Molecular Medicine Select

Recently, genome-wide association studies have linked variations in alleles of the FTO (fat mass and obesity associated) gene to obesity. Gerken et al. (2007) now reveal that FTO encodes a nucleic acid demethylase. Upon examination of the sequence of FTO, the authors noticed a domain that had homology to 2-oxoglutarate oxygenases. These enzymes are involved in a variety of processes including DNA repair and histone lysine demethylation. The authors expressed and purified murine Fto from bacteria and demonstrated that it displayed the enzymatic activity of a 2-oxoglutarate oxygenase. To identify potential substrates of FTO, the authors investigated whether FTO could act on the substrates of other 2-oxoglutarate oxygenases. This analysis revealed that FTO could remove methyl groups from methylated single-stranded DNA and that this enzyme had a preference for 3-methylthymine as a methylated substrate. Interestingly, FTO single nucleotide polymorphisms that are linked to obesity are in the introns of the FTO gene and may affect expression of FTO mRNA. The authors examined the expression pattern of Fto mRNA in mice and found that it is highly enriched in the hypothalamus, a site in the brain that is important for regulating energy balance. Gerken et al. then examined the amounts of Fto mRNA in the hypothalamus of mice that were deprived of food. In the arcuate nucleus of the hypothalamus, Fto mRNA was decreased by 60% in mice that were fasting, indicating that levels of Fto mRNA fluctuate with nutritional status. The next steps are to determine whether FTO is involved in nucleic acid demethylation or in DNA repair in vivo and how its enzymatic activity impinges on metabolism. Perhaps FTO specifically regulates the transcription of genes involved in metabolism through demethylation. Analysis of the effects of Fto mutations on the demethylase activity of the enzyme and on obesity in mice should be informative. T. Gerken et al. (2007). Science. Published online November 8, 2007. 10.1126/science.1151710.