Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Metabolic communication during exercise

Abstract

The coordination of nutrient sensing, delivery, uptake and utilization is essential for maintaining cellular, tissue and whole-body homeostasis. Such synchronization can be achieved only if metabolic information is communicated between the cells and tissues of the entire organism. During intense exercise, the metabolic demand of the body can increase approximately 100-fold. Thus, exercise is a physiological state in which intertissue communication is of paramount importance. In this Review, we discuss the physiological processes governing intertissue communication during exercise and the molecules mediating such cross-talk.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Muscle secretory factors during exercise.
Fig. 2: Hepatokines during exercise.
Fig. 3: EVs traffic biological signals during exercise.

References

  1. Pedersen, B. K. & Febbraio, M. A. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8, 457–465 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Booth, F. W., Roberts, C. K. & Laye, M. J. Lack of exercise is a major cause of chronic diseases. Compr. Physiol. 2, 1143–1211 (2012).

    PubMed  PubMed Central  Google Scholar 

  3. Whitham, M. & Febbraio, M. A. The ever-expanding myokinome: discovery challenges and therapeutic implications. Nat. Rev. Drug Discov. 15, 719–729 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Gaitanos, G. C., Williams, C., Boobis, L. H. & Brooks, S. Human muscle metabolism during intermittent maximal exercise. J. Appl. Physiol. 75, 712–719 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Hawley, J. A., Maughan, R. J. & Hargreaves, M. Exercise metabolism: historical perspective. Cell Metab. 22, 12–17 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Boushel, R. et al. Muscle mitochondrial capacity exceeds maximal oxygen delivery in humans. Mitochondrion 11, 303–307 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Saltin, B. & Rowell, L. B. Functional adaptations to physical activity and inactivity. Fed. Proc. 39, 1506–1513 (1980).

    CAS  PubMed  Google Scholar 

  8. Allen, D. G., Lamb, G. D. & Westerblad, H. Skeletal muscle fatigue: cellular mechanisms. Physiol. Rev. 88, 287–332 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Brooks, G. A. Lactate doesn’t necessarily cause fatigue: why are we surprised? J. Physiol. (Lond.) 536, 1 (2001).

    Article  CAS  Google Scholar 

  10. Dutka, T. L. & Lamb, G. D. Effect of lactate on depolarization-induced Ca2+ release in mechanically skinned skeletal muscle fibers. Am. J. Physiol. Cell Physiol. 278, C517–C525 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Pedersen, T. H., Nielsen, O. B., Lamb, G. D. & Stephenson, D. G. Intracellular acidosis enhances the excitability of working muscle. Science 305, 1144–1147 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. de Paoli, F. V., Ørtenblad, N., Pedersen, T. H., Jørgensen, R. & Nielsen, O. B. Lactate per se improves the excitability of depolarized rat skeletal muscle by reducing the Cl- conductance. J. Physiol. (Lond.) 588, 4785–4794 (2010).

    Article  CAS  Google Scholar 

  13. Westerblad, H., Allen, D. G. & Lännergren, J. Muscle fatigue: lactic acid or inorganic phosphate the major cause? News Physiol. Sci. 17, 17–21 (2002).

    CAS  PubMed  Google Scholar 

  14. Angus, D. J., Febbraio, M. A., Lasini, D. & Hargreaves, M. Effect of carbohydrate ingestion on glucose kinetics during exercise in the heat. J. Appl. Physiol. 90, 601–605 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Coggan, A. R. & Coyle, E. F. Reversal of fatigue during prolonged exercise by carbohydrate infusion or ingestion. J. Appl. Physiol. 63, 2388–2395 (1987).

    Article  CAS  PubMed  Google Scholar 

  16. Nielsen, J. N. et al. Glycogen synthase localization and activity in rat skeletal muscle is strongly dependent on glycogen content. J. Physiol. (Lond.) 531, 757–769 (2001).

    Article  CAS  Google Scholar 

  17. Baldwin, K. M., Fitts, R. H., Booth, F. W., Winder, W. W. & Holloszy, J. O. Depletion of muscle and liver glycogen during exercise: protective effect of training. Pflugers Arch. 354, 203–212 (1975).

