The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase by Gerken Thomas, Girard Christophe A, Tung Yi-Chun Loraine, Webby Celia J, Saudek Vladimir, Hewitson Kirsty S, Yeo Giles S H, McDonough Michael A, Cunliffe Sharon, McNeill Luke A, Galvanovskis Juris, Rorsman Patrik, Robins Peter, Prieur Xavier, Coll Anthony P, Ma Marcella, Jovanovic Zorica, Farooqi I Sadaf, Sedgwick Barbara, Barroso InĂªs, Lindahl Tomas, Ponting Chris P, Ashcroft Frances M, O'Rahilly Stephen, Schofield Christopher J in Science (New York, N.Y.) (2007).

[PMID: 17991826] PubMed


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.

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