{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T23:53:13Z","timestamp":1791071593483,"version":"4.1.0"},"reference-count":109,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T00:00:00Z","timestamp":1611100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"This work was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea","award":["NRF-2018S1A5A8027802, 2018-R1A2A3074998"],"award-info":[{"award-number":["NRF-2018S1A5A8027802, 2018-R1A2A3074998"]}]},{"name":"This work was supported by by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education","award":["NRF-2018R1D1A1B07040370"],"award-info":[{"award-number":["NRF-2018R1D1A1B07040370"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Exercise has health benefits and prevents a range of chronic diseases caused by physiological and biological changes in the whole body. Generally, the metabolic regulation of skeletal muscle through exercise is known to have a protective effect on the pathogenesis of metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and cardiovascular disease (CVD). Besides this, the importance of the liver as an endocrine organ is a hot research topic. Hepatocytes also secrete many hepatokines in response to nutritional conditions and\/or physical activity. In particular, certain hepatokines play a major role in the regulation of whole-body metabolic homeostasis. In this review, we summarize the recent research findings on the exercise-mediated regulation of hepatokines, including fibroblast growth factor 21, fetuin-A, angiopoietin-like protein 4, and follistatin. These hepatokines serve as molecular transducers of the metabolic benefits of physical activity in chronic metabolic diseases, including NAFLD, T2D, and CVDs, in various tissues.<\/jats:p>","DOI":"10.3390\/jcm10030385","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T12:16:18Z","timestamp":1611144978000},"page":"385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Hepatokines as a Molecular Transducer of Exercise"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4377-5792","authenticated-orcid":false,"given":"Dae Yun","family":"Seo","sequence":"first","affiliation":[{"name":"National Research Laboratory for Mitochondrial Signaling, Department of Physiology, BK21 Plus Project Team, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje University, Busan 47392, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5312-8372","authenticated-orcid":false,"given":"Se Hwan","family":"Park","sequence":"additional","affiliation":[{"name":"School of Kinesiology, Yeungnam University, Gyeongsan 38541, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jubert","family":"Marquez","sequence":"additional","affiliation":[{"name":"National Research Laboratory for Mitochondrial Signaling, Department of Physiology, BK21 Plus Project Team, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje University, Busan 47392, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0451-4554","authenticated-orcid":false,"given":"Hyo-Bum","family":"Kwak","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, Inha University, Incheon 22212, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6568-2469","authenticated-orcid":false,"given":"Tae Nyun","family":"Kim","sequence":"additional","affiliation":[{"name":"National Research Laboratory for Mitochondrial Signaling, Department of Physiology, BK21 Plus Project Team, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje University, Busan 47392, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1918-9213","authenticated-orcid":false,"given":"Jun Hyun","family":"Bae","sequence":"additional","affiliation":[{"name":"Institute of Sport Science, Seoul National University, Seoul 08826, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Ho","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Yeungnam University, Daegu 42415, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1859-3425","authenticated-orcid":false,"given":"Jin","family":"Han","sequence":"additional","affiliation":[{"name":"National Research Laboratory for Mitochondrial Signaling, Department of Physiology, BK21 Plus Project Team, College of Medicine, Smart Marine Therapeutics Center, Cardiovascular and Metabolic Disease Center, Inje University, Busan 47392, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zou, L., Zhang, Y., Sasaki, J.E., Yeung, A.S., Yang, L., Loprinzi, P.D., Sun, J., Liu, S., Yu, J.J., and Sun, S. (2019). Wuqinxi Qigong as an Alternative Exercise for Improving Risk Factors Associated with Metabolic Syndrome: A Meta-Analysis of Randomized Controlled Trials. Int. J. Environ. Res. Public Health, 16.","DOI":"10.3390\/ijerph16081396"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sabaratnam, R., Pedersen, A.J.T., Kristensen, J.M., Handberg, A., Wojtaszewski, J.F.P., and Hojlund, K. (2018). Intact regulation of muscle expression and circulating levels of myokines in response to exercise in patients with type 2 diabetes. Physiol. Rep., 6.","DOI":"10.14814\/phy2.13723"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Piccirillo, R. (2019). Exercise-Induced Myokines With Therapeutic Potential for Muscle Wasting. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00287"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1007\/s00125-019-4927-9","article-title":"Myokines in metabolic homeostasis and diabetes","volume":"62","author":"Eckel","year":"2019","journal-title":"Diabetologia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1016\/j.molmet.2017.06.018","article-title":"Angiopoietin-like protein 4 is an exercise-induced hepatokine in humans, regulated by glucagon and cAMP","volume":"6","author":"Ingerslev","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/nm.4295","article-title":"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","volume":"23","author":"Misu","year":"2017","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1136\/gutjnl-2017-313884","article-title":"Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases","volume":"66","author":"Adams","year":"2017","journal-title":"Gut"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15430","DOI":"10.1073\/pnas.0904944106","article-title":"Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity","volume":"106","author":"Fabbrini","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S2213-8587(18)30154-2","article-title":"Non-alcoholic fatty liver disease: Causes, diagnosis, cardiometabolic consequences, and treatment strategies","volume":"7","author":"Stefan","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.clinre.2019.01.001","article-title":"Non-alcoholic fatty liver disease causes dissociated changes in metabolic liver functions","volume":"43","author":"Sorensen","year":"2019","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1038\/ijo.2017.309","article-title":"Protective effect of black relative to white race against non-alcoholic fatty liver disease in patients with severe obesity, independent of type 2 diabetes","volume":"42","author":"Browning","year":"2018","journal-title":"Int. J. Obes."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1016\/j.celrep.2019.02.014","article-title":"Exercise Alleviates Obesity-Induced Metabolic Dysfunction via Enhancing FGF21 Sensitivity in Adipose Tissues","volume":"26","author":"Geng","year":"2019","journal-title":"Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1007\/s00424-018-2185-1","article-title":"Impact of skeletal muscle IL-6 on regulation of liver and adipose tissue metabolism during fasting","volume":"470","author":"Bertholdt","year":"2018","journal-title":"Pflug. Arch."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.metabol.2013.08.018","article-title":"Effects of exercise on C-reactive protein, inflammatory cytokine and adipokine in patients with type 2 diabetes: A meta-analysis of randomized controlled trials","volume":"63","author":"Hayashino","year":"2014","journal-title":"Metabolism"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s12192-017-0767-z","article-title":"Attenuation of exercise-induced heat shock protein 72 expression blunts improvements in whole-body insulin resistance in rats with type 2 diabetes","volume":"22","author":"Tsuzuki","year":"2017","journal-title":"Cell Stress Chaperones"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1172\/jci.insight.129492","article-title":"The hepatokine Tsukushi is released in response to NAFLD and impacts cholesterol homeostasis","volume":"4","author":"Mouchiroud","year":"2019","journal-title":"JCI Insight"},{"key":"ref_17","first-page":"1","article-title":"Angptl8 mediates food-driven resetting of hepatic circadian clock in mice","volume":"10","author":"Chen","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1507\/endocrj.EJ19-0255","article-title":"Identification of hepatokines involved in pathology of type 2 diabetes and obesity","volume":"66","author":"Misu","year":"2019","journal-title":"Endocr. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1530\/JME-17-0267","article-title":"LECT2 promotes inflammation and insulin resistance in adipocytes via P38 pathways","volume":"61","author":"Jung","year":"2018","journal-title":"J. Mol. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1055\/a-0879-2968","article-title":"Circulating FGF21 Levels in Human Health and Metabolic Disease","volume":"128","author":"Keuper","year":"2019","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"474","DOI":"10.4093\/dmj.2018.0171","article-title":"Plasma Fetuin-A Levels and Risk of Type 2 Diabetes Mellitus in A Chinese Population: A Nested Case-Control Study","volume":"43","author":"Wang","year":"2019","journal-title":"Diabetes Metab. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.atherosclerosis.2014.10.028","article-title":"Angiopoietin-like protein 4 significantly predicts future cardiovascular events in coronary patients","volume":"237","author":"Muendlein","year":"2014","journal-title":"Atherosclerosis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/mus.26653","article-title":"Viral Vector Delivery of Follistatin Enhances Recovery of Reinnervated Muscle","volume":"60","author":"Isaacs","year":"2019","journal-title":"Muscle Nerve"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ko, J.R., Seo, D.Y., Kim, T.N., Park, S.H., Kwak, H.B., Ko, K.S., Rhee, B.D., and Han, J. (2019). Aerobic Exercise Training Decreases Hepatic Asprosin in Diabetic Rats. J. Clin. Med., 8.","DOI":"10.3390\/jcm8050666"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.cell.2016.02.063","article-title":"Asprosin, a Fasting-Induced Glucogenic Protein Hormone","volume":"165","author":"Romere","year":"2016","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"715","DOI":"10.2165\/00007256-200838090-00002","article-title":"Heat shock protein 72 response to exercise in humans","volume":"38","author":"Yamada","year":"2008","journal-title":"Sports Med."},{"key":"ref_27","first-page":"1","article-title":"Impact of acute exercise on immediate and following early post-exercise FGF-21 concentration in adults: Systematic review and meta-analysis","volume":"4","author":"Khalafi","year":"2020","journal-title":"Hormones"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1139\/apnm-2018-0818","article-title":"Effect of exercise intensity on circulating hepatokine concentrations in healthy men","volume":"44","author":"Willis","year":"2019","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"H1642","DOI":"10.1152\/ajpheart.00338.2015","article-title":"Aerobic exercise training-induced changes in serum adropin level are associated with reduced arterial stiffness in middle-aged and older adults","volume":"309","author":"Fujie","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-18086-3","article-title":"Aerobic exercise improves endothelial function and serum adropin levels in obese adolescents independent of body weight loss","volume":"7","author":"Zhang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E1043","DOI":"10.1073\/pnas.1400889111","article-title":"Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise","volume":"111","author":"Catoire","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1556\/2060.106.2019.01","article-title":"Effects of aerobic versus resistance training on serum fetuin-A, fetuin-B, and fibroblast growth factor-21 levels in male diabetic patients","volume":"106","author":"Keihanian","year":"2019","journal-title":"Physiol. Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"164","DOI":"10.15171\/jcvtr.2016.33","article-title":"The effect of eight weeks resistance and aerobic training on myostatin and follistatin expression in cardiac muscle of rats","volume":"8","author":"Rashidlamir","year":"2016","journal-title":"J. Cardiovasc. Thorac. Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Tezze, C., Romanello, V., and Sandri, M. (2019). FGF21 as Modulator of Metabolism in Health and Disease. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00419"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Jimenez, V., Jambrina, C., Casana, E., Sacristan, V., Munoz, S., Darriba, S., Rodo, J., Mallol, C., Garcia, M., and Leon, X. (2018). FGF21 gene therapy as treatment for obesity and insulin resistance. EMBO Mol. Med., 10.","DOI":"10.15252\/emmm.201708791"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.molmet.2014.09.008","article-title":"Fructose ingestion acutely stimulates circulating FGF21 levels in humans","volume":"4","author":"Dushay","year":"2015","journal-title":"Mol. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4931","DOI":"10.1210\/en.2009-0532","article-title":"Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis","volume":"150","author":"Badman","year":"2009","journal-title":"Endocrinology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1113\/EP086629","article-title":"Fibroblast growth factor 21 increases hepatic oxidative capacity but not physical activity or energy expenditure in hepatic peroxisome proliferator-activated receptor gamma coactivator-1alpha-deficient mice","volume":"103","author":"Fletcher","year":"2018","journal-title":"Exp. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.molmet.2017.12.008","article-title":"Hepatic regulation of VLDL receptor by PPARbeta\/delta and FGF21 modulates non-alcoholic fatty liver disease","volume":"8","author":"Zarei","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"42","DOI":"10.12997\/jla.2018.7.1.42","article-title":"Relationship between Circulating FGF21 Concentrations and the Severity of Coronary Artery Damage in Subjects with Cardiovascular Disease","volume":"7","author":"Park","year":"2018","journal-title":"J. Lipid Atheroscler."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4084","DOI":"10.1210\/en.2009-0221","article-title":"Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity","volume":"150","author":"Berglund","year":"2009","journal-title":"Endocrinology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1038\/s41366-018-0080-7","article-title":"FGF21 decreases body weight without reducing food intake or bone mineral density in high-fat fed obese rhesus macaque monkeys","volume":"42","author":"Andersen","year":"2018","journal-title":"Int. J. Obes"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1210\/en.2011-1496","article-title":"FGF21 is increased by inflammatory stimuli and protects leptin-deficient ob\/ob mice from the toxicity of sepsis","volume":"153","author":"Feingold","year":"2012","journal-title":"Endocrinology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1016\/j.bbadis.2015.02.012","article-title":"Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet","volume":"1852","author":"Tanaka","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/dom.12408","article-title":"Fibroblast growth factor 21 analogue LY2405319 lowers blood glucose in streptozotocin-induced insulin-deficient diabetic mice by restoring brown adipose tissue function","volume":"17","author":"Kim","year":"2015","journal-title":"Diabetes Obes. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.cmet.2013.08.005","article-title":"The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes","volume":"18","author":"Gaich","year":"2013","journal-title":"Cell Metab."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"He, Z., Tian, Y., Valenzuela, P.L., Huang, C., Zhao, J., Hong, P., He, Z., Yin, S., and Lucia, A. (2019). Myokine\/Adipokine Response to \u201cAerobic\u201d Exercise: Is It Just a Matter of Exercise Load?. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00691"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3805","DOI":"10.1016\/j.febslet.2008.10.021","article-title":"FGF21 is an Akt-regulated myokine","volume":"582","author":"Izumiya","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.molmet.2015.06.001","article-title":"Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans","volume":"4","author":"Hansen","year":"2015","journal-title":"Mol. Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1152\/japplphysiol.00456.2016","article-title":"Fibroblast growth factor 21 is required for beneficial effects of exercise during chronic high-fat feeding","volume":"121","author":"Loyd","year":"2016","journal-title":"J. Appl. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"E607","DOI":"10.1152\/ajpendo.00263.2010","article-title":"Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARalpha and FGF21 transcripts in vivo","volume":"299","author":"Berglund","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.bbrc.2013.09.026","article-title":"Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation","volume":"440","author":"Kim","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.2337\/dc09-0684","article-title":"Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance","volume":"32","author":"Chavez","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1210\/jc.2015-3308","article-title":"Endurance Exercise Reduces Hepatic Fat Content and Serum Fibroblast Growth Factor 21 Levels in Elderly Men","volume":"101","author":"Taniguchi","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kong, Z., Sun, S., Liu, M., and Shi, Q. (2016). Short-Term High-Intensity Interval Training on Body Composition and Blood Glucose in Overweight and Obese Young Women. J. Diabetes Res., 2016.","DOI":"10.1155\/2016\/4073618"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1139\/h2012-091","article-title":"Modulating fibroblast growth factor 21 in hyperphagic OLETF rats with daily exercise and caloric