A Gene Contributing to Human Obesity

The Fto gene was first cloned after identification of a Fused toe (Ft) mutant mouse, whose phenotype arised from a 1.6mb deletion of six genes, including Fto [1, 2]. FTO is a very large gene, also known as fat mass and obesity associated gene. In human, it is located on chromosome 16, consisting of 9 exons and spanning more than 400kb [3]. FTO mRNA is widely expressed in different tissues, especially in the brain, but also in skeletal muscles and adipose tissue [3, 4, 5, 6]. In the mice brain, Fto is highly expressed in hypothalamic nuclei that control eating behavior [7, 8]. It was believed, that only vertebrates are carriers of the FTO/Fto gene. To date, also FTO homologs in evolutionary diverse marine eukaryotic algae were identified. The biological roles of these FTO homologs are still unknown [9]. Four regions in the FTO gene are particularly well conserved and three of them are homologous to E. coli AlkB and its eukaryotic homologs, members of the ABH (AlkB homolog) family [4]. AlkB is a member of the 2OG-FE(II) oxygenase superfamiliy that oxidatively demethylates DNA [4, 10]. 2OG-FE(II) oxygenases are involved in diverse processes, such as DNA repair, fatty acid metabolism and posttranslational modifications. In vitro studies have shown, that FTO can catalyze the demethylation of 3-methyluracil in single-stranded RNA with a slightly higher efficiency over that of 3-methylthymine in doubleor single-stranded DNA [11]. Crystal structure analysis of the FTO protein provides a structural basis for the substrate specificity and the ability of FTO to distinguish 3-methyluracil and 3-methylFTO A Gene Contributing to Human Obesity