The FTO gene, associated with obesity, encodes a 2-oxoglutarate-dependent nucleic acid demethylase. The study shows that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate (2OG)-dependent oxygenases. Recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, producing succinate, formaldehyde, and carbon dioxide. Fto localizes to the nucleus in transfected cells. Fto mRNA is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and its levels in the arcuate nucleus are regulated by feeding and fasting. Studies suggest that FTO may regulate energy homeostasis by demethylating nucleic acids. Fto is inhibited by Krebs cycle intermediates, particularly fumarate. The FTO SNPs associated with adiposity are intronic and may affect FTO mRNA expression. Fto activity was tested with various substrates, and it showed a preference for 3-methylthymine in DNA. Fto activity was stimulated by ascorbate and inhibited by fumarate and succinate. The study also shows that Fto localizes to the nucleus and does not colocalize with mitochondria. Fto mRNA levels in the hypothalamus are nutritionally regulated, with reduced levels in fasted mice and no rescue by leptin. The study highlights the potential role of FTO in nucleic acid demethylation and its possible link to obesity. Further research is needed to determine the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass. The findings suggest that FTO may regulate gene transcription involved in metabolism by nucleic acid demethylation. The study also suggests that FTO may act as a nucleic acid repair enzyme, as breakdown of genomic repair processes is linked to obesity and metabolic syndrome. The results indicate that FTO is a 2OG oxygenase that may play a role in the hypoxic response and histone demethylation. The study provides insights into the function of FTO and its potential role in obesity pathogenesis.The FTO gene, associated with obesity, encodes a 2-oxoglutarate-dependent nucleic acid demethylase. The study shows that FTO shares sequence motifs with Fe(II)- and 2-oxoglutarate (2OG)-dependent oxygenases. Recombinant murine Fto catalyzes the Fe(II)- and 2OG-dependent demethylation of 3-methylthymine in single-stranded DNA, producing succinate, formaldehyde, and carbon dioxide. Fto localizes to the nucleus in transfected cells. Fto mRNA is most abundant in the brain, particularly in hypothalamic nuclei governing energy balance, and its levels in the arcuate nucleus are regulated by feeding and fasting. Studies suggest that FTO may regulate energy homeostasis by demethylating nucleic acids. Fto is inhibited by Krebs cycle intermediates, particularly fumarate. The FTO SNPs associated with adiposity are intronic and may affect FTO mRNA expression. Fto activity was tested with various substrates, and it showed a preference for 3-methylthymine in DNA. Fto activity was stimulated by ascorbate and inhibited by fumarate and succinate. The study also shows that Fto localizes to the nucleus and does not colocalize with mitochondria. Fto mRNA levels in the hypothalamus are nutritionally regulated, with reduced levels in fasted mice and no rescue by leptin. The study highlights the potential role of FTO in nucleic acid demethylation and its possible link to obesity. Further research is needed to determine the physiologically relevant FTO substrate and how nucleic acid methylation status is linked to increased fat mass. The findings suggest that FTO may regulate gene transcription involved in metabolism by nucleic acid demethylation. The study also suggests that FTO may act as a nucleic acid repair enzyme, as breakdown of genomic repair processes is linked to obesity and metabolic syndrome. The results indicate that FTO is a 2OG oxygenase that may play a role in the hypoxic response and histone demethylation. The study provides insights into the function of FTO and its potential role in obesity pathogenesis.