    Article  CAS  PubMed  Google Scholar 

  18. Saitoh, S., Shimomura, Y., Tasaki, Y. & Suzuki, M. Effect of short-term exercise training on muscle glycogen in resting conditions in rats fed a high fat diet. Eur. J. Appl. Physiol. Occup. Physiol. 64, 62–67 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Matsui, T., Soya, M. & Soya, H. Endurance and brain glycogen: a clue toward understanding central fatigue. Adv. Neurobiol. 23, 331–346 (2019).

    Article  PubMed  Google Scholar 

  20. Goldstein, M. S. Humoral nature of the hypoglycemic factor of muscular work. Diabetes 10, 232–234 (1961).

    Article  CAS  PubMed  Google Scholar 

  21. Owles, W. H. Alterations in the lactic acid content of the blood as a result of light exercise, and associated changes in the CO2-combining power of the blood and in the alveolar CO2 pressure. J. Physiol. (Lond.) 69, 214–237 (1930).

    Article  CAS  Google Scholar 

  22. Roberts, L. D. et al. β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 19, 96–108 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Roberts, L. D. et al. Inorganic nitrate mimics exercise-stimulated muscular fiber-type switching and myokine and γ-aminobutyric acid release. Diabetes 66, 674–688 (2017).

    Article  CAS  PubMed  Google Scholar 

  24. Handschin, C. & Spiegelman, B. M. The role of exercise and PGC1α in inflammation and chronic disease. Nature 454, 463–469 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kammoun, H. L. & Febbraio, M. A. Come on BAIBA light my fire. Cell Metab. 19, 1–2 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Febbraio, M. A. & Pedersen, B. K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB J. 16, 1335–1347 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Ullum, H. et al. Bicycle exercise enhances plasma IL-6 but does not change IL-1 alpha, IL-1 beta, IL-6, or TNF-alpha pre-mRNA in BMNC. J. Appl. Physiol. 77, 93–97 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Starkie, R. L., Angus, D. J., Rolland, J., Hargreaves, M. & Febbraio, M. A. Effect of prolonged, submaximal exercise and carbohydrate ingestion on monocyte intracellular cytokine production in humans. J. Physiol. (Lond.) 528, 647–655 (2000).

    Article  CAS  Google Scholar 

  29. Starkie, R. L., Rolland, J., Angus, D. J., Anderson, M. J. & Febbraio, M. A. Circulating monocytes are not the source of elevations in plasma IL-6 and TNF-alpha levels after prolonged running. Am. J. Physiol. Cell Physiol. 280, C769–C774 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Febbraio, M. A. et al. Hepatosplanchnic clearance of interleukin-6 in humans during exercise. Am. J. Physiol. Endocrinol. Metab. 285, E397–E402 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Ostrowski, K., Rohde, T., Zacho, M., Asp, S. & Pedersen, B. K. Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running. J. Physiol. (Lond.) 508, 949–953 (1998).

    Article  CAS  Google Scholar 

  32. Starkie, R. L., Arkinstall, M. J., Koukoulas, I., Hawley, J. A. & Febbraio, M. A. Carbohydrate ingestion attenuates the increase in plasma interleukin-6, but not skeletal muscle interleukin-6 mRNA, during exercise in humans. J. Physiol. (Lond.) 533, 585–591 (2001).

    Article  CAS  Google Scholar 

  33. Hiscock, N., Chan, M. H., Bisucci, T., Darby, I. A. & Febbraio, M. A. Skeletal myocytes are a source of interleukin-6 mRNA expression and protein release during contraction: evidence of fiber type specificity. FASEB J. 18, 992–994 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Steensberg, A. et al. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J. Physiol. (Lond.) 529, 237–242 (2000).

    Article  CAS  Google Scholar 

  35. Steensberg, A. et al. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J. Physiol. (Lond.) 537, 633–639 (2001).

    Article  CAS  Google Scholar 

  36. Whitham, M. et al. Contraction-induced interleukin-6 gene transcription in skeletal muscle is regulated by c-Jun terminal kinase/activator protein-1. J. Biol. Chem. 287, 10771–10779 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Starkie, R., Ostrowski, S. R., Jauffred, S., Febbraio, M. & Pedersen, B. K. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 17, 884–886 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Febbraio, M. A., Hiscock, N., Sacchetti, M., Fischer, C. P. & Pedersen, B. K. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 53, 1643–1648 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Chan, M. H., Carey, A. L., Watt, M. J. & Febbraio, M. A. Cytokine gene expression in human skeletal muscle during concentric contraction: evidence that IL-8, like IL-6, is influenced by glycogen availability. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R322–R327 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Nielsen, A. R. et al. Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J. Physiol. (Lond.) 584, 305–312 (2007).

