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It has a beneficial role in the regulation of glucose and energy metabolism. Herein, we identify apoptosis signal regulating kinase 1 (ASK1) as an inducer of hepatic FGF21 synthesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Glucose and energy metabolism were assessed in liver\u2010specific ASK1 overexpressing (ASK1\n                      <jats:sup>+hep<\/jats:sup>\n                      ) and control littermate (ASK1\n                      <jats:sup>f\/f<\/jats:sup>\n                      ) mice fed a regular chow or high fat diet (HFD) for 20\u2009weeks. Liver and fat depots were analyzed using RNA sequencing. Hepatic\n                      <jats:italic>Fgf21<\/jats:italic>\n                      expression was downregulated using adeno\u2010associated virus (AAV) expressing short\u2010hairpin RNA sequences.\n                      <jats:italic>ASK1<\/jats:italic>\n                      and\n                      <jats:italic>FGF21<\/jats:italic>\n                      expression was determined in human liver samples.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HFD\u2010fed ASK1\n                      <jats:sup>+hep<\/jats:sup>\n                      mice exhibited improved glucose metabolism, elevated energy expenditure, and reduced body weight. FGF21 plasma levels were increased in HFD\u2010fed ASK1\n                      <jats:sup>+hep<\/jats:sup>\n                      mice, and its reduction in\u00a0vivo blunted beneficial effects on obesity. Mechanistically, ASK1 promoted hepatic\n                      <jats:italic>Fgf21<\/jats:italic>\n                      gene expression via the transcription factor ATF4. In humans, hepatic\n                      <jats:italic>ASK1<\/jats:italic>\n                      expression correlated positively with\n                      <jats:italic>FGF21<\/jats:italic>\n                      and negatively with BMI and visceral fat area.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We describe a novel role of hepatic ASK1 in the synthesis of FGF21. Hence, increasing hepatic\n                      <jats:italic>ASK1<\/jats:italic>\n                      expression might be a novel strategy to combat obesity\u2010associated metabolic complications.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/oby.70261","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T15:03:26Z","timestamp":1784214206000},"page":"1635-1646","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>ASK1<\/scp>\n                    \u2010Induced\n                    <scp>FGF21<\/scp>\n                    Synthesis in the Liver Prevents Obesity in Mice"],"prefix":"10.1002","volume":"34","author":[{"given":"Anne","family":"Goergen","sequence":"first","affiliation":[{"name":"Division of Pediatric Endocrinology and Diabetology University of Zurich  Zurich Switzerland"},{"name":"Children's Research Center, University Children's Hospital University of Zurich  Zurich Switzerland"},{"name":"Rosen Lab, Division of Endocrinology, Diabetes, and Metabolism Beth Israel Deaconess Medical Center  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenagne D.","family":"Challa","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology and Diabetology University of Zurich  Zurich Switzerland"},{"name":"Children's Research Center, University Children's Hospital University of Zurich  Zurich Switzerland"},{"name":"Institute of Food, Nutrition and Health ETH Zurich  Schwerzenbach Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Villaroel\u2010Vicente","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology and Diabetology University of Zurich  Zurich Switzerland"},{"name":"Children's Research Center, University Children's Hospital University of Zurich  Zurich 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