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The Role of the GWAS Identified FTO Locus in Regulating Body Size and Composition

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Molecular Mechanisms Underpinning the Development of Obesity

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Abstract

Genome-wide association studies (GWAS) have indicated that SNPs on a chromosome 16 locus encompassing FTO, as well as IRX3, 5, 6, FTM and FTL are robustly associated with human obesity. GWAS however, are by nature gene agnostic, and SNPs reaching the appropriate statistical threshold for a given phenotype can appear anywhere in the genome, within, near or far away from any coding sequence. Thus a major challenge in the field has been to translate these statistical hits into real biological insight. The key question is which of these genes are responsible for the association with obesity, and what is the underlying mechanism? With loss of function FTO mutations in both mice and humans resulting in severe growth retardation and mice globally over-expressing FTO being obese, the initial attention was focussed on this gene. We and others have shown that in vitro, recombinant FTO is able to catalyze the Fe(II)- and 2OG-dependent demethylation of single stranded nucleic-acids, with a preference for RNA. We have shown that FTO expression is regulated by essential amino acids (AAs) and that it couples amino acid levels to mammalian Target Of Rapamycin Complex 1 (mTORC1) signaling, through a mechanism dependent on its ability to demethylate. Thus FTO is an AA sensor and plays a key role regulating appropriate growth and translation. However, recent data have shown that obesity-associated SNPs in FTO intron 1 are associated with expression of IRX3, but not FTO, in human brains, and that Irx3-deficient mice have reduced body-weight. Additionally, hypothalamic expression of a dominant negative form of Irx3 reproduces the metabolic phenotypes of Irx3- deficient mice. IRX3 is therefore a prime candidate to be the causative gene that links the risk SNPs to obesity. However, given what we know about FTO’s function in AA sensing and regulation of growth and translation, it appears likely that the whole region plays a role in determining body composition and weight.

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References

  1. Stunkard AJ, Foch TT, Hrubec Z (1986) A twin study of human obesity. JAMA 256:51–54

    Article  CAS  PubMed  Google Scholar 

  2. Stunkard AJ, Harris JR, Pedersen NL, McClearn GE (1990) The body-mass index of twins who have been reared apart. N Engl J Med 322:1483–1487

    Article  CAS  PubMed  Google Scholar 

  3. Yeo GS, Heisler LK (2012) Unraveling the brain regulation of appetite: lessons from genetics. Nat Neurosci 15:1343–1349

    Article  CAS  PubMed  Google Scholar 

  4. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J et al (2007) Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 3:e115

    Article  PubMed Central  PubMed  Google Scholar 

  6. Dina C, Meyre D, Gallina S, Durand E, Korner A, Jacobson P et al (2007) Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 39:724–726

    Article  CAS  PubMed  Google Scholar 

  7. Berndt SI, Gustafsson S, Magi R, Ganna A, Wheeler E, Feitosa MF et al (2013) Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nat Genet 45:501–512

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Bradfield JP, Taal HR, Timpson NJ, Scherag A, Lecoeur C, Warrington NM et al (2012) A genome-wide association meta-analysis identifies new childhood obesity loci. Nat Genet 44:526–531

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Lindgren CM, Heid IM, Randall JC, Lamina C, Steinthorsdottir V, Qi L et al (2009) Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution. PLoS Genet 5:e1000508

    Article  PubMed Central  PubMed  Google Scholar 

  10. Meyre D, Delplanque J, Chevre JC, Lecoeur C, Lobbens S, Gallina S et al (2009) Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat Genet 41:157–159

    Article  CAS  PubMed  Google Scholar 

  11. Scherag A, Dina C, Hinney A, Vatin V, Scherag S, Vogel CI et al (2010) Two new Loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and German study groups. PLoS Genet 6:e1000916

    Article  PubMed Central  PubMed  Google Scholar 

  12. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU et al (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42:937–948

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A et al (2009) Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41:18–24

    Article  CAS  PubMed  Google Scholar 

  14. Wheeler E, Huang N, Bochukova EG, Keogh JM, Lindsay S, Garg S et al (2013) Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat Genet 45:513–517

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, Berndt SI et al (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41:25–34

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ et al (2009) A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 41:527–534

    Article  CAS  PubMed  Google Scholar 

  17. Okada Y, Kubo M, Ohmiya H, Takahashi A, Kumasaka N, Hosono N, Maeda S et al (2012) Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations. Nat Genet 44:302–306

    Article  CAS  PubMed  Google Scholar 

  18. Wen W, Cho YS, Zheng W, Dorajoo R, Kato N, Qi L et al (2012) Meta-analysis identifies common variants associated with body mass index in east Asians. Nat Genet 44:307–311

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Loos RJ, Yeo GS (2014) The bigger picture of FTO–the first GWAS-identified obesity gene. Nat Rev Endocrinol 10:51–61