    Article  CAS  Google Scholar 

  41. Carbó, N. et al. Interleukin-15 mediates reciprocal regulation of adipose and muscle mass: a potential role in body weight control. Biochim. Biophys. Acta 1526, 17–24 (2001).

    Article  PubMed  Google Scholar 

  42. Quinn, L. S., Strait-Bodey, L., Anderson, B. G., Argilés, J. M. & Havel, P. J. Interleukin-15 stimulates adiponectin secretion by 3T3-L1 adipocytes: evidence for a skeletal muscle-to-fat signaling pathway. Cell Biol. Int. 29, 449–457 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Knudsen, N. H. et al. Interleukin-13 drives metabolic conditioning of muscle to endurance exercise. Science 368, eaat3987 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bostrom, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Jedrychowski, M. P. et al. Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metab. 22, 734–740 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kim, H. et al. Irisin mediates effects on bone and fat via αV integrin receptors. Cell 175, 1756–1768.e17 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Albrecht, E. et al. Irisin: a myth rather than an exercise-inducible myokine. Sci. Rep. 5, 8889 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Erickson, H. P. Irisin and FNDC5 in retrospect: an exercise hormone or a transmembrane receptor? Adipocyte 2, 289–293 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Albrecht, E. et al. Irisin: still chasing shadows. Mol. Metab. 34, 124–135 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rao, R. R. et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279–1291 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Priest, C. & Tontonoz, P. Inter-organ cross-talk in metabolic syndrome. Nat. Metab. 1, 1177–1188 (2019).

    Article  PubMed  Google Scholar 

  52. Bortoluzzi, S., Scannapieco, P., Cestaro, A., Danieli, G. A. & Schiaffino, S. Computational reconstruction of the human skeletal muscle secretome. Proteins 62, 776–792 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Whitham, M. et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 27, 237–251.e4 (2018).

    Article  CAS  PubMed  Google Scholar 

  54. Tsai, C. L., Pai, M. C., Ukropec, J. & Ukropcová, B. Distinctive effects of aerobic and resistance exercise modes on neurocognitive and biochemical changes in individuals with mild cognitive impairment. Curr. Alzheimer Res. 16, 316–332 (2019).

    Article  CAS  PubMed  Google Scholar 

  55. Tsai, C. L., Ukropec, J., Ukropcová, B. & Pai, M. C. An acute bout of aerobic or strength exercise specifically modifies circulating exerkine levels and neurocognitive functions in elderly individuals with mild cognitive impairment. Neuroimage Clin. 17, 272–284 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lourenco, M. V. et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat. Med. 25, 165–175 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Agudelo, L. Z. et al. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159, 33–45 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Moon, H. Y. et al. Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab. 24, 332–340 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Moore, S. C. et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern. Med. 176, 816–825 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Aoi, W. et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut 62, 882–889 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Gormsen, L. C. et al. Impact of body composition on very-low-density lipoprotein-triglycerides kinetics. Am. J. Physiol. Endocrinol. Metab. 296, E165–E173 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Sondergaard, E. et al. Effects of exercise on VLDL-triglyceride oxidation and turnover. Am. J. Physiol. Endocrinol. Metab. 300, E939–E944 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Watt, M. J., Miotto, P. M., De Nardo, W. & Montgomery, M. K. The liver as an endocrine organ-linking NAFLD and insulin resistance. Endocr. Rev. 40, 1367–1393 (2019).

    Article  PubMed  Google Scholar 

  64. Hoene, M. & Weigert, C. The stress response of the liver to physical exercise. Exerc. Immunol. Rev. 16, 163–183 (2010).

    PubMed  Google Scholar 

  65. Hoene, M. et al. Activation of the mitogen-activated protein kinase (MAPK) signalling pathway in the liver of mice is related to plasma glucose levels after acute exercise. Diabetologia 53, 1131–1141 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Azimifar, S. B., Nagaraj, N., Cox, J. & Mann, M. Cell-type-resolved quantitative proteomics of murine liver. Cell Metab. 20, 1076–1087 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Meex, R. C. et al. Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism. Cell Metab. 22, 1078–1089 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Febbraio, M. A. et al. Exercise induces hepatosplanchnic release of heat shock protein 72 in humans. J. Physiol. (Lond.) 544, 957–962 (2002).

