{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:56:16Z","timestamp":1790733376424,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Physiology","reference-count":103,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) arise, in part, from excessive free fatty acid flux from adipose tissue to the liver. Activin E (ActE, encoded by\n                  <jats:italic>INHBE<\/jats:italic>\n                  ) suppresses adipocyte lipolysis through the type I receptor ALK7 (ACVR1C). Loss-of-function variants in\n                  <jats:italic>INHBE<\/jats:italic>\n                  and\n                  <jats:italic>ACVR1C<\/jats:italic>\n                  reduce waist-to-hip ratio in humans, yet genetic knockouts in mice produce insulin resistance and hepatic steatosis, suggesting discrepancies between human and mouse biology. We identify GDF3, a TGF-\u03b2 superfamily ligand upregulated in obese adipose tissue, as the principal endogenous antagonist of ActE\/ALK7 signaling. Human transcriptomic datasets reveal coordinated dysregulation: hepatic\n                  <jats:italic>INHBE<\/jats:italic>\n                  expression and circulating ActE protein are elevated in obesity, while adipose\n                  <jats:italic>ACVR1C<\/jats:italic>\n                  is downregulated and\n                  <jats:italic>GDF3<\/jats:italic>\n                  is reciprocally upregulated. Using ALK7-selective reporter assays, we show GDF3 inhibits ActE-driven SMAD2\/3 signaling as a competitive antagonist rather than the weak agonist previously proposed. ActE suppressed beta-adrenergic-stimulated lipolysis in mouse and human adipocytes and primary human adipose tissue; GDF3 overexpression abolished this effect. In diet-induced obese mice, inducible\n                  <jats:italic>Gdf3<\/jats:italic>\n                  deletion reduced adipose lipolysis, resolved hepatic steatosis and fibrosis, and improved insulin sensitivity, benefits abolished by\n                  <jats:italic>Inhbe<\/jats:italic>\n                  knockdown, confirming dependence on ActE signaling. Predicted loss-of-function variants in\n                  <jats:italic>INHBE<\/jats:italic>\n                  show only nominal, WHR-dependent associations with type 2 diabetes risk, potentially confounded by hematological effects on HbA1c.\n                  <jats:italic>Gdf3<\/jats:italic>\n                  deficiency synergized with the clinical-stage anti-activin receptor antibody Bimagrumab to amplify fat-mass loss and improve glucose homeostasis in multiple MASH models. These findings establish GDF3 as an endogenous antagonist of ActE-ALK7 signaling and nominate GDF3 inhibition as a therapeutic strategy for MASLD\/MASH.\n                <\/jats:p>","DOI":"10.64898\/2026.09.18.752693","type":"posted-content","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:40:19Z","timestamp":1790307619000},"source":"Crossref","is-referenced-by-count":0,"title":["GDF3 is an endogenous antagonist of the ActE-ALK7\/ACVR2 pathway in adipocytes"],"prefix":"10.64898","author":[{"given":"Nagasuryaprasad","family":"Kotikalapudi","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepti","family":"Ramachandran","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn Y.","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Howard","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA"},{"name":"Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Vieira","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-An","family":"Chen","sequence":"additional","affiliation":[{"name":"Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Hsu","sequence":"additional","affiliation":[{"name":"Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Cheul","family":"Shin","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirish","family":"Naz","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z. Gordon","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep M.","family":"Mercader","sequence":"additional","affiliation":[{"name":"Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 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