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Adeyemo A, Chen G, Zhou J, Shriner D, Doumatey A, Huang H, Rotimi C (2010) FTO genetic variation and association with obesity in West Africans and African Americans. Diabetes 59:1549–1554

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Hassanein MT, Lyon HN, Nguyen TT, Akylbekova EL, Waters K, Lettre G et al (2010) Fine mapping of the association with obesity at the FTO locus in African-derived populations. Hum Mol Genet 19:2907–2916

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Peters U, North KE, Sethupathy P, Buyske S, Haessler J, Jiao S, Fesinmeyer MD et al (2013) A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. PLoS Genet 9:e1003171

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Monda KL, Chen GK, Taylor KC, Palmer C, Edwards TL, Lange LA et al (2013) A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. Nat Genet 45:690–696

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Horikoshi M, Yaghootkar H, Mook-Kanamori DO, Sovio U, Taal HR, Hennig BJ et al (2013) New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism. Nat Genet 45:76–82

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Jess T, Zimmermann E, Kring SI, Berentzen T, Holst C, Toubro S, Astrup A, Hansen T, Pedersen O, Sorensen TI (2008) Impact on weight dynamics and general growth of the common FTO rs9939609: a longitudinal Danish cohort study. Int J Obes (Lond) 32:1388–1394

    Article  CAS  Google Scholar 

  26. Kilpelainen TO, den Hoed M, Ong KK, Grontved A, Brage S, Early Growth Genetics Consortium et al (2011) Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals. Am J Cli Nutr 93:851–860

    Article  CAS  Google Scholar 

  27. Graff M, Ngwa JS, Workalemahu T, Homuth G, Schipf S, Teumer A et al (2013) Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course. Hum Mol Genet 22:3597–3607

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Hardy R, Wills AK, Wong A, Elks CE, Wareham NJ, Loos RJ, Kuh D, Ong KK (2010) Life course variations in the associations between FTO and MC4R gene variants and body size. Hum Mol Genet 19:545–552

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Sovio U, Mook-Kanamori DO, Warrington NM, Lawrence R, Briollais L, Palmer CN et al (2011) Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development. PLoS Genet 7:e1001307

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CN (2008) An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med 359:2558–2566

    Article  CAS  PubMed  Google Scholar 

  31. Speakman JR, Rance KA, Johnstone AM (2008) Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity (Silver Spring) 16:1961–1965

    Article  CAS  Google Scholar 

  32. Timpson NJ, Emmett PM, Frayling TM, Rogers I, Hattersley AT, McCarthy MI, Davey Smith G (2008) The fat mass- and obesity-associated locus and dietary intake in children. Am J Clin Nutr 88:971–978

    CAS  PubMed  Google Scholar 

  33. Park SL, Cheng I, Pendergrass SA, Kucharska-Newton AM, Lim U, Ambite JL et al (2013) Association of the FTO obesity risk variant rs8050136 with percentage of energy intake from fat in multiple racial/ethnic populations: the PAGE study. Am J Epidemiol 178:780–790

    Article  PubMed Central  PubMed  Google Scholar 

  34. Sonestedt E, Roos C, Gullberg B, Ericson U, Wirfalt E, Orho-Melander M (2009) Fat and carbohydrate intake modify the association between genetic variation in the FTO genotype and obesity. Am J Clin Nutr 90:1418–1425

    Article  CAS  PubMed  Google Scholar 

  35. Wardle J, Carnell S, Haworth CM, Farooqi IS, O’Rahilly S, Plomin R (2008) Obesity associated genetic variation in FTO is associated with diminished satiety. J Clin Endocrinol Metab 93:3640–3643

    Article  CAS  PubMed  Google Scholar 

  36. Wardle J, Llewellyn C, Sanderson S, Plomin R (2009) The FTO gene and measured food intake in children. Int J Obes (Lond) 33:42–45

    Article  CAS  Google Scholar 

  37. Tanofsky-Kraff M, Han JC, Anandalingam K, Shomaker LB, Columbo KM, Wolkoff LE et al (2009) The FTO gene rs9939609 obesity-risk allele and loss of control over eating. Am J Clin Nutr 90:1483–1488

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Tanaka T, Ngwa JS, van Rooij FJ, Zillikens MC, Wojczynski MK, Frazier-Wood AC et al (2013) Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am J Clin Nutr 97:1395–1402

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Ahmad T, Chasman DI, Mora S, Pare G, Cook NR, Buring JE, Ridker PM, Lee IM (2010) The fat-mass and obesity-associated (FTO) gene, physical activity, and risk of incident cardiovascular events in white women. Am Heart J 160:1163–1169