    Article  CAS  Google Scholar 

  69. von Holstein-Rathlou, S. et al. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab. 23, 335–343 (2016).

    Article  CAS  Google Scholar 

  70. Talukdar, S. et al. FGF21 regulates sweet and alcohol preference. Cell Metab. 23, 344–349 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Soberg, S. et al. FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans. Cell Metab. 25, 1045–1053.e1046 (2017).

    Article  PubMed  CAS  Google Scholar 

  72. Kurosu, H. et al. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 282, 26687–26695 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Ding, X. et al. βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab. 16, 387–393 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Fisher, F. M. & Maratos-Flier, E. Understanding the physiology of FGF21. Annu. Rev. Physiol. 78, 223–241 (2016).

    Article  CAS  PubMed  Google Scholar 

  75. Babaknejad, N., Nayeri, H., Hemmati, R., Bahrami, S. & Esmaillzadeh, A. An overview of FGF19 and FGF21: the therapeutic role in the treatment of the metabolic disorders and obesity. Horm. Metab. Res. 50, 441–452 (2018).

    Article  CAS  PubMed  Google Scholar 

  76. Kim, K. H. et al. Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS ONE 8, e63517 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hansen, J. S. et al. Exercise-induced secretion of FGF21 and follistatin are blocked by pancreatic clamp and impaired in type 2 diabetes. J. Clin. Endocrinol. Metab. 101, 2816–2825 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. Willis, S. A. et al. Effect of exercise intensity on circulating hepatokine concentrations in healthy men. Appl. Physiol. Nutr. Metab. 44, 1065–1072 (2019).

    Article  CAS  PubMed  Google Scholar 

  79. Tsiloulis, T. et al. No evidence of white adipocyte browning after endurance exercise training in obese men. Int. J. Obes. 42, 721–727 (2018).

    Article  CAS  Google Scholar 

  80. Aldiss, P. et al. Exercise-induced ‘browning’ of adipose tissues. Metabolism 81, 63–70 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Loyd, C. et al. Fibroblast growth factor 21 is required for beneficial effects of exercise during chronic high-fat feeding. J. Appl. Physiol. 121, 687–698 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hansen, J. et al. Exercise induces a marked increase in plasma follistatin: evidence that follistatin is a contraction-induced hepatokine. Endocrinology 152, 164–171 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Hansen, J. S. et al. Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans. Mol. Metab. 4, 551–560 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Schumann, C. et al. Increasing lean muscle mass in mice via nanoparticle-mediated hepatic delivery of follistatin mRNA. Theranostics 8, 5276–5288 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Davey, J. R. et al. Intravascular follistatin gene delivery improves glycemic control in a mouse model of type 2 diabetes. FASEB J. 34, 5697–5714 (2020).

    Article  CAS  PubMed  Google Scholar 

  86. Tao, R. et al. Inactivating hepatic follistatin alleviates hyperglycemia. Nat. Med. 24, 1058–1069 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Aryal, B., Price, N. L., Suarez, Y. & Fernández-Hernando, C. ANGPTL4 in metabolic and cardiovascular disease. Trends Mol. Med. 25, 723–734 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Górecka, M. et al. Effect of mountain ultra-marathon running on plasma angiopoietin-like protein 4 and lipid profile in healthy trained men. Eur. J. Appl. Physiol. 120, 117–125 (2020).

    Article  PubMed  Google Scholar 

  89. Norheim, F. et al. Regulation of angiopoietin-like protein 4 production during and after exercise. Physiol. Rep. 2, e12109 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Ingerslev, B. et al. Angiopoietin-like protein 4 is an exercise-induced hepatokine in humans, regulated by glucagon and cAMP. Mol. Metab. 6, 1286–1295 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lundsgaard, A. M., Fritzen, A. M. & Kiens, B. The importance of fatty acids as nutrients during post-exercise recovery. Nutrients 12, 280 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  92. Misu, H. et al. A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metab. 12, 483–495 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Misu, H. et al. Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle. Nat. Med. 23, 508–516 (2017).

    Article  CAS  PubMed  Google Scholar 

  94. Sargeant, J. A. et al. The influence of adiposity and acute exercise on circulating hepatokines in normal-weight and overweight/obese men. Appl. Physiol. Nutr. Metab. 43, 482–490 (2018).

    Article  CAS  PubMed  Google Scholar 

  95. Weigert, C., Hoene, M. & Plomgaard, P. Hepatokines: a novel group of exercise factors. Pflugers Arch. 471, 383–396 (2019).

    Article  CAS  PubMed  Google Scholar 

  96. Tsiloulis, T. & Watt, M. J. Exercise and the regulation of adipose tissue metabolism. Prog. Mol. Biol. Transl. Sci. 135, 175–201 (2015).

    Article  PubMed  Google Scholar 

  97. Ahlborg, G., Felig, P., Hagenfeldt, L., Hendler, R. & Wahren, J. Substrate turnover during prolonged exercise in man: splanchnic and leg metabolism of glucose, free fatty acids, and amino acids. J. Clin. Invest. 53, 1080–1090 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Deshmukh, A. S. et al. Proteomics-based comparative mapping of the secretomes of human brown and white adipocytes reveals EPDR1 as a novel batokine. Cell Metab. 30, 963–975.e967 (2019).

    Article  CAS  PubMed  Google Scholar 

  99. Crowe, S. et al. Pigment epithelium-derived factor contributes to insulin resistance in obesity. Cell Metab. 10, 40–47 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Roca-Rivada, A. et al. CILAIR-based secretome analysis of obese visceral and subcutaneous adipose tissues reveals distinctive ECM remodeling and inflammation mediators. Sci. Rep. 5, 12214 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Raajendiran, A. et al. Identification of metabolically distinct adipocyte progenitor cells in human adipose tissues. Cell Rep. 27, 1528–1540.e1527 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Funcke, J. B. & Scherer, P. E. Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication. J. Lipid Res. 60, 1648–1684 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Stanford, K. I. & Goodyear, L. J. Muscle-adipose tissue cross talk. Cold Spring Harb. Perspect. Med. 8, a029801 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Takahashi, H. et al. TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nat. Metab. 1, 291–303 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Otero-Díaz, B. et al. Exercise induces white adipose tissue browning across the weight spectrum in humans. Front. Physiol. 9, 1781 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Becic, T., Studenik, C. & Hoffmann, G. Exercise increases adiponectin and reduces leptin levels in prediabetic and diabetic individuals: systematic review and meta-analysis of randomized controlled trials. Med. Sci. (Basel) 6, 97 (2018).

    CAS  Google Scholar 

  107. Yu, N., Ruan, Y., Gao, X. & Sun, J. Systematic review and meta-analysis of randomized, controlled trials on the effect of exercise on serum leptin and adiponectin in overweight and obese individuals. Horm. Metab. Res. 49, 164–173 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. Fedewa, M. V., Hathaway, E. D., Ward-Ritacco, C. L., Williams, T. D. & Dobbs, W. C. The effect of chronic exercise training on leptin: a systematic review and meta-analysis of randomized controlled trials. Sports Med. 48, 1437–1450 (2018).

    Article  PubMed  Google Scholar 

  109. Krist, J. et al. Effects of weight loss and exercise on apelin serum concentrations and adipose tissue expression in human obesity. Obes. Facts 6, 57–69 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Numao, S. et al. Effects of exercise training on circulating retinol-binding protein 4 and cardiovascular disease risk factors in obese men. Obes. Facts 5, 845–855 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Choi, H. Y. et al. Effects of a combined aerobic and resistance exercise program on C1q/TNF-related protein-3 (CTRP-3) and CTRP-5 levels. Diabetes Care 36, 3321–3327 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Haus, J. M. et al. Decreased visfatin after exercise training correlates with improved glucose tolerance. Med. Sci. Sports Exerc. 41, 1255–1260 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Seo, D. I. et al. Effects of 12 weeks of combined exercise training on visfatin and metabolic syndrome factors in obese middle-aged women. J. Sports Sci. Med. 10, 222–226 (2011).

    PubMed  PubMed Central  Google Scholar 

  114. Chakaroun, R. et al. Effects of weight loss and exercise on chemerin serum concentrations and adipose tissue expression in human obesity. Metabolism 61, 706–714 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Moghadasi, M. & Mohammadi Domieh, A. Effects of resistance versus endurance training on plasma lipocalin-2 in young men. Asian J. Sports Med. 5, 108–114 (2014).

