.
    1. Blundell JE, Gibbons C, Caudwell P, Finlayson G, Hopkins M. Appetite control and energy balance: impact of exercise. Obes Rev. 2015;16 Suppl (1):67-76.
    1. Kelley GA, Kelley KS. Exercise and sleep: a systematic review of previous meta-analyses. J Evid Based Med. 2017;10(1):26-36.
    1. Crush EA, Frith E, Loprinzi PD. Experimental effects of acute exercise duration and exercise recovery on mood state. J Affect Disord. 2018;229:282-287.
    1. Kobilo T, Liu QR, Gandhi K, Mughal M, Shaham Y, van Praag H. Running is the neurogenic and neurotrophic stimulus in environmental enrichment. Learn Mem. 2011;18(9):605-609.
    1. Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011;108(7):3017-3022.
    1. Leardini-Tristao M, Charles AL, Lejay A, et al. Beneficial effect of exercise on cognitive function during peripheral arterial disease: potential involvement of myokines and microglial anti-inflammatory phenotype enhancement. J Clin Med. 2019;8(5):653.
    1. Rai M, Demontis F. Systemic nutrient and stress signaling via myokines and myometabolites. Annu Rev Physiol. 2016;78:85-107.
    1. Makarova JA, Maltseva DV, Galatenko VV, et al. Exercise immunology meets MiRNAs. Exerc Immunol Rev. 2014;20:135-164.
    1. Loprinzi PD, Frith E. A brief primer on the mediational role of BDNF in the exercise-memory link. Clin Physiol Funct Imaging. 2019;39(1):9-14.
    1. Neeper SA, Gómez-Pinilla F, Choi J, Cotman C. Exercise and brain neurotrophins. Nature. 1995;373(6510):109.
    1. Liu PZ, Nusslock R. Exercise-mediated neurogenesis in the hippocampus via BDNF. Front Neurosci. 2018;12:52.
    1. Oliff HS, Berchtold NC, Isackson P, Cotman CW. Exercise-induced regulation of brain-derived neurotrophic factor (BDNF) transcripts in the rat hippocampus. Brain Res Mol Brain Res. 1998;61(1-2):147-153.
    1. Van Hoomissen JD, Chambliss HO, Holmes PV, Dishman RK. Effects of chronic exercise and imipramine on mRNA for BDNF after olfactory bulbectomy in rat. Brain Res. 2003;974(1-2):228-235.
    1. Farmer J, Zhao X, van Praag H, Wodtke K, Gage FH, Christie BR. Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo. Neuroscience. 2004;124(1):71-79.
    1. Adlard PA, Perreau VM, Cotman CW. The exercise-induced expression of BDNF within the hippocampus varies across life-span. Neurobiol Aging. 2005;26(4):511-520.
    1. Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci. 2004;20(10):2580-2590.
    1. Vaynman S, Ying Z, Gómez-Pinilla F. Exercise induces BDNF and synapsin I to specific hippocampal subfields. J Neurosci Res. 2004;76(3):356-362.
    1. Rasmussen P, Brassard P, Adser H, et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp Physiol. 2009;94(10):1062-1069.
    1. Seifert T, Brassard P, Wissenberg M, et al. Endurance training enhances BDNF release from the human brain. Am J Physiol Regul Integr Comp Physiol. 2010;298(2):R372-R377.
    1. Pajonk FG, Wobrock T, Gruber O, et al. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry. 2010;67(2):133-143.
    1. Wrann CD, White JP, Salogiannnis J, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 2013;18(5):649-659.
    1. Moon HY, Becke A, Berron D, et al. Running-induced systemic cathepsin b secretion is associated with memory function. Cell Metab. 2016;24(2):332-340.
    1. Suzuki WA. How body affects brain. Cell Metab. 2016;24(2):192-193.
    1. 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.
    1. Albrecht E, Norheim F, Thiede B, et al. Irisin - a myth rather than an exercise-inducible myokine. Sci Rep. 2015;5:8889.
    1. Wrann CD. FNDC5/irisin - their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Brain Plast. 2015;1(1):55-61.
    1. Kim HJ, Higashimori T, Park SY, et al. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes. 2004;53(4):1060-1067.
    1. Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11(2):183-190.