restriction","volume":"37","author":"Fletcher","year":"2012","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1530\/JOE-17-0190","article-title":"Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21","volume":"235","author":"Porter","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4057","DOI":"10.2337\/db14-0595","article-title":"Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding","volume":"63","author":"Markan","year":"2014","journal-title":"Diabetes"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4147","DOI":"10.1210\/endo.139.10.6258","article-title":"Alpha2-Heremans Schmid glycoprotein inhibits insulin-stimulated Elk-1 phosphorylation, but not glucose transport, in rat adipose cells","volume":"139","author":"Chen","year":"1998","journal-title":"Endocrinology"},{"key":"ref_60","first-page":"1445","article-title":"Serum alpha 2-HS-glycoprotein is an inhibitor of the human insulin receptor at the tyrosine kinase level","volume":"7","author":"Srinivas","year":"1993","journal-title":"Mol. Endocrinol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2018\/7918714","article-title":"Relationship of Circulating Fetuin-A Levels with Body Size and Metabolic Phenotypes","volume":"2018","author":"Chung","year":"2018","journal-title":"Int. J. Endocrinol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1111\/j.1365-2265.2011.04070.x","article-title":"Serum fetuin-A concentrations are elevated in subjects with impaired glucose tolerance and newly diagnosed type 2 diabetes","volume":"75","author":"Ou","year":"2011","journal-title":"Clin. Endocrinol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4717","DOI":"10.1210\/jc.2012-2414","article-title":"Increased fetuin-A concentrations in impaired glucose tolerance with or without nonalcoholic fatty liver disease, but not impaired fasting glucose","volume":"97","author":"Ou","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.2337\/diabetes.51.8.2450","article-title":"Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene","volume":"51","author":"Mathews","year":"2002","journal-title":"Diabetes"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"20789","DOI":"10.1074\/jbc.271.34.20789","article-title":"The serum protein alpha2-HS glycoprotein\/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. A possible role in mineralization and calcium homeostasis","volume":"271","author":"Schinke","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1111\/1440-1681.13131","article-title":"Protectin DX ameliorates palmitate-induced hepatic insulin resistance through AMPK\/SIRT1-mediated modulation of fetuin-A and SeP expression","volume":"46","author":"Jung","year":"2019","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"E250","DOI":"10.1152\/ajpendo.00089.2018","article-title":"Phosphorylation status of fetuin-A is critical for inhibition of insulin action and is correlated with obesity and insulin resistance","volume":"317","author":"Ren","year":"2019","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"818","DOI":"10.2337\/db17-1348","article-title":"Hepatic F-Box Protein FBXW7 Maintains Glucose Homeostasis Through Degradation of Fetuin-A","volume":"67","author":"Zhao","year":"2018","journal-title":"Diabetes"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Takahashi, H., Kotani, K., Tanaka, K., Egucih, Y., and Anzai, K. (2018). Therapeutic Approaches to Nonalcoholic Fatty Liver Disease: Exercise Intervention and Related Mechanisms. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00588"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1093\/ndt\/gfv250","article-title":"Indoxyl sulfate suppresses hepatic fetuin-A expression via the aryl hydrocarbon receptor in HepG2 cells","volume":"30","author":"Ochi","year":"2015","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1172\/JCI28898","article-title":"TLR4 links innate immunity and fatty acid-induced insulin resistance","volume":"116","author":"Shi","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1038\/nm.2851","article-title":"Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance","volume":"18","author":"Pal","year":"2012","journal-title":"Nat. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1139\/apnm-2017-0639","article-title":"The influence of adiposity and acute exercise on circulating hepatokines in normal-weight and overweight\/obese men","volume":"43","author":"Sargeant","year":"2018","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Mathews, S., Ren, G., He, X., Bowers, R., Araya-Ramirez, F., Littlefield, L., and Grandjean, P. (2014). Plasma fetuin-A and phosphofetuin-A (Ser312) responses to a single or short-term repeated bout of exercise in obese and normal-weight individuals (1028.2). FASEB J., 28.","DOI":"10.1096\/fasebj.28.1_supplement.1028.2"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1139\/cjpp-2013-0043","article-title":"Preventive roles of swimming exercise and pioglitazone treatment on hepatic dysfunction in a rat model of metabolic syndrome","volume":"92","author":"Sakr","year":"2014","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1152\/japplphysiol.00237.2013","article-title":"Fetuin-A is linked to improved glucose tolerance after short-term exercise training in nonalcoholic fatty liver disease","volume":"115","author":"Malin","year":"2013","journal-title":"J. Appl. Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1249\/MSS.0000000000000338","article-title":"Exercise-induced lowering of fetuin-A may increase hepatic insulin sensitivity","volume":"46","author":"Malin","year":"2014","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s12944-018-0681-0","article-title":"Increased plasma and adipose tissue levels of ANGPTL8\/Betatrophin and ANGPTL4 in people with hypertension","volume":"17","author":"Cherian","year":"2018","journal-title":"Lipids Health Dis."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Lee, S., Norheim, F., Gulseth, H.L., Langleite, T.M., Kolnes, K.J., Tangen, D.S., Stadheim, H.K., Gilfillan, G.D., Holen, T., and Birkeland, K.I. (2017). Interaction between plasma fetuin-A and free fatty acids predicts changes in insulin sensitivity in response to long-term exercise. Physiol. Rep., 5.","DOI":"10.14814\/phy2.13183"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"25593","DOI":"10.1074\/jbc.M109.025452","article-title":"Angiopoietin-like 4 (ANGPTL4, fasting-induced adipose factor) is a direct glucocorticoid receptor target and participates in glucocorticoid-regulated triglyceride metabolism","volume":"284","author":"Koliwad","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.molmed.2019.05.010","article-title":"ANGPTL4 in Metabolic and Cardiovascular Disease","volume":"25","author":"Aryal","year":"2019","journal-title":"Trends Mol. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.molmet.2017.06.007","article-title":"Angiopoietin-like 4 directs uptake of dietary fat away from adipose during fasting","volume":"6","author":"Cushing","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4943","DOI":"10.1210\/en.2005-0476","article-title":"Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: Regulation of triglyceride metabolism","volume":"146","author":"Koster","year":"2005","journal-title":"Endocrinology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6086","DOI":"10.1073\/pnas.0408452102","article-title":"Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice","volume":"102","author":"Xu","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1161\/ATVBAHA.107.151894","article-title":"Angptl4 upregulates cholesterol synthesis in liver via inhibition of LPL- and HL-dependent hepatic cholesterol uptake","volume":"27","author":"Lichtenstein","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1007\/s00125-018-4583-5","article-title":"Loss of angiopoietin-like 4 (ANGPTL4) in mice with diet-induced obesity uncouples visceral obesity from glucose intolerance partly via the gut microbiota","volume":"61","author":"Janssen","year":"2018","journal-title":"Diabetologia"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1161\/ATVBAHA.108.182147","article-title":"Caloric restriction and exercise increase plasma ANGPTL4 levels in humans via elevated free fatty acids","volume":"29","author":"Kersten","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1002\/oby.20060","article-title":"Effect of weight loss and exercise on angiogenic factors in the circulation and in adipose tissue in obese subjects","volume":"21","author":"Cullberg","year":"2013","journal-title":"Obesity"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1002\/jcsm.12474","article-title":"Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle","volume":"10","author":"Han","year":"2019","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"E543","DOI":"10.1152\/ajpendo.00430.2010","article-title":"Follistatin-derived peptide expression in muscle decreases adipose tissue mass and prevents hepatic steatosis","volume":"300","author":"Nakatani","year":"2011","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Sylow, L., Vind, B.F., Kruse, R., Moller, P.M., Wojtaszewski, J.F.P., Richter, E.A., and Hojlund, K. (2020). Circulating follistatin and activin A and their regulation by insulin in obesity and type 2 diabetes. J. Clin. Endocrinol. Metab., 105.","DOI":"10.1210\/clinem\/dgaa090"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1016\/j.metabol.2016.07.009","article-title":"Activin A and follistatin in patients with nonalcoholic fatty liver disease","volume":"65","author":"Polyzos","year":"2016","journal-title":"Metabolism"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1111\/dom.13572","article-title":"Follistatins in glucose regulation in healthy and obese individuals","volume":"21","author":"Perakakis","year":"2019","journal-title":"Diabetes Obes. Metab."