    PubMed  PubMed Central  Google Scholar 

  116. Joham, A. E. et al. Pigment epithelium-derived factor, insulin sensitivity, and adiposity in polycystic ovary syndrome: impact of exercise training. Obesity (Silver Spring) 20, 2390–2396 (2012).

    Article  CAS  Google Scholar 

  117. Duggan, C., Tapsoba, J. D., Wang, C. Y., Schubert, K. E. F. & McTiernan, A. Long-term effects of weight loss and exercise on biomarkers associated with angiogenesis. Cancer Epidemiol. Biomarkers Prev. 26, 1788–1794 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ge, S. & Ryan, A. S. Zinc-α2-glycoprotein expression in adipose tissue of obese postmenopausal women before and after weight loss and exercise + weight loss. Metabolism 63, 995–999 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Youn, B. S. et al. Serum vaspin concentrations in human obesity and type 2 diabetes. Diabetes 57, 372–377 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Kadoglou, N. P., Vrabas, I. S., Kapelouzou, A. & Angelopoulou, N. The association of physical activity with novel adipokines in patients with type 2 diabetes. Eur. J. Intern. Med. 23, 137–142 (2012).

    Article  CAS  PubMed  Google Scholar 

  121. Rancoule, C. et al. Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice. Diabetologia 56, 1394–1402 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. D’Souza, K., Paramel, G. V. & Kienesberger, P. C. Lysophosphatidic acid signaling in obesity and insulin resistance. Nutrients 10, 399 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  123. Michalczyk, A., Budkowska, M., Dołęgowska, B., Chlubek, D. & Safranow, K. Lysophosphatidic acid plasma concentrations in healthy subjects: circadian rhythm and associations with demographic, anthropometric and biochemical parameters. Lipids Health Dis. 16, 140 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Brezinova, M. et al. Exercise training induces insulin-sensitizing PAHSAs in adipose tissue of elderly women. Biochim Biophys Acta Mol Cell Biol Lipids 1865, 158576 (2020).

    Article  CAS  PubMed  Google Scholar 

  126. Sanchez-Delgado, G. et al. Role of exercise in the activation of brown adipose tissue. Ann. Nutr. Metab. 67, 21–32 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Lynes, M. D. et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat. Med. 23, 631–637 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Stanford, K. I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1111–1120.e1113 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Davis, J. M. & Bailey, S. P. Possible mechanisms of central nervous system fatigue during exercise. Med. Sci. Sports Exerc. 29, 45–57 (1997).

    Article  CAS  PubMed  Google Scholar 

  130. Roelands, B., de Koning, J., Foster, C., Hettinga, F. & Meeusen, R. Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing. Sports Med. 43, 301–311 (2013).

    Article  PubMed  Google Scholar 

  131. Roelands, B., De Pauw, K. & Meeusen, R. Neurophysiological effects of exercise in the heat. Scand. J. Med. Sci. Sports 25, 65–78 (2015). (Suppl. 1).

    Article  PubMed  Google Scholar 

  132. Jørgensen, L. G., Perko, M., Perko, G. & Secher, N. H. Middle cerebral artery velocity during head-up tilt induced hypovolaemic shock in humans. Clin. Physiol. 13, 323–336 (1993).

    Article  PubMed  Google Scholar 

  133. Jorgensen, L. G., Perko, G. & Secher, N. H. Regional cerebral artery mean flow velocity and blood flow during dynamic exercise in humans. J. Appl. Physiol. 73, 1825–1830 (1992).

    Article  CAS  PubMed  Google Scholar 

  134. Jorgensen, L. G., Perko, M., Hanel, B., Schroeder, T. V. & Secher, N. H. Middle cerebral artery flow velocity and blood flow during exercise and muscle ischemia in humans. J. Appl. Physiol. 72, 1123–1132 (1992).

    Article  CAS  PubMed  Google Scholar 

  135. Secher, N. H., Seifert, T. & Van Lieshout, J. J. Cerebral blood flow and metabolism during exercise: implications for fatigue. J. Appl. Physiol. 104, 306–314 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Ide, K., Horn, A. & Secher, N. H. Cerebral metabolic response to submaximal exercise. J. Appl. Physiol. 87, 1604–1608 (1999).

