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Fibroblast growth factor (FGF) 1 is the first paracrine FGF family member identified to exhibit promising metabolic regulatory properties capable of conferring glucose\u2010lowering and insulin\u2010sensitizing effect. This study explores the role and molecular underpinnings of FGF1 in obesity\u2010associated hepatic steatosis. In a mouse high\u2010fat diet (HFD)\u2010induced MAFLD model, chronic treatment with recombinant FGF1(rFGF1) was found to effectively reduce the severity of insulin resistance, hyperlipidemia, and inflammation. FGF1 treatment decreased lipid accumulation in the mouse liver and palmitic acid\u2010treated AML12 cells. These effects were associated with decreased mature form SREBF1 expression and its target genes FASN and SCD1. Interestingly, we uncovered that rFGF1 significantly induced IGFBP2 expression at both mRNA and protein levels in HFD\u2010fed mouse livers and cultured hepatocytes treated with palmitic acid. Adeno\u2010associated virus\u2010mediated IGFBP2 suppression significantly diminished the therapeutic benefit of rFGF1 on MAFLD\u2010associated phenotypes, indicating that IGFBP2 plays a crucial role in the FGF1\u2010mediated reduction of hepatic steatosis. Further analysis revealed that rFGF1 treatment reduces the recruitment of DNA methyltransferase 3 alpha to the IGFBP2 genomic locus, leading to decreased IGFBP2 gene methylation and increased mRNA and protein expression. Collectively, our findings reveal FGF1 modulation of lipid metabolism via epigenetic regulation of IGFBP2 expression, and unravel the therapeutic potential of the FGF1\u2010IGFBP2 axis in metabolic diseases associated with obesity.<\/jats:p>","DOI":"10.1096\/fj.202201950r","type":"journal-article","created":{"date-parts":[[2023,3,19]],"date-time":"2023-03-19T11:18:41Z","timestamp":1679224721000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["<scp>FGF1<\/scp>\n                    ameliorates obesity\u2010associated hepatic steatosis by reversing\n                    <scp>IGFBP2<\/scp>\n                    hypermethylation"],"prefix":"10.1096","volume":"37","author":[{"given":"Jie","family":"Wang","sequence":"first","affiliation":[{"name":"The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital  Quzhou China"},{"name":"International Collaborative Center on Growth Factor Research, 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