    1. Matthews VB, Allen TL, Risis S, et al. Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia. 2010;53(11):2431-2441.
    1. Wallenius V, Wallenius K, Ahrén B, et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med. 2002;8(1):75-79.
    1. Ellingsgaard H, Hauselmann I, Schuler B, et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med. 2011;17(11):1481-1489.
    1. Mauer J, Chaurasia B, Goldau J, et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol. 2014;15(5):423-430.
    1. Mauer J, Denson JL, Brüning JC. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 2015;36(2):92-101.
    1. Lang Lehrskov L, Lyngbaek MP, Soederlund L, et al. Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control. Cell Metab. 2018;27(6):1201-1211.e3.
    1. Steensberg A, Fischer CP, Keller C, Møller K, Pedersen BK. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab. 2003;285(2):E433-E437.
    1. Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003;17(8):884-886.
    1. Febbraio MA, Pedersen BK. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J. 2002;16(11):1335-1347.
    1. Keller C, Hellsten Y, Steensberg A, Pedersen BK. Differential regulation of IL-6 and TNF-alpha via calcineurin in human skeletal muscle cells. Cytokine. 2006;36(3-4):141-147.
    1. Hidalgo J, Florit S, Giralt M, Ferrer B, Keller C, Pilegaard H. Transgenic mice with astrocyte-targeted production of interleukin-6 are resistant to high-fat diet-induced increases in body weight and body fat. Brain Behav Immun. 2010;24(1):119-126.
    1. Señarís RM, Trujillo ML, Navia B, et al. Interleukin-6 regulates the expression of hypothalamic neuropeptides involved in body weight in a gender-dependent way. J Neuroendocrinol. 2011;23(8):675-686.
    1. Molinero A, Fernandez-Perez A, Mogas A, et al. Role of muscle IL-6 in gender-specific metabolism in mice. PLoS One. 2017;12(3):e0173675.
    1. Timper K, Denson JL, Steculorum SM, et al. IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-signaling. Cell Rep. 2017;19(2):267-280.
    1. Pedersen BK. Muscle as a secretory organ. Compr Physiol. 2013;3(3):1337-1362.
    1. Pedersen BK. The physiology of optimizing health with a focus on exercise as medicine. Annu Rev Physiol. 2019;81:607-627.
    1. Fosgerau K, Galle P, Hansen T, et al. Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes. J Endocrinol. 2010;204(3):265-273.
    1. Bays HE. “Sick fat,” metabolic disease, and atherosclerosis. Am J Med. 2009;122(1 Suppl):S26-S37.
    1. Haffner SM. Abdominal adiposity and cardiometabolic risk: do we have all the answers? Am J Med. 2007;120(9 Suppl 1):S10-S16; discussion S16.
    1. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology. 2008;71(14):1057-1064.
    1. Giovannucci E. Metabolic syndrome, hyperinsulinemia, and colon cancer: a review. Am J Clin Nutr. 2007;86(3):s836-s842.
    1. Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence. Am J Clin Nutr. 2007;86(3):s823-s835.
    1. Pischon T, Boeing H, Hoffmann K, et al. General and abdominal adiposity and risk of death in Europe. N Engl J Med. 2008;359(20):2105-2120.
    1. Wedell-Neergaard AS, Krogh-Madsen R, Petersen GL, et al. Cardiorespiratory fitness and the metabolic syndrome: roles of inflammation and abdominal obesity. PLoS One. 2018;13(3):e0194991.
    1. Wedell-Neergaard AS, Eriksen L, Grønbæk M, Pedersen BK, Krogh-Madsen R, Tolstrup J. Low fitness is associated with abdominal adiposity and low-grade inflammation independent of BMI. PLoS One. 2018;13(1):e0190645.
    1. Yudkin JS, Eringa E, Stehouwer CD. “Vasocrine” signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease. Lancet. 2005;365(9473):1817-1820.
    1. Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature. 2008;454(7203):463-469.
    1. Olsen RH, Krogh-Madsen R, Thomsen C, Booth FW, Pedersen BK. Metabolic responses to reduced daily steps in healthy nonexercising men. JAMA. 2008;299(11):1261-1263.
    1. Nordby P, Auerbach PL, Rosenkilde M, et al. Endurance training per se increases metabolic health in young, moderately overweight men. Obesity (Silver Spring). 2012;20(11):2202-2212.