    Article  CAS  PubMed  Google Scholar 

  137. Astrand, P. O., Cuddy, T. E., Saltin, B. & Stenberg, J. Cardiac output during submaximal and maximal work. J. Appl. Physiol. 19, 268–274 (1964).

    Article  CAS  PubMed  Google Scholar 

  138. González-Alonso, J. et al. Brain and central haemodynamics and oxygenation during maximal exercise in humans. J. Physiol. (Lond.) 557, 331–342 (2004).

    Article  CAS  Google Scholar 

  139. Madsen, P. L. & Secher, N. H. Near-infrared oximetry of the brain. Prog. Neurobiol. 58, 541–560 (1999).

    Article  CAS  PubMed  Google Scholar 

  140. Mattson, M. P., Maudsley, S. & Martin, B. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 27, 589–594 (2004).

    Article  CAS  PubMed  Google Scholar 

  141. Tsai, S. J. Brain-derived neurotrophic factor: a bridge between major depression and Alzheimer’s disease? Med. Hypotheses 61, 110–113 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Radak, Z. et al. Exercise plays a preventive role against Alzheimer’s disease. J. Alzheimers Dis. 20, 777–783 (2010).

    Article  PubMed  Google Scholar 

  143. Voss, M. W., Vivar, C., Kramer, A. F. & van Praag, H. Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn. Sci. 17, 525–544 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Duzel, E., van Praag, H. & Sendtner, M. Can physical exercise in old age improve memory and hippocampal function? Brain 139, 662–673 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  145. van Praag, H., Kempermann, G. & Gage, F. H. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266–270 (1999).

    Article  PubMed  Google Scholar 

  146. Choi, S. H. et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science 361, eaan8821 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Lazarov, O. et al. Environmental enrichment reduces Aβ levels and amyloid deposition in transgenic mice. Cell 120, 701–713 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. Matthews, V. B. 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 52, 1409–1418 (2009).

    Article  CAS  PubMed  Google Scholar 

  149. Fujimura, H. et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb. Haemost. 87, 728–734 (2002).

    Article  CAS  PubMed  Google Scholar 

  150. Seifert, T. et al. Endurance training enhances BDNF release from the human brain. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R372–R377 (2010).

    Article  CAS  PubMed  Google Scholar 

  151. Rasmussen, P. et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp. Physiol. 94, 1062–1069 (2009).

    Article  CAS  PubMed  Google Scholar 

  152. Lancaster, G. I. et al. Exercise induces the release of heat shock protein 72 from the human brain in vivo. Cell Stress Chaperones 9, 276–280 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Nybo, L., Nielsen, B., Pedersen, B. K., Møller, K. & Secher, N. H. Interleukin-6 release from the human brain during prolonged exercise. J. Physiol. (Lond.) 542, 991–995 (2002).

    Article  CAS  Google Scholar 

  154. Harding, C. & Stahl, P. Transferrin recycling in reticulocytes: pH and iron are important determinants of ligand binding and processing. Biochem. Biophys. Res. Commun. 113, 650–658 (1983).

    Article  CAS  PubMed  Google Scholar 

  155. Pan, B. T. & Johnstone, R. M. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33, 967–978 (1983).

    Article  CAS  PubMed  Google Scholar 

  156. Kalra, H., Drummen, G. P. & Mathivanan, S. Focus on extracellular vesicles: introducing the next small big thing. Int. J. Mol. Sci. 17, 170 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Mathivanan, S., Ji, H. & Simpson, R. J. Exosomes: extracellular organelles important in intercellular communication. J. Proteomics 73, 1907–1920 (2010).

    Article  CAS  PubMed  Google Scholar 

  158. Deatherage, B. L. & Cookson, B. T. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect. Immun. 80, 1948–1957 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Vechetti, I. J., Valentino, T., Mobley, C. B. & McCarthy, J. J. The role of exosomes in skeletal muscle and systematic adaption to exercise. J. Physiol. https://doi.org/10.1113/JP278929 (2020).

  160. Whitham, M. & Febbraio, M. A. Redefining tissue crosstalk via shotgun proteomic analyses of plasma extracellular vesicles. Proteomics 19, e1800154 (2019).

    Article  PubMed  CAS  Google Scholar 

  161. Lötvall, J. et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J. Extracell. Vesicles 3, 26913 (2014).

    Article  PubMed  Google Scholar 

  162. Kowal, J. et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc. Nat. Acad. Sci. USA 113, E968–E977 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Frühbeis, C., Helmig, S., Tug, S., Simon, P. & Krämer-Albers, E. M. Physical exercise induces rapid release of small extracellular vesicles into the circulation. J. Extracell. Vesicles 4, 28239 (2015).

    Article  PubMed  Google Scholar 

  164. Willms, E. et al. Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci. Rep. 6, 22519 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Haraszti, R. A. et al. High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources. J. Extracell. Vesicles 5, 32570 (2016).

    Article  PubMed  CAS  Google Scholar 

  166. Keerthikumar, S. et al. Proteogenomic analysis reveals exosomes are more oncogenic than ectosomes. Oncotarget 6, 15375–15396 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Brahmer, A. et al. Platelets, endothelial cells and leukocytes contribute to the exercise-triggered release of extracellular vesicles into the circulation. J. Extracell. Vesicles 8, 1615820 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Gleeson, M. Interleukins and exercise. J. Physiol. (Lond.) 529, 1 (2000).

    Article  CAS  Google Scholar 

  169. Krüger, M. et al. SILAC mouse for quantitative proteomics uncovers kindlin-3 as an essential factor for red blood cell function. Cell 134, 353–364 (2008).

    Article  PubMed  CAS  Google Scholar 

  170. Garcia, N. A., Moncayo-Arlandi, J., Sepulveda, P. & Diez-Juan, A. Cardiomyocyte exosomes regulate glycolytic flux in endothelium by direct transfer of GLUT transporters and glycolytic enzymes. Cardiovasc. Res. 109, 397–408 (2016).

    Article  CAS  PubMed  Google Scholar 

  171. Zhao, H. et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife 5, e10250 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Thomou, T. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450–455 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Mori, M. A., Ludwig, R. G., Garcia-Martin, R., Brandão, B. B. & Kahn, C. R. Extracellular miRNAs: from biomarkers to mediators of physiology and disease. Cell Metab. 30, 656–673 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Fletcher, W. M. Lactic acid in amphibian muscle. J. Physiol. (Lond.) 35, 247–309 (1907).

    Article  CAS  Google Scholar 

  175. Van Hall, G. et al. Leg and arm lactate and substrate kinetics during exercise. Am. J. Physiol. Endocrinol. Metab. 284, E193–E205 (2003).

    Article  PubMed  Google Scholar 

  176. Schurr, A. Cerebral glycolysis: a century of persistent misunderstanding and misconception. Front. Neurosci. 8, 360 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Quastel, J. H. & Wheatley, A. H. Oxidations by the brain. Biochem. J. 26, 725–744 (1932).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Machler, P. et al. In vivo evidence for a lactate gradient from astrocytes to neurons. Cell Metab. 23, 94–102 (2016).

    Article  CAS  PubMed  Google Scholar 

  179. van Hall, G. et al. Blood lactate is an important energy source for the human brain. J. Cereb. Blood Flow Metab. 29, 1121–1129 (2009).

    Article  PubMed  CAS  Google Scholar 

  180. Villarroya, F., Cereijo, R., Villarroya, J. & Giralt, M. Brown adipose tissue as a secretory organ. Nat. Rev. Endocrinol. 13, 26–35 (2017).

    Article  CAS  PubMed  Google Scholar 

  181. Ruan, C. C. et al. A2A receptor activation attenuates hypertensive cardiac remodeling via promoting brown adipose tissue-derived FGF21. Cell Metab. 28, 476–489.e475 (2018).

    Article  CAS  PubMed  Google Scholar 

  182. Kong, X. et al. Brown adipose tissue controls skeletal muscle function via the secretion of myostatin. Cell Metab. 28, 631–643.e633 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

M.A.F. is supported by a Senior Principal Research Fellowship (APP1116936) and an Investigator Award (APP1194141) from the National Health & Medical Research Council of Australia.

Author information

Authors and Affiliations

Authors

Contributions

R.M.M., M.J.W. and M.A.F. wrote sections of the manuscript. M.A.F. prepared the figures.

Corresponding author

Correspondence to Mark A. Febbraio.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Primary Handling Editor: Christoph Schmitt.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Murphy, R.M., Watt, M.J. & Febbraio, M.A. Metabolic communication during exercise. Nat Metab 2, 805–816 (2020). https://doi.org/10.1038/s42255-020-0258-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-020-0258-x

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing