Pharmacological Inhibition of FTO

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.

[1]  A. Buchan,et al.  HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice , 2014, Journal of neurochemistry.

[2]  F. Ashcroft,et al.  Changes in Gene Expression Associated with FTO Overexpression in Mice , 2014, PloS one.

[3]  N. Cox,et al.  Obesity-associated variants within FTO form long-range functional connections with IRX3 , 2014, Nature.

[4]  P. Ratcliffe,et al.  Sudestada1, a Drosophila ribosomal prolyl-hydroxylase required for mRNA translation, cell homeostasis, and organ growth , 2014, Proceedings of the National Academy of Sciences.

[5]  Rachelle S. Singleton,et al.  OGFOD1 catalyzes prolyl hydroxylation of RPS23 and is involved in translation control and stress granule formation , 2014, Proceedings of the National Academy of Sciences.

[6]  P. Ratcliffe,et al.  Hydroxylation of the eukaryotic ribosomal decoding center affects translational accuracy , 2014, Proceedings of the National Academy of Sciences.

[7]  Simon Hess,et al.  The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry , 2013, Nature Neuroscience.

[8]  P. Ratcliffe,et al.  Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases. , 2013, ACS chemical biology.

[9]  Michael A McDonough,et al.  Structural basis for inhibition of the fat mass and obesity associated protein (FTO). , 2013, Journal of medicinal chemistry.

[10]  F. Ashcroft,et al.  Role for the obesity-related FTO gene in the cellular sensing of amino acids , 2013, Proceedings of the National Academy of Sciences.

[11]  F. Ashcroft,et al.  Adult Onset Global Loss of the Fto Gene Alters Body Composition and Metabolism in the Mouse , 2013, PLoS genetics.

[12]  L. Klein-Hitpass,et al.  FTO levels affect RNA modification and the transcriptome , 2012, European Journal of Human Genetics.

[13]  Akane Kawamura,et al.  Inhibition of 2‐Oxoglutarate Dependent Oxygenases , 2011 .

[14]  K. Clarke,et al.  37 Use of prolyl hydroxylase inhibitors to induce HIF-related metabolic changes and increase c-Kit expression in cardiosphere-derived cells , 2011, Heart.

[15]  Chengqi Yi,et al.  N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO , 2011, Nature chemical biology.

[16]  P. Ratcliffe,et al.  Differential Sensitivity of Hypoxia Inducible Factor Hydroxylation Sites to Hypoxia and Hydroxylase Inhibitors* , 2011, The Journal of Biological Chemistry.

[17]  R. Schmieder,et al.  Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. , 2010, Journal of the American Society of Nephrology : JASN.

[18]  Fei Wang,et al.  The Fat Mass and Obesity Associated Gene FTO Functions in the Brain to Regulate Postnatal Growth in Mice , 2010, PloS one.

[19]  Roger D. Cox,et al.  Overexpression of Fto leads to increased food intake and results in obesity , 2010, Nature Genetics.

[20]  K. Pienta,et al.  Erythropoietin Couples Hematopoiesis with Bone Formation , 2010, PloS one.

[21]  Qiang Wang,et al.  Crystal structure of the FTO protein reveals basis for its substrate specificity , 2010, Nature.

[22]  Seng H. Cheng,et al.  Inhibition of osteoclastogenesis by prolyl hydroxylase inhibitor dimethyloxallyl glycine , 2010, Journal of Bone and Mineral Metabolism.

[23]  Roger D. Cox,et al.  A Mouse Model for the Metabolic Effects of the Human Fat Mass and Obesity Associated FTO Gene , 2009, PLoS genetics.

[24]  Philippe Froguel,et al.  Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. , 2009, American journal of human genetics.

[25]  Jens C. Brüning,et al.  Inactivation of the Fto gene protects from obesity , 2009, Nature.

[26]  P. Ratcliffe,et al.  Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1alpha. , 2008, The Biochemical journal.

[27]  M. Hofrichter,et al.  Pyridine as novel substrate for regioselective oxygenation with aromatic peroxygenase from Agrocybe aegerita , 2008, FEBS letters.

[28]  Chengqi Yi,et al.  Oxidative demethylation of 3‐methylthymine and 3‐methyluracil in single‐stranded DNA and RNA by mouse and human FTO , 2008, FEBS letters.

[29]  M. McCarthy,et al.  Regulation of Fto/Ftm gene expression in mice and humans. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[30]  Christopher J Schofield,et al.  Expanding chemical biology of 2-oxoglutarate oxygenases. , 2008, Nature chemical biology.

[31]  Chris P. Ponting,et al.  The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase , 2007, Science.

[32]  J. Tisdale,et al.  HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. , 2007, Blood.

[33]  Wei-zhong Chang,et al.  Components of the Collagen Prolyl 3-Hydroxylation Complex are Crucial for Normal Bone Development , 2007, Cell cycle.

[34]  M. Jarvelin,et al.  A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity , 2007, Science.

[35]  V. Sridharan,et al.  The prolyl hydroxylase oxygen-sensing pathway is cytoprotective and allows maintenance of mitochondrial membrane potential during metabolic inhibition. , 2007, American journal of physiology. Cell physiology.

[36]  Min Wu,et al.  Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. , 2007, American journal of physiology. Cell physiology.

[37]  N. Denko,et al.  HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. , 2006, Cell metabolism.

[38]  G. Semenza,et al.  HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. , 2006, Cell metabolism.

[39]  K. Kivirikko,et al.  Collagens, modifying enzymes and their mutations in humans, flies and worms. , 2004, Trends in genetics : TIG.

[40]  C. Okerberg,et al.  Qualitative and Quantitative Analysis of Nonneoplastic Lesions in Toxicology Studies , 2002, Toxicologic pathology.

[41]  P. O’Farrell.  Faculty Opinions recommendation of HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. , 2001 .

[42]  Michael I. Wilson,et al.  C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation , 2001, Cell.

[43]  M. Ivan,et al.  HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing , 2001, Science.

[44]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.