title: The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.
abstract: Variants in the FTO (fat mass and obesity associated) gene are associated with increased body mass index in humans. Here, we show by bioinformatics analysis that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate-dependent oxygenases. We find that recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, with concomitant production of succinate, formaldehyde, and carbon dioxide. Consistent with a potential role in nucleic acid demethylation, Fto localizes to the nucleus in transfected cells. Studies of wild-type mice indicate that Fto messenger RNA (mRNA) is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and that Fto mRNA levels in the arcuate nucleus are regulated by feeding and fasting. Studies can now be directed toward determining the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass.
authors.affiliation: Chemistry Research Laboratory and Oxford Centre for Integrative Systems Biology, University of Oxford, 12 Mansfield Road, Oxford, Oxon OX1 3TA, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gerken
authors.forename: Christophe A
authors.initials: CA
authors.lastname: Girard
authors.forename: Yi-Chun Loraine
authors.initials: YC
authors.lastname: Tung
authors.forename: Celia J
authors.initials: CJ
authors.lastname: Webby
authors.forename: Vladimir
authors.initials: V
authors.lastname: Saudek
authors.forename: Kirsty S
authors.initials: KS
authors.lastname: Hewitson
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDonough
authors.forename: Sharon
authors.initials: S
authors.lastname: Cunliffe
authors.forename: Luke A
authors.initials: LA
authors.lastname: McNeill
authors.forename: Juris
authors.initials: J
authors.lastname: Galvanovskis
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Peter
authors.initials: P
authors.lastname: Robins
authors.forename: Xavier
authors.initials: X
authors.lastname: Prieur
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Coll
authors.forename: Marcella
authors.initials: M
authors.lastname: Ma
authors.forename: Zorica
authors.initials: Z
authors.lastname: Jovanovic
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Barbara
authors.initials: B
authors.lastname: Sedgwick
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.forename: Tomas
authors.initials: T
authors.lastname: Lindahl
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002467:Cell Nucleus / Q000201:enzymology; D019295:Computational Biology; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation; D004277:DNA, Single-Stranded / Q000378:metabolism; D004435:Eating; D004734:Energy Metabolism; D005215:Fasting; D005296:Ferrous Compounds / Q000378:metabolism; D007031:Hypothalamus / Q000201:enzymology / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism*; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases; D008969:Molecular Sequence Data; D007652:Oxo-Acid-Lyases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism; D013941:Thymine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D004277:DNA, Single-Stranded; D005296:Ferrous Compounds; D007656:Ketoglutaric Acids; D012333:RNA, Messenger; D011994:Recombinant Proteins; D004247:DNA; D019802:Succinic Acid; D006899:Mixed Function Oxygenases; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D007652:Oxo-Acid-Lyases; D013941:Thymine; C002347:3-methylthymine