The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase

Chemistry Research Laboratory and Oxford Centre for Integrative Systems Biology, University of Oxford, 12 Mansfield Road, Oxford, Oxon OX1 3TA, UK.
Science (Impact Factor: 31.48). 12/2007; 318(5855):1469-72. DOI: 10.1126/science.1151710
Source: PubMed

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.

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Available from: Vladimir Saudek, Jul 09, 2015
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    • "The FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase (Gerken et al., 2007) but is also a transcriptional coactivator (Wu et al., 2010) and a possible regulator of telomere length (Dlouha et al., 2012). FTO is abundantly expressed in the hypothalamus, and epidemiological and functional studies have suggested it is directly involved in the regulation of energy intake (Cecil et al., 2008; Haupt et al., 2009). "
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    ABSTRACT: To investigate in a population sample of Portuguese young adults the association of the FTO variant rs9939609 with obesity, BMI, and body-fat and interaction with physical activity (PA) on obesity-susceptibility. SNP rs9939609 A/T was genotyped in 550 subjects (231 males and 319 females; 18-36 years old; mean age 21 years old) by TaqMan assay. PA was assessed with a validated self-reported questionnaire of IPAQ. We replicated the association of rs9939609-A risk allele with BMI (P = 0.04) and fat-mass (P = 0.031), and with overweight (including obesity) under a recessive model (P = 0.034). Stratified analyses showed (i) a significant association with overweight/obesity in inactive individuals (P = 0.02) but not in a group reporting participation in sports (P = 0.97). Spearman's correlation test suggested that the impact of a successive increase in PA was a decrease in the body-fat percentage (r = -0.16; P = 0.0002), which is accentuated for homozygous AA (r = -0.34; P = 0.002), and an increase in BMI (r = 0.14; P = 0.001), with a statistically significant correlation for homozygous TT (r = 0.22; P = 0.002). This study reveals interactions between rs9939609 and PA on obesity indices in Portuguese young adults, suggesting a change in the different body components (lean and fat mass) depending on the FTO genotypes. Am. J. Hum. Biol., 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Human Biology 03/2015; 00:0-0. DOI:10.1002/ajhb.22712 · 1.93 Impact Factor
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    • "Moreover, several dioxygenases can coexist in one cell; thus, questions arise about the specific function of these proteins, especially in eukaryotic cells. Through bioinformatic analysis nine human AlkB homologues were identified, ALKBH1-8 and FTO (Kurowski et al., 2003; Gerken et al., 2007), all containing a conserved 2OG–Fe(II) dioxygenase domain. Among these homologues, ALKBH1, ALKBH2, ALKBH3, and FTO exhibit methyl moiety oxidation activity, typical for EcAlkB. "
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    ABSTRACT: Alkylating agents are widespread in the environment and also occur endogenously. They can be cytotoxic or mutagenic to the cells introducing alkylated bases to DNA or RNA. All organisms have evolved multiple DNA repair mechanisms to counteract the effects of DNA alkylation: the most cytotoxic lesion, N(3) -methyladenine (3meA), is excised by AlkA glycosylase initiating base excision repair (BER); toxic N(1) -methyladenine (1meA) and N(3) -methylcytosine (3meC), induced in DNA and RNA, are removed by AlkB dioxygenase; and mutagenic and cytotoxic O(6) -methylguanine (O(6) meG) is repaired by Ada methyltransferase. In Escherichia coli, Ada response involves the expression of four genes, ada, alkA, alkB, and aidB, encoding respective proteins Ada, AlkA, AlkB, and AidB proteins, respectively. The Ada response is conserved among many bacterial species; however, it can be organized differently, with diverse substrate specificity of the particular proteins. Here, an overview of the organization of the Ada regulon and function of individual proteins is presented. We put special effort into the characterization of AlkB dioxygenases, also present in eukaryotic cells: their substrate specificity, and function in the repair of alkylation lesions in DNA/RNA. This article is protected by copyright. All rights reserved.
    FEMS Microbiology Letters 05/2014; 355(1). DOI:10.1111/1574-6968.12462 · 2.72 Impact Factor
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    • "This is however certainly the case for the brainstem and the hypothalamus, and it was in this latter region that Smemo and colleagues found Irx3 expression to play a role for the metabolic parameters regulated by this gene [1]. Fto is however also highly expressed in especially the hypothalamus and its arcuate, paraventricular, dorsomedial and ventromedial nuclei [3], all of which are recognized to be much more highly involved in the regulation of appetite and energy metabolism than the cerebellum. It is possible that FTO expression in humans in e.g. "
    05/2014; 3(5):505-6. DOI:10.1016/j.molmet.2014.05.003
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