The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.
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.
Gerken
Thomas
T
Chemistry Research Laboratory and Oxford Centre for Integrative Systems Biology, University of Oxford, 12 Mansfield Road, Oxford, Oxon OX1 3TA, UK.
Girard
Christophe A
CA
Tung
Yi-Chun Loraine
YC
Webby
Celia J
CJ
Saudek
Vladimir
V
Hewitson
Kirsty S
KS
Yeo
Giles S H
GS
McDonough
Michael A
MA
Cunliffe
Sharon
S
McNeill
Luke A
LA
Galvanovskis
Juris
J
Rorsman
Patrik
P
Robins
Peter
P
Prieur
Xavier
X
Coll
Anthony P
AP
Ma
Marcella
M
Jovanovic
Zorica
Z
Farooqi
I Sadaf
IS
Sedgwick
Barbara
B
Barroso
Inês
I
Lindahl
Tomas
T
Ponting
Chris P
CP
Ashcroft
Frances M
FM
O'Rahilly
Stephen
S
Schofield
Christopher J
CJ
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
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