    Article  PubMed Central  PubMed  Google Scholar 

  40. Franks PW, Jablonski KA, Delahanty LM, McAteer JB, Kahn SE, Knowler WC et al (2008) Assessing gene-treatment interactions at the FTO and INSIG2 loci on obesity-related traits in the Diabetes Prevention Program. Diabetologia 51:2214–2223

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Vimaleswaran KS, Li S, Zhao JH, Luan J, Bingham SA, Khaw KT, Ekelund U, Wareham NJ, Loos RJ (2009) Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene. Am J Clin Nutr 90:425–428

    Article  CAS  PubMed  Google Scholar 

  42. Kilpelainen TO, Qi L, Brage S, Sharp SJ, Sonestedt E, Demerath E et al (2011) Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children. PLoS Med 8:e1001116

    Article  PubMed Central  PubMed  Google Scholar 

  43. Yang J, Loos RJ, Powell JE, Medland SE, Speliotes EK, Chasman DI et al (2012) FTO genotype is associated with phenotypic variability of body mass index. Nature 490:267–272

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Cantor RM, Lange K, Sinsheimer JS (2010) Prioritizing GWAS results: a review of statistical methods and recommendations for their application. Am J Hum Genet 86:6–22

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Stratigopoulos G, Padilla SL, LeDuc CA, Watson E, Hattersley AT, McCarthy MI, Zeltser LM, Chung WK, Leibel RL (2008) Regulation of FTO/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol 294:R1185–1196

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS et al (2007) The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318:1469–1472

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Tung YC, Ayuso E, Shan X, Bosch F, O’Rahilly S, Coll AP, Yeo GS (2010) Hypothalamic-specific manipulation of FTO, the ortholog of the human obesity gene FTO, affects food intake in rats. PloS ONE 5:e8771

    Article  PubMed Central  PubMed  Google Scholar 

  48. Delous M, Baala L, Salomon R, Laclef C, Vierkotten J, Tory K et al (2007) The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 39:875–881

    Article  CAS  PubMed  Google Scholar 

  49. Jia G, Yang CG, Yang S, Jian X, Yi C, Zhou Z, He C (2008) Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS Lett 582:3313–3319

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y et al (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7:885–887

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Han Z, Niu T, Chang J, Lei X, Zhao M, Wang Q, Cheng W, Wang J, Feng Y, Chai J (2010) Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature 464:1205–1209

    Article  CAS  PubMed  Google Scholar 

  52. Meyre D, Proulx K, Kawagoe-Takaki H, Vatin V, Gutierrez-Aguilar R, Lyon D et al (2010) Prevalence of loss-of-function FTO mutations in lean and obese individuals. Diabetes 59:311–318

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Desrosiers R, Friderici K, Rottman F (1974) Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci U S A 71:3971–3975

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Kowalak JA, Pomerantz SC, Crain PF, McCloskey JA (1993) A novel method for the determination of post-transcriptional modification in RNA by mass spectrometry. Nucleic Acids Res 21:4577–4585

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Challis BG, Pritchard LE, Creemers JW, Delplanque J, Keogh JM, Luan J et al (2002) A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum Mol Genet 11:1997–2004

    Article  CAS  PubMed  Google Scholar 

  56. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:155–157

    Article  CAS  PubMed  Google Scholar 

  57. Benzinou M, Creemers JW, Choquet H, Lobbens S, Dina C, Durand E et al (2008) Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet 40:943–945

    Article  CAS  PubMed  Google Scholar 

  58. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O’Rahilly S (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16:303–306

    Article  CAS  PubMed  Google Scholar 

  59. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I et al (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40:768–775

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O’Rahilly S (1998) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 20:111–112

    Article  CAS  PubMed  Google Scholar 

  61. Gray J, Yeo GS, Cox JJ, Morton J, Adlam AL, Keogh JM et al (2006) Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 55:3366–3371

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Peters T, Ausmeier K, Ruther U (1999) Cloning of Fatso (FTO), a novel gene deleted by the Fused toes (Ft) mouse mutation. Mamm Genome 10:983–986

    Article  CAS  PubMed  Google Scholar 

  63. Anselme I, Laclef C, Lanaud M, Ruther U, Schneider-Maunoury S (2007) Defects in brain patterning and head morphogenesis in the mouse mutant Fused toes. Dev biol 304:208–220

    Article  CAS  PubMed  Google Scholar 

  64. van der Hoeven F, Schimmang T, Volkmann A, Mattei MG, Kyewski B, Ruther U (1994) Programmed cell death is affected in the novel mouse mutant Fused toes (Ft). Development 120:2601–2607

    PubMed  Google Scholar 

  65. Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, Ruther U (2009) Inactivation of the FTO gene protects from obesity. Nature 458:894–898

