Journal
SCIENCE
Volume 318, Issue 5855, Pages 1469-1472Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1151710
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Funding
- Biotechnology and Biological Sciences Research Council [BB/D011523/1] Funding Source: researchfish
- Medical Research Council [MC_U137761446, G108/617, G9824984] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/D011523/1] Funding Source: Medline
- Medical Research Council [G108/617, MC_U137761446, G9824984] Funding Source: Medline
- NIGMS NIH HHS [U54 GM064346] Funding Source: Medline
- Wellcome Trust [068086, 077016] Funding Source: Medline
- BBSRC [BB/D011523/1] Funding Source: UKRI
- MRC [G9824984, MC_U137761446, G108/617] Funding Source: UKRI
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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-methylthyminein 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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