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1210\/jc.2015-3668","article-title":"Circulating Follistatin Is Liver-Derived and Regulated by the Glucagon-to-Insulin Ratio","volume":"101","author":"Hansen","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/S0167-4781(97)00085-7","article-title":"Regulation of the expression of follistatin in rat hepatocytes","volume":"1354","author":"Zhang","year":"1997","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1038\/mt.2015.29","article-title":"Overcoming Insulin Insufficiency by Forced Follistatin Expression in beta-cells of db\/db Mice","volume":"23","author":"Zhao","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1210\/en.2012-1844","article-title":"Increased activin bioavailability enhances hepatic insulin sensitivity while inducing hepatic steatosis in male mice","volume":"154","author":"Ungerleider","year":"2013","journal-title":"Endocrinology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1210\/jc.2016-1681","article-title":"Exercise-Induced Secretion of FGF21 and Follistatin Are Blocked by Pancreatic Clamp and Impaired in Type 2 Diabetes","volume":"101","author":"Hansen","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1210\/en.2010-0868","article-title":"Exercise induces a marked increase in plasma follistatin: Evidence that follistatin is a contraction-induced hepatokine","volume":"152","author":"Hansen","year":"2011","journal-title":"Endocrinology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"E11","DOI":"10.1152\/ajpendo.00433.2018","article-title":"Role of exercise-induced hepatokines in metabolic disorders","volume":"317","author":"Ennequin","year":"2019","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"579","DOI":"10.2337\/db07-1438","article-title":"Muscle-derived angiopoietin-like protein 4 is induced by fatty acids via peroxisome proliferator-activated receptor (PPAR)-delta and is of metabolic relevance in humans","volume":"58","author":"Staiger","year":"2009","journal-title":"Diabetes"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1172\/jci.insight.97918","article-title":"Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis","volume":"3","author":"Aryal","year":"2018","journal-title":"JCI Insight"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1038\/s41591-018-0048-0","article-title":"Inactivating hepatic follistatin alleviates hyperglycemia","volume":"24","author":"Tao","year":"2018","journal-title":"Nat. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"65","DOI":"10.2147\/DMSO.S159315","article-title":"Metabolic profiling of follistatin overexpression: A novel therapeutic strategy for metabolic diseases","volume":"11","author":"Singh","year":"2018","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/nrendo.2012.258","article-title":"The role of hepatokines in metabolism","volume":"9","author":"Stefan","year":"2013","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Gonzalez-Gil, A.M., and Elizondo-Montemayor, L. (2020). The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review. Nutrients, 12.","DOI":"10.3390\/nu12061899"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/s00424-018-2216-y","article-title":"Hepatokines\u2014A novel group of exercise factors","volume":"471","author":"Weigert","year":"2019","journal-title":"Pflug. Arch."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"G832","DOI":"10.1152\/ajpgi.00355.2015","article-title":"Fibroblast growth factor 21 and exercise-induced hepatic mitochondrial adaptations","volume":"310","author":"Fletcher","year":"2016","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1152\/japplphysiol.00984.2016","article-title":"Role of Angptl4\/Fiaf in exercise-induced skeletal muscle AMPK activation","volume":"125","author":"Chang","year":"2018","journal-title":"J. Appl. Physiol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/3\/385\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:13:06Z","timestamp":1760159586000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/3\/385"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,20]]},"references-count":109,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["jcm10030385"],"URL":"https:\/\/doi.org\/10.3390\/jcm10030385","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,20]]}}}