    1. Ross R, Dagnone D, Jones PJ, et al. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med. 2000;133(2):92-103.
    1. Wedell-Neergaard AS, Lang Lehrskov L, Christensen RH, et al. Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: a randomized controlled trial. Cell Metab. 2019;29(4):844-855.e3.
    1. Christensen RH, Wedell-Neergaard AS, Lehrskov LL, et al. The role of exercise combined with tocilizumab in visceral and epicardial adipose tissue and gastric emptying rate in abdominally obese participants: protocol for a randomised controlled trial. Trials. 2018;19(1):266.
    1. Christensen RH, Lehrskov LL, Wedell-Neergaard AS, et al. Aerobic exercise induces cardiac fat loss and alters cardiac muscle mass through an interleukin-6 receptor-dependent mechanism: cardiac analysis of a double-blind randomized controlled clinical trial in abdominally obese humans. Circulation. 2019;140(20):1684-1686.
    1. Townsend LK, Wright DC. Looking on the “brite” side exercise-induced browning of white adipose tissue. Pflugers Arch. 2019;471(3):455-465.
    1. Dinas PC, Lahart IM, Timmons JA, et al. Effects of physical activity on the link between PGC-1a and FNDC5 in muscle, circulating Ιrisin and UCP1 of white adipocytes in humans: a systematic review. F1000Res. 2017;6:286.
    1. Rao R, Long J, White J, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to Increase BEige Fat Thermogenesis. Cell. 2014;157(6):1279-1291.
    1. Pedersen BK. Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease. Eur J Clin Invest. 2017;47(8):600-611.
    1. Karstoft K, Pedersen BK. Skeletal muscle as a gene regulatory endocrine organ. Curr Opin Clin Nutr Metab Care. 2016;19(4):270-275.
    1. Karstoft K, Pedersen BK. Exercise and type 2 diabetes: focus on metabolism and inflammation. Immunol Cell Biol. 2016;94(2):146-150.
    1. Knudsen SH, Pedersen BK. Targeting inflammation through a physical active lifestyle and pharmaceuticals for the treatment of type 2 diabetes. Curr Diab Rep. 2015;15(10):82.
    1. Knudsen JG, Murholm M, Carey AL, et al. Role of IL-6 in exercise training- and cold-induced UCP1 expression in subcutaneous white adipose tissue. PLoS One. 2014;9(1):e84910.
    1. Kristóf E, Klusóczki Á, Veress R, et al. Interleukin-6 released from differentiating human beige adipocytes improves browning. Exp Cell Res. 2019;377(1-2):47-55.
    1. 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(1):96-108.
    1. Kammoun HL, Febbraio MA. Come on BAIBA light my fire. Cell Metab. 2014;19(1):1-2.
    1. Hansen JS, Clemmesen JO, Secher NH, et al. Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans. Mol Metab. 2015;4(8):551-560.
    1. Hansen JS, Rutti S, Arous C, et al. Circulating follistatin is liver-derived and regulated by the glucagon-to-insulin ratio. J Clin Endocrinol Metab. 2016;101(2):550-560.
    1. Hansen JS, Pedersen BK, Xu G, Lehmann R, Weigert C, Plomgaard P. 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.
    1. Singh R, Braga M, Pervin S. Regulation of brown adipocyte metabolism by myostatin/follistatin signaling. Front Cell Dev Biol. 2014;2:60.
    1. Véniant MM, Sivits G, Helmering J, et al. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab. 2015;21(5):731-738.
    1. Norheim F, Langleite TM, Hjorth M, et al. The effects of acute and chronic exercise on PGC-1α, irisin and browning of subcutaneous adipose tissue in humans. Febs J. 2014;281(3):739-749.
    1. Vosselman MJ, Hoeks J, Brans B, et al. Low brown adipose tissue activity in endurance-trained compared with lean sedentary men. Int J Obes (Lond). 2015;39(12):1696-1702.
    1. Schipilow JD, Macdonald HM, Liphardt AM, Kan M, Boyd SK. Bone micro-architecture, estimated bone strength, and the muscle-bone interaction in elite athletes: an HR-pQCT study. Bone. 2013;56(2):281-289.
    1. Verschueren S, Gielen E, O’Neill TW, et al. Sarcopenia and its relationship with bone mineral density in middle-aged and elderly European men. Osteoporos Int. 2013;24(1):87-98.
    1. Guo B, Zhang ZK, Liang C, et al. Molecular communication from skeletal muscle to bone: a review for muscle-derived myokines regulating bone metabolism. Calcif Tissue Int. 2017;100(2):184-192.
    1. Gomarasca M, Banfi G, Lombardi G. Myokines: the endocrine coupling of skeletal muscle and bone. Adv Clin Chem. 2020;94:155-218.
    1. Bialek P, Parkington J, Li X, et al. A myostatin and activin decoy receptor enhances bone formation in mice. Bone. 2014;60:162-171.
    1. Dankbar B, Fennen M, Brunert D, et al. Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice. Nat Med. 2015;21(9):1085-1090.
    1. De Benedetti F, Rucci N, Del Fattore A, et al. Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum. 2006;54(11):3551-3563.
    1. Jilka RL, Hangoc G, Girasole G, et al. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science. 1992;257(5066):88-91.
    1. Le Goff B, Blanchard F, Berthelot JM, Heymann D, Maugars Y. Role for interleukin-6 in structural joint damage and systemic bone loss in rheumatoid arthritis. Joint Bone Spine. 2010;77(3):201-205.
    1. Axmann R, Böhm C, Krönke G, Zwerina J, Smolen J, Schett G. Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum. 2009;60(9):2747-2756.
    1. Palmqvist P, Persson E, Conaway HH, Lerner UH. IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol. 2002;169(6):3353-3362.
    1. Saidenberg-Kermanac’h N, Cohen-Solal M, Bessis N, De Vernejoul MC, Boissier MC. Role for osteoprotegerin in rheumatoid inflammation. Joint Bone Spine. 2004;71(1):9-13.
    1. Lombardi G, Sanchis-Gomar F, Perego S, Sansoni V, Banfi G. Implications of exercise-induced adipo-myokines in bone metabolism. Endocrine. 2016;54(2):284-305.
    1. Yakar S, Rosen CJ, Beamer WG, et al. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest. 2002;110(6):771-781.
    1. Perrini S, Laviola L, Carreira MC, Cignarelli A, Natalicchio A, Giorgino F. The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis. J Endocrinol. 2010;205(3):201-210.
    1. Chan CY, Masui O, Krakovska O, et al. Identification of differentially regulated secretome components during skeletal myogenesis. Mol Cell Proteomics. 2011;10(5):M110.004804.
    1. Chan CY, McDermott JC, Siu KW. Secretome analysis of skeletal myogenesis using SILAC and shotgun proteomics. Int J Proteomics. 2011;2011:329467.
    1. Kaji H. Effects of myokines on bone. Bonekey Rep. 2016;5:826.
    1. Wasserman DH, Lacy DB, Colburn CA, Bracy D, Cherrington AD. Efficiency of compensation for absence of fall in insulin during exercise. Am J Physiol. 1991;261(5 Pt 1):E587-E597.
    1. Febbraio MA, Hiscock N, Sacchetti M, Fischer CP, Pedersen BK. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes. 2004;53(7):1643-1648.
    1. Steensberg A, Fischer CP, Sacchetti M, et al. Acute interleukin-6 administration does not impair muscle glucose uptake or whole body glucose disposal in healthy humans. J Physiol. 2003;548(Pt 2):631-638.
    1. Peppler WT, Townsend LK, Meers GM, et al. Acute administration of IL-6 improves indices of hepatic glucose and insulin homeostasis in lean and obese mice. Am J Physiol Gastrointest Liver Physiol. 2019;316(1):G166-G178.
    1. Woerle HJ, Albrecht M, Linke R, et al. Importance of changes in gastric emptying for postprandial plasma glucose fluxes in healthy humans. Am J Physiol Endocrinol Metab. 2008;294(1): E103-E109.
    1. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes. 2005;54(10):2939-2945.
    1. Bouzakri K, Plomgaard P, Berney T, Donath MY, Pedersen BK, Halban PA. Bimodal effect on pancreatic β-cells of secretory products from normal or insulin-resistant human skeletal muscle. Diabetes. 2011;60(4):1111-1121.
    1. Rutti S, Dusaulcy R, Hansen JS, et al. Angiogenin and Osteoprotegerin are type II muscle specific myokines protecting pancreatic beta-cells against proinflammatory cytokines. Sci Rep. 2018;8(1):10072.
    1. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98-107.
    1. Eguchi K, Manabe I. Macrophages and islet inflammation in type 2 diabetes. Diabetes Obes Metab. 2013;15 Suppl (3):152-158.
    1. Ehses JA, Perren A, Eppler E, et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes. 2007;56(9):2356-2370.
    1. Westwell-Roper CY, Ehses JA, Verchere CB. Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1β production and β-cell dysfunction. Diabetes. 2014;63(5):1698-1711.
    1. Alluisi EA, Beisel WR, Caldwell LS. Effects of sandfly fever on isometric muscular strength, endurance, and recovery. J Mot Behav. 1980;12(1):1-11.
    1. Cabrera SM, Wang X, Chen YG, et al. ; Type 1 Diabetes TrialNet Canakinumab Study Group; AIDA Study Group . Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset. Eur J Immunol. 2016;46(4): 1030-1046.
    1. Urwyler SA, Schuetz P, Ebrahimi F, Donath MY, Christ-Crain M. Interleukin-1 antagonism decreases cortisol levels in obese individuals. J Clin Endocrinol Metab. 2017;102(5):1712-1718.
    1. Everett BM, Donath MY, Pradhan AD, et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J Am Coll Cardiol. 2018;71(21):2392-2401.
    1. Ellingsgaard H, Ehses JA, Hammar EB, et al. Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc Natl Acad Sci U S A. 2008;105(35):13163-13168.
    1. Izumiya Y, Hopkins T, Morris C, et al. Fast/Glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab. 2008;7(2):159-172.
    1. Shimano M, Ouchi N, Walsh K. Cardiokines: recent progress in elucidating the cardiac secretome. Circulation. 2012;126(21):e327-e332.
    1. Ouchi N, Oshima Y, Ohashi K, et al. Follistatin-like 1, a secreted muscle protein, promotes endothelial cell function and revascularization in ischemic tissue through a nitric-oxide synthase-dependent mechanism. J Biol Chem. 2008;283(47):32802-32811.
    1. Oshima Y, Ouchi N, Sato K, Izumiya Y, Pimentel DR, Walsh K. Follistatin-like 1 is an Akt-regulated cardioprotective factor that is secreted by the heart. Circulation. 2008;117(24):3099-3108.
    1. El-Armouche A, Ouchi N, Tanaka K, et al. Follistatin-like 1 in chronic systolic heart failure: a marker of left ventricular remodeling. Circ Heart Fail. 2011;4(5):621-627.
    1. Tanaka K, Valero-Muñoz M, Wilson RM, et al. Follistatin like 1 regulates hypertrophy in heart failure with preserved ejection fraction. JACC Basic Transl Sci. 2016;1(4):207-221.
    1. Ogura Y, Ouchi N, Ohashi K, et al. Therapeutic impact of follistatin-like 1 on myocardial ischemic injury in preclinical models. Circulation. 2012;126(14):1728-1738.
    1. Seki M, Powers JC, Maruyama S, et al. Acute and chronic increases of circulating FSTL1 normalize energy substrate metabolism in pacing-induced heart failure. Circ Heart Fail. 2018;11(1):e004486.
    1. Crane JD, MacNeil LG, Lally JS, et al. Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging. Aging Cell. 2015;14(4):625-634.
    1. Duggal NA, Niemiro G, Harridge SDR, Simpson RJ, Lord JM. Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity? Nat Rev Immunol. 2019;19(9):563-572.
    1. McCarthy DA, Dale MM. The leucocytosis of exercise. A review and model. Sports Med. 1988;6(6):333-363.
    1. Pedersen BK, Hoffman-Goetz L. Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev. 2000;80(3):1055-1081.
    1. Nieman DC, Fagoaga OR, Butterworth DE, et al. Carbohydrate supplementation affects blood granulocyte and monocyte trafficking but not function after 2.5 h or running. Am J Clin Nutr. 1997;66(1):153-159.
    1. Nehlsen-Cannarella SL, Fagoaga OR, Nieman DC, et al. Carbohydrate and the cytokine response to 2.5 h of running. J Appl Physiol (1985). 1997;82(5):1662-1667.
    1. Fischer CP, Hiscock NJ, Penkowa M, et al. Supplementation with vitamins C and E inhibits the release of interleukin-6 from contracting human skeletal muscle. J Physiol. 2004;558(Pt 2):633-645.
