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. 2015 Apr 1;10(4):e0121829.
doi: 10.1371/journal.pone.0121829. eCollection 2015.

Pharmacological inhibition of FTO

Affiliations

Pharmacological inhibition of FTO

Fiona McMurray et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Chemical structure of IOX3 and IC50 values for FTO and PHD2.
Fig 2
Fig 2. Oxygen Consumption Rate (OCR), Extracellular Acidification Rate (ECAR) of C2C12, and wild-type and FTO knockout MEFs treated with 1 μM IOX3 or an equivalent amount of vehicle control for 16 hours.
A) OCR and, B) basal ECAR measured in C2C12 cells treated with vehicle (n = 10) and 1 μM IOX3 (n = 10) at baseline and after Oligomycin, FCCP and Rotenone treatment, data normalised to live stain. C) OCR and, D] ECAR measured in Fto +/+ and Fto -/- MEFs cells treated with vehicle and 1 μM IOX3 (n = 5 per group) at baseline and after Oligomycin, FCCP and Rotenone treatment, data normalised to live stain. Data were analysed using a 2 way ANOVA with Bonferroni post-hoc test. Data is of readings following each compound injection and are expressed as mean ± SEM. E) Expression of FTO, phosphorylated-AMPKα and HIF-1α with representative ACTIN in cells treated with vehicle, 1uM IOX3, control scrambled siRNA or Fto siRNA for 24 hours. N = 3 biological replicates per condition.
Fig 3
Fig 3. Plasma EPO levels in vehicle and 60 mg/kg/2days IOX3 treated mice and the effect on FTO protein levels.
A) Plasma EPO levels after one week of dosing in vehicle (n = 20) and 60 mg/kg every two days IOX3 (n = 20) treated mice. B) Terminal plasma EPO levels at 40 days after beginning of the trial, vehicle (n = 20) and 60 mg/kg every two days IOX3 (n = 20) treated mice. C) Weekly body weight of Vehicle (n = 20) and 60 mg/kg every two days IOX3 (n = 20). D) Area under the curve calculated from blood glucose curves. Data were analysed using a student’s t-test and time course data were analysed by 2-way ANOVA with Bonferroni post-hoc test *P<0.05, **P<0.01, ***P<0.001. Data are expressed as mean ± SEM.
Fig 4
Fig 4. DEXA and organ weights of vehicle and 60 mg/kg every two days IOX3-treated mice.
A) Bone Mineral Density (BMD), B) Bone Mineral Content (BMC), C) Liver mass, D) Epigonadal white adipose tissue (WAT), E) Abdominal WAT, F) Peri-renal WAT, G) Brown adipose tissue (BAT), H) Calf muscle weight of vehicle (n = 20) and 60 mg/kg every two days IOX3 (n = 20) treated mice. Data analysed by student’s t-test *P<0.05, **P<0.01, ***P<0.001. Data are expressed as mean ± SEM and individual data points are shown.

References

    1. Frayling TM, Timpson NJ, Weedon MN. A common variant in the FTO gene is associated with body mass index and predisposes to. Science. 2007;316:889–94. - PMC - PubMed
    1. Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Brüning JC, et al. Inactivation of the Fto gene protects from obesity. Nature. 2009;458(7240):894–8. 10.1038/nature07848 - DOI - PubMed
    1. Church C, Lee S, Bagg E a L, McTaggart JS, Deacon R, Gerken T, et al. A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genet. 2009;5(8):e1000599 10.1371/journal.pgen.1000599 - DOI - PMC - PubMed
    1. Gao X, Shin Y-H, Li M, Wang F, Tong Q, Zhang P. The fat mass and obesity associated gene FTO functions in the brain to regulate postnatal growth in mice. PLoS One. 2010;5(11):e14005 10.1371/journal.pone.0014005 - DOI - PMC - PubMed
    1. Church C, Moir L, McMurray F, Girard C, Banks GT, Teboul L, et al. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet. 2010;42(12):1086–92. 10.1038/ng.713 - DOI - PMC - PubMed

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