title: Pharmacological inhibition of FTO.
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.
authors.affiliation: MRC Harwell, Harwell Oxford Campus, Oxfordshire, Oxford, OX11 0RD, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: McMurray
authors.affiliation: Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, United Kingdom.
authors.forename: Marina
authors.initials: M
authors.lastname: Demetriades
authors.affiliation: Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, United Kingdom.
authors.forename: WeiShen
authors.initials: W
authors.lastname: Aik
authors.affiliation: Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, United Kingdom.
authors.forename: Myrte
authors.initials: M
authors.lastname: Merkestein
authors.affiliation: Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, United Kingdom.
authors.forename: Holger
authors.initials: H
authors.lastname: Kramer
authors.affiliation: MRC Harwell, Harwell Oxford Campus, Oxfordshire, Oxford, OX11 0RD, United Kingdom.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Andrew
authors.affiliation: MRC Harwell, Harwell Oxford Campus, Oxfordshire, Oxford, OX11 0RD, United Kingdom.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Scudamore
authors.affiliation: MRC Harwell, Harwell Oxford Campus, Oxfordshire, Oxford, OX11 0RD, United Kingdom.
authors.forename: Tertius A
authors.initials: TA
authors.lastname: Hough
authors.affiliation: MRC Harwell, Harwell Oxford Campus, Oxfordshire, Oxford, OX11 0RD, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.affiliation: Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, United Kingdom.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
authors.affiliation: Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDonough
authors.affiliation: Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: MRC Harwell, Harwell Oxford Campus, Oxfordshire, Oxford, OX11 0RD, United Kingdom.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cox
mesh_terms: D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D007652:Oxo-Acid-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C000606259:(1-chloro-4-hydroxyisoquinoline-3-carbonyl)amino)acetic acid; D019440:Anti-Obesity Agents; D007546:Isoquinolines; D006899:Mixed Function Oxygenases; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D007652:Oxo-Acid-Lyases; D005998:Glycine
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