    1. Petersen AM, Pedersen BK. The role of IL-6 in mediating the anti-inflammatory effects of exercise. J Physiol Pharmacol. 2006;57 Suppl (10):43-51.
    1. Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol (1985). 2005;98(4):1154-1162.
    1. Pedersen BK, Steensberg A, Keller P, et al. Muscle-derived interleukin-6: lipolytic, anti-inflammatory and immune regulatory effects. Pflugers Arch. 2003;446(1):9-16.
    1. Pedersen BK. The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. Essays Biochem. 2006;42:105-117.
    1. Dinarello CA. The interleukin-1 family: 10 years of discovery. Faseb J. 1994;8(15):1314-1325.
    1. Opp MR, Smith EM, Hughes TK Jr. Interleukin-10 (cytokine synthesis inhibitory factor) acts in the central nervous system of rats to reduce sleep. J Neuroimmunol. 1995;60(1-2):165-168.
    1. Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA. Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood. 1990;75(1):40-47.
    1. Mizuhara H, O’Neill E, Seki N, et al. T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6. J Exp Med. 1994;179(5):1529-1537.
    1. Han MS, White A, Perry RJ, et al. Regulation of adipose tissue inflammation by interleukin 6. Proc Natl Acad Sci U S A. 2020;117(6):2751-2760.
    1. Rosenkilde M, Nordby P, Stallknecht B. Maintenance of improvements in fitness and fatness 1 year after a 3-month lifestyle intervention in overweight men. Eur J Clin Nutr. 2016;70(10):1212-1214.
    1. Laye MJ, Thyfault JP, Stump CS, Booth FW. Inactivity induces increases in abdominal fat. J Appl Physiol (1985). 2007;102(4):1341-1347.
    1. Krogh-Madsen R, Pedersen M, Solomon TP, et al. Normal physical activity obliterates the deleterious effects of a high-caloric intake. J Appl Physiol (1985). 2014;116(3):231-239.
    1. Krogh-Madsen R, Thyfault JP, Broholm C, et al. A 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity. J Appl Physiol (1985). 2010;108(5):1034-1040.
    1. Harder-Lauridsen NM, Nielsen ST, Mann SP, et al. The effect of alternate-day caloric restriction on the metabolic consequences of 8 days of bed rest in healthy lean men: a randomized trial. J Appl Physiol (1985). 2017;122(2):230-241.
    1. Christensen RH, Wedell-Neergaard AS, Lehrskov LL, et al. Effect of aerobic and resistance exercise on cardiac adipose tissues: secondary analyses from a randomized clinical trial. JAMA Cardiol. 2019;4(8):778-787.
    1. Moore SC, Lee IM, Weiderpass E, et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern Med. 2016;176(6):816-825.
    1. Christensen JF, Simonsen C, Hojman P. Exercise training in cancer control and treatment. Compr Physiol. 2018;9(1):165-205.
    1. Hojman P, Dethlefsen C, Brandt C, Hansen J, Pedersen L, Pedersen BK. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab. 2011;301(3):E504-E510.
    1. 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(6):882-889.
    1. Lucia A, Ramírez M. Muscling in on cancer. N Engl J Med. 2016;375(9):892-894.
    1. Manole E, Ceafalan LC, Popescu BO, Dumitru C, Bastian AE. Myokines as possible therapeutic targets in cancer cachexia. J Immunol Res. 2018;2018:8260742.
    1. Cook KS, Min HY, Johnson D, et al. Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science. 1987;237(4813):402-405.
    1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425-432.
    1. Scherer PE. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes. 2006;55(6):1537-1545.
    1. Funcke JB, Scherer PE. Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication. J Lipid Res. 2019;60(10):1648-1684.
    1. Weigert C, Hoene M, Plomgaard P. Hepatokines-a novel group of exercise factors. Pflugers Arch. 2019;471(3):383-396.
    1. Jespersen NZ, Larsen TJ, Peijs L, et al. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab. 2013;17(5):798-805.
    1. Deshmukh AS, Peijs L, Beaudry JL, et al. Proteomics-based comparative mapping of the secretomes of human brown and white adipocytes reveals EPDR1 as a novel batokine. Cell Metab. 2019;30(5):963-975.e7.

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