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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.

Original publication

DOI

10.1126/science.1151710

Type

Journal article

Journal

Science

Publication Date

30/11/2007

Volume

318

Pages

1469 - 1472

Keywords

Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Amino Acid Sequence, Animals, Brain, Cell Nucleus, Computational Biology, DNA, DNA Methylation, DNA, Single-Stranded, Eating, Energy Metabolism, Fasting, Ferrous Compounds, Hypothalamus, Ketoglutaric Acids, Male, Mice, Mixed Function Oxygenases, Molecular Sequence Data, Oxo-Acid-Lyases, RNA, Messenger, Recombinant Proteins, Succinic Acid, Thymine