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Here, it is found that liver undergoes dramatic metabolic reprogramming during ADF, accompanied surprisingly with unique complex II dysfunction attributing to suspended complex II assembly via suppressing SDHAF4, a recently identified assembly factor. Despite moderate mitochondrial complex II dysfunction, hepatic <jats:italic>Sdhaf4<\/jats:italic> knockout mice present intriguingly improved glucose tolerance and systemic insulin sensitivity, consistent with mice after ADF intervention. Mechanistically, it is found that hepatocytes activate arginine\u2010nitric oxide (NO) biosynthesis axle in response to complex II and citric acid cycle dysfunction, the release of NO from liver can target muscle and adipocytes in addition to its autocrine action for enhanced insulin sensitivity. These results highlight the pivotal role of liver in ADF\u2010associated systemic benefits, and suggest that targeting hepatic complex II assembly can be an intriguing strategy against metabolic disorders.<\/jats:p>","DOI":"10.1002\/advs.202105587","type":"journal-article","created":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T05:34:01Z","timestamp":1642397641000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Hepatic Suppression of Mitochondrial Complex II Assembly Drives Systemic Metabolic Benefits"],"prefix":"10.1002","volume":"9","author":[{"given":"Xueqiang","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqiang","family":"Lv","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Zeng","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Cao","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Cui","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial Biology and Medicine The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongping","family":"Shao","sequence":"additional","affiliation":[{"name":"Frontier Institute of Science and Technology Xi'an Jiaotong University  Xi'an Shaanxi 710049 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine  Xi'an Shanghai 200240 China"},{"name":"National Clinical Research Center for Eye Diseases  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Zou","sequence":"additional","affiliation":[{"name":"National &amp; 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