Abstract
In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells) and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO’s demethylase activity could be therapeutically useful for the treatment of obesity.
Highlights
Single nucleotide polymorphisms (SNPs) within intron one of the FTO gene are associated with body mass index (BMI) in human populations[1]
Basal Oxygen consumption rate (OCR) was significantly reduced in IOX3-treated C2C12 cells (Fig. 2A), and there was a trend for increased basal extracellular acidification rate (ECAR) (Fig. 2B), which together suggests an increase in glycolytic metabolism
After addition of rotenone and antimycin A, which inhibit complex I and complex III of the electron transport chain respectively, OCR levels dropped in both groups and there was no significant difference in the remaining non-mitochondrial respiration levels
Summary
Single nucleotide polymorphisms (SNPs) within intron one of the FTO gene are associated with body mass index (BMI) in human populations[1]. It has been suggested that the element marked by the FTO intron 1 SNPs affect other genes nearby such as called IRX3 or RPGRIP1L, rather than FTO itself[6,7]. These studies cannot rule out a role for the FTO gene, or the possibility that FTO expression is regulated by the obesity SNPs in particular cells and tissues or at particular developmental ages. We predicted by sequence analysis that the FTO protein had a double-stranded beta-helix fold homologous to those of other Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases, such as AlkB
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