title: FTO influences adipogenesis by regulating mitotic clonal expansion.
abstract: The fat mass and obesity-associated (FTO) gene plays a pivotal role in regulating body weight and fat mass; however, the underlying mechanisms are poorly understood. Here we show that primary adipocytes and mouse embryonic fibroblasts (MEFs) derived from FTO overexpression (FTO-4) mice exhibit increased potential for adipogenic differentiation, while MEFs derived from FTO knockout (FTO-KO) mice show reduced adipogenesis. As predicted from these findings, fat pads from FTO-4 mice fed a high-fat diet show more numerous adipocytes. FTO influences adipogenesis by regulating events early in adipogenesis, during the process of mitotic clonal expansion. The effect of FTO on adipogenesis appears to be mediated via enhanced expression of the pro-adipogenic short isoform of RUNX1T1, which enhanced adipocyte proliferation, and is increased in FTO-4 MEFs and reduced in FTO-KO MEFs. Our findings provide novel mechanistic insight into how upregulation of FTO leads to obesity.
authors.affiliation: 1] MRC Harwell, Mammalian Genetics Unit, Harwell Oxford OX11 0RD, UK [2] Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
authors.forename: Myrte
authors.initials: M
authors.lastname: Merkestein
authors.affiliation: 1] MRC Harwell, Mammalian Genetics Unit, Harwell Oxford OX11 0RD, UK [2] Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Laber
authors.affiliation: MRC Harwell, Mammalian Genetics Unit, Harwell Oxford OX11 0RD, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: McMurray
authors.affiliation: MRC Harwell, Mammalian Genetics Unit, Harwell Oxford OX11 0RD, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Andrew
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
authors.forename: Gregor
authors.initials: G
authors.lastname: Sachse
authors.affiliation: MRC Harwell, Mammalian Genetics Unit, Harwell Oxford OX11 0RD, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sanderson
authors.affiliation: MRC Harwell, Mammalian Genetics Unit, Harwell Oxford OX11 0RD, UK.
authors.forename: Mengdi
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
authors.forename: Samuel
authors.initials: S
authors.lastname: Usher
authors.affiliation: 1] MRC Harwell, Mammalian Genetics Unit, Harwell Oxford OX11 0RD, UK [2] Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
authors.forename: Dyan
authors.initials: D
authors.lastname: Sellayah
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
authors.affiliation: MRC Harwell, Mammalian Genetics Unit, Harwell Oxford OX11 0RD, UK.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cox
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics*; D000273:Adipose Tissue / Q000166:cytology*; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D059305:Diet, High-Fat; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C493598:MTG8 protein, mouse; D011506:Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO