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Here, we show that reduced BDNF expression is associated with weight gain and the chronic liver disease non\u2010alcoholic steatohepatitis (NASH). At 10\u2009months of age, BDNF\u2010heterozygous (<jats:italic>BDNF<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>) mice developed symptoms of NASH: centrilobular\/perivenular steatosis, lobular inflammation with infiltration of neutrophils, ballooning hepatocytes, and fibrosis of the liver. Obesity and higher serum levels of glucose and insulin \u2013 major pathologic features in human NASH \u2013 were dramatic. Dying adipocytes were surrounded by macrophages in visceral fat, suggesting that chronic inflammation occurs in peripheral organs. RNA sequencing (RNA\u2010seq) studies of the liver revealed that the most significantly enriched Gene Ontology term involved fatty acid metabolic processes and the modulation of neutrophil aggregation, pathologies that well characterise NASH. Gene expression analysis by RNA\u2010seq also support the notion that <jats:italic>BDNF<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice are under oxidative stress, as indicated by alterations in the expression of the cytochrome P450 family and a reduction in glutathione S\u2010transferase p, an antioxidant enzyme. Histopathologic phenotypes of NASH were also observed in a knock\u2010in mouse (<jats:italic>BDNF<\/jats:italic><jats:sup><jats:italic>+\/pro<\/jats:italic><\/jats:sup>), in which the precursor BDNF is inefficiently converted into the mature form of BDNF. Lastly, as BDNF reduction causes overeating and subsequent obesity, a food restriction study was conducted in <jats:italic>BDNF<\/jats:italic><jats:sup><jats:italic>+\/pro<\/jats:italic><\/jats:sup> mice. Pair\u2010fed <jats:italic>BDNF<\/jats:italic><jats:sup><jats:italic>+\/pro<\/jats:italic><\/jats:sup> mice developed hepatocellular damage and showed infiltration of inflammatory cells, including neutrophils in the liver, despite having body weights and blood parameters that were comparable to those of controls. This is the first report demonstrating that reduced BDNF expression plays a role in the pathogenic mechanism of NASH, which is a hepatic manifestation of metabolic syndrome. \u00a9 2023 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6204","type":"journal-article","created":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T06:40:32Z","timestamp":1696228832000},"page":"465-476","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Brain\u2010derived neurotrophic factor knock\u2010out mice develop non\u2010alcoholic steatohepatitis"],"prefix":"10.1002","volume":"261","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4030-1249","authenticated-orcid":false,"given":"Mayuko","family":"Ichimura\u2010Shimizu","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Tokushima University Graduate School  Tokushima 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