{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:21:27Z","timestamp":1790734887919,"version":"4.1.0"},"reference-count":77,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,8,11]],"date-time":"2019-08-11T00:00:00Z","timestamp":1565481600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002848","name":"Comisi\u00f3n Nacional de Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["#32082"],"award-info":[{"award-number":["#32082"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["#15182"],"award-info":[{"award-number":["#15182"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008394","name":"Natur og Univers, Det Frie Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["DFF\u20106108\u201000203A"],"award-info":[{"award-number":["DFF\u20106108\u201000203A"]}],"id":[{"id":"10.13039\/100008394","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008394","name":"Natur og Univers, Det Frie Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["DFF\u20104004\u201000233"],"award-info":[{"award-number":["DFF\u20104004\u201000233"]}],"id":[{"id":"10.13039\/100008394","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Skeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor \u03b2 (TGF\u2010\u03b2) superfamily, including activin A, which causes atrophy. TGF\u2010\u03b2 superfamily ligands also negatively regulate insulin\u2010sensitive proteins, but whether this pathway contributes to insulin action remains to be determined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To elucidate if TGF\u2010\u03b2 superfamily ligands regulate insulin action, we used an adeno\u2010associated virus gene editing approach to overexpress an activin A inhibitor, follistatin (Fst288), in mouse muscle of lean and diet\u2010induced obese mice. We determined basal and insulin\u2010stimulated 2\u2010deoxy\u2010glucose uptake using isotopic tracers\n                      <jats:italic>in vivo<\/jats:italic>\n                      . Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans, we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux\u2010en\u2010Y gastric bypass (RYGB).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Fst288 muscle overexpression markedly increased\n                      <jats:italic>in vivo<\/jats:italic>\n                      insulin\u2010stimulated (but not basal) glucose uptake (+75%,\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase\u2010E1\u03b1, and p70S6K, while decreasing TBC1D1 signaling (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.05). Fst288 increased both basal and insulin\u2010stimulated protein synthesis, but no correlation was observed between the Fst288\u2010driven hypertrophy and the increase in insulin\u2010stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin\u2010resistant diet\u2010induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (\u221224%,\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We here present evidence that Fst is a potent regulator of insulin action in muscle, and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4, pyruvate dehydrogenase\u2010E1\u03b1, and PAK1 as Fst targets. Circulating Fst more than doubled post\u2010RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. These findings demonstrate the therapeutic potential of inhibiting TGF\u2010\u03b2 superfamily ligands to improve insulin action and Fst's relevance to muscle wasting\u2010associated insulin\u2010resistant conditions in mice and humans.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.12474","type":"journal-article","created":{"date-parts":[[2019,8,11]],"date-time":"2019-08-11T23:06:18Z","timestamp":1565564778000},"page":"1241-1257","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Mechanisms involved in follistatin\u2010induced hypertrophy and increased insulin action in skeletal muscle"],"prefix":"10.1002","volume":"10","author":[{"given":"Xiuqing","family":"Han","sequence":"first","affiliation":[{"name":"Section of Molecular Physiology, Department of Nutrition, Exercise, and Sports, Faculty of Science University of Copenhagen  Copenhagen 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