The ‘Fat Mass and Obesity Related’ (FTO) gene: Mechanisms of Impact on Obesity and Energy Balance

Abstract

A cluster of single nucleotide polymorphisms (SNPs) in the first intron of the fat mass and obesity related (FTO) gene were the first common variants discovered to be associated with body mass index and body fatness. This review summarises what has been later discovered about the biology of FTO drawing together information from both human and animal studies. Subsequent work showed that the ‘at risk’ alleles of these SNPs are associated with greater food intake and increased hunger/lowered satiety, but are not associated with altered resting energy expenditure or low physical activity in humans. FTO is an FE (II) and 2-oxoglutarate dependent DNA/RNA methylase. Contrasting the impact of the SNPs on energy balance in humans, knocking out or reducing activity of the Fto gene in the mouse resulted in lowered adiposity, elevated energy expenditure with no impact on food intake (but the impact on expenditure is disputed). In contrast, overexpression of the gene in mice led to elevated food intake and adiposity, with no impact on expenditure. In rodents, the Fto gene is widely expressed in the brain including hypothalamic nuclei linked to food intake regulation. Since its activity is 2-oxoglutarate dependent it could potentially act as a sensor of citrate acid cycle flux, but this function has been dismissed, and instead it has been suggested to be much more likely to act as an amino acid sensor, linking circulating AAs to the mammalian target of rapamycin complex 1. This may be fundamental to its role in development but the link to obesity is less clear. It has been recently suggested that although the obesity related SNPs reside in the first intron of FTO, they may not only impact FTO but mediate their obesity effects via nearby genes (notably RPGRIP1L and IRX3).

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References

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  1. 1.

    van der Hoeven F, Schimmang T, Volkmann A, Mattei MG, Kyewski B, Ru¨ther U. Programmed cell death is affected in the novel mouse mutant Fused toes (Ft). Development. 1994;120:2601–7.

    PubMed  Google Scholar 

  2. 2.

    Peters T, Ausmeier K, Ruther U. Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation. Mamm Genome. 1999;10:983–6.

    CAS  PubMed  Google Scholar 

  3. 3.

    Boissel S, Reish O, Proulx K, et al. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet. 2009;85:106–11.

    PubMed Central  CAS  PubMed  Google Scholar 

  4. 4.••

    Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, et al. Inactivation of the Fto gene protects from obesity. Nature. 2009;458:894–8. First mouse knockout study of Fto gene produced surprising phenotype relative to effects of the SNP variants in humans, with suggested effects on energy expenditure rather than food intake.

  5. 5.

    Gao X, Shin YH, Li M, Wang F, Tong QA, Zhang PM. The Fat Mass and Obesity Associated Gene FTO Functions in the Brain to Regulate Postnatal Growth in Mice. PLoS One. 2010;5:e14005.

    PubMed Central  PubMed  Google Scholar 

  6. 6.••

    Frayling TM, Timpson NJ, Weedon MN, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889–94. This was the first study where common human variants in the FTO gene affecting BMI were described. It was also the first study to indicate common forms of obesity with a genetic basis thereby putting the genetics of obesity firmly beyond the realm of rare oddities. It was reported widely in the press around the world including the front page of the UK Daily Mail.

  7. 7.

    Scuteri A, Sanna S, Chen WM, et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007;3:1200–10.

    CAS  Google Scholar 

  8. 8.

    Loos RJF, Yeo GSH. The bigger picture of FTO-the first GWAS-identified obesity gene. Nat Rev Endocrinol. 2014;10:51–61.

    PubMed Central  CAS  PubMed  Google Scholar 

  9. 9.

    Dhurandhar NV, Schoeller DA, Brown AW, Heymsfield SB, Thomas D, Sørensen TIA, Speakman JR, Jeansonne M, Allison DB and the Energy Balance Measurement Working Group. Energy Balance Measurement: When Something is Not Better than Nothing. Int J Obes. 2014. doi:10.1038/ijo.2014.199.

  10. 10.•

    Do R, Bailey SD, Desbiens K, Belisle A, Montpetit A, Bouchard C, et al. Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study. Diabetes. 2008;57:1147–50. First study demonstrating no impact of a variant in FTO on energy expenditure in humans.

  11. 11.

    Bauer F, Elbers CC, Adan RAH, Loos RJF, Onland-Moret NC, Grobbee DE, et al. Obesity genes identified in genome-wide association studies are associated with adiposity measures and potentially with nutrient-specific food preference. Am J Clin Nutr. 2009;90:951–9.

    CAS  PubMed  Google Scholar 

  12. 12.

    Hasselbalch ALA, Christiansen L, Heitmann L, Kyvik BL, Sorensen KO, TIA. A Variant in the Fat Mass and Obesity-Associated Gene