    Article  CAS  PubMed  Google Scholar 

  66. McMurray F, Church CD, Larder R, Nicholson G, Wells S, Teboul L et al (2013) Adult onset global loss of the FTO gene alters body composition and metabolism in the mouse. PLoS Genet 9:e1003166

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Boissel S, Reish O, Proulx K, Kawagoe-Takaki H, Sedgwick B, Yeo GS et al (2009) Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet 85:106–111

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Church C, Moir L, McMurray F, Girard C, Banks GT, Teboul L et al (2010) Overexpression of FTO leads to increased food intake and results in obesity. Nat Genet 42:1086–1092

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Gao X, Shin YH, Li M, Wang F, Tong Q, Zhang P (2010) The fat mass and obesity associated gene FTO functions in the brain to regulate postnatal growth in mice. PloS ONE 5:e14005

    Article  PubMed Central  PubMed  Google Scholar 

  70. Ma M, Harding HP, O’Rahilly S, Ron D, Yeo GS (2012) Kinetic analysis of FTO (fat mass and obesity-associated) reveals that it is unlikely to function as a sensor for 2-oxoglutarate. Biochem J 444(2):183–187

    Article  CAS  PubMed  Google Scholar 

  71. Cheung MK, Gulati P, O’Rahilly S, Yeo GS (2013) FTO expression is regulated by availability of essential amino acids. Int J Obes (Lond) 37(5):744–747

    Article  CAS  Google Scholar 

  72. Gulati P, Cheung MK, Antrobus R, Church CD, Harding HP, Tung YC, Rimmington D, Ma M, Ron D, Lehner PJ, Ashcroft FM, Cox RD, Coll AP, O’Rahilly S, Yeo GS (2013) Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc Natl Acad Sci U S A 110(7):2557–2562

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Quevillon S, Robinson JC, Berthonneau E, Siatecka M, Mirande M (1999) Macromolecular assemblage of aminoacyl-tRNA synthetases: identification of protein-protein interactions and characterization of a core protein. J Mol Biol 285(1):183–195

    Article  CAS  PubMed  Google Scholar 

  74. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485(7397):201–206

    Article  CAS  PubMed  Google Scholar 

  75. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR (2012) Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons. Cell 149(7):1635–1646

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM (1997) Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA 3(11):1233–1247

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vågbø CB, Shi Y, Wang WL, Song SH, Lu Z, Bosmans RP, Dai Q, Hao YJ, Yang X, Zhao WM, Tong WM, Wang XJ, Bogdan F, Furu K, Fu Y, Jia G, Zhao X, Liu J, Krokan HE, Klungland A, Yang YG, He C (2013) ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 49(1):18–29

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Hess ME, Hess S, Meyer KD, Verhagen LA, Koch L, Brönneke HS, Dietrich MO, Jordan SD, Saletore Y, Elemento O, Belgardt BF, Franz T, Horvath TL, Rüther U, Jaffrey SR, Kloppenburg P, Brüning JC (2013) The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci 16(8):1042–1048

    Article  CAS  PubMed  Google Scholar 

  79. Karra E, O’Daly OG, Choudhury AI, Yousseif A, Millership S, Neary MT, Scott WR, Chandarana K, Manning S, Hess ME, Iwakura H, Akamizu T, Millet Q, Gelegen C, Drew ME, Rahman S, Emmanuel JJ, Williams SC, Rüther UU, Brüning JC, Withers DJ, Zelaya FO, Batterham RL (2013) A link between FTO, ghrelin, and impaired brain food-cue responsivity. J Clin Invest 123(8):3539–3551

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gómez-Marín C et al (2014) Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507(7492):371–375

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Stratigopoulos G, LeDuc CA, Cremona ML, Chung WK, Leibel RL (2011) Cut-like homeobox 1 (CUX1) regulates expression of the fat mass and obesity-associated and retinitis pigmentosa GTPase regulator-interacting protein-1-like (RPGRIP1L) genes and coordinates leptin receptor signaling. J Biol Chem 286(3):2155–2170

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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  1. MRC Metabolic Diseases Unit, Metabolic Research Laboratories, University of Cambridge, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke’s Hospital, CB2 0QQ, Cambridge, UK

    Giles S. H. Yeo

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  1. Cntr for Neurosciences and Cell Biology University of Coimbra, Coimbra, Portugal

    Clévio Nóbrega

  2. Nutrition and Gastroenterology Department, Armand-Trousseau Hospital, Valencia, Spain

    Raquel Rodriguez-López

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Yeo, G. (2014). The Role of the GWAS Identified FTO Locus in Regulating Body Size and Composition. In: Nóbrega, C., Rodriguez-López, R. (eds) Molecular Mechanisms Underpinning the Development of Obesity. Springer, Cham. https://doi.org/10.1007/978-3-319-12766-8_5

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