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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,14]]},"abstract":"<jats:p>\n                    Up to a third of the global population is afflicted by metabolic dysfunction-associated steatotic liver disease with excessive triglyceride accumulation in the liver. Prolonged fasting rapidly causes hepatic steatosis via excessive influx of free fatty acids from adipose tissue. However, it is unclear whether skeletal muscle is involved in the etiology of hepatic steatosis during starvation. Here, we demonstrate a critical connection between the liver and skeletal muscle via FoxO transcription factors. During prolonged fasting, hepatic steatosis was exacerbated in skeletal muscle\u2013specific FoxO-deficient mice (mFoxO1,3,4\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) despite preventing skeletal muscle wasting, suggesting that skeletal muscle FoxOs prevent hepatic steatosis during energy deprivation. FoxO deficiency in skeletal muscle weakened fatty acid oxidation and induced abnormal glycogen accumulation in skeletal muscle during fasting. Mechanistically, the starvation-induced transcriptional regulation of triglyceride lipase was attenuated in skeletal muscle of FoxO-deficient mice. Conversely, skeletal muscle\u2013specific FOXO1 overexpression was sufficient to increase triglyceride lipase in vivo and protected the liver from Western diet\u2013induced metabolic dysfunction\u2013associated steatohepatitis-like phenotype. Taken together, our results demonstrate the physiological importance of skeletal muscle FoxO signaling on the liver pathophysiology.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2600036123","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T17:04:44Z","timestamp":1775667884000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Loss of FoxO in skeletal muscle leads to disrupted muscle metabolism and exacerbates starvation-induced hepatic steatosis"],"prefix":"10.1073","volume":"123","author":[{"given":"Mamoru","family":"Oyabu","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University","place":["Kyoto, Japan"]},{"name":"Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology","place":["Obu, Aichi, 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Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University","place":["Uji, Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Nishi","sequence":"additional","affiliation":[{"name":"Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo","place":["Tokyo, Japan"]},{"name":"Department of Science and Engineering, Saitama University","place":["Saitama City, Saitama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Yamanaka","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medical Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Sato","sequence":"additional","affiliation":[{"name":"Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka","place":["Shizuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiki","family":"Mori","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of Osaka","place":["Suita, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Eguchi","sequence":"additional","affiliation":[{"name":"Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology","place":["Obu, Aichi, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Ito","sequence":"additional","affiliation":[{"name":"Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology","place":["Obu, Aichi, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4051-5108","authenticated-orcid":false,"given":"So-ichiro","family":"Fukada","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of Osaka","place":["Suita, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayoshi","family":"Suganami","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University","place":["Nagoya, Japan"]},{"name":"Department of Immunometabolism, Nagoya University Graduate School of Medicine","place":["Nagoya, 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Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2778-926X","authenticated-orcid":false,"given":"Yasutomi","family":"Kamei","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University","place":["Kyoto, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-022-00635-5"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.08.026"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.109"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.015"},{"key":"e_1_3_4_5_2","first-page":"167","article-title":"Pathogenesis and prevention of hepatic steatosis","volume":"11","author":"Nassir 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Oyabu Y. Kamei Microarray analysis of quadriceps muscle of fed or 24 h-fasted wild type mice and skeletal muscle-specific FoxO1 3 4 knockout mice. NCBI GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE314981. Deposited 24 December 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2600036123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T17:05:54Z","timestamp":1775667954000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2600036123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,8]]},"references-count":53,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2026,4,14]]}},"alternative-id":["10.1073\/pnas.2600036123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2600036123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,8]]},"assertion":[{"value":"2026-01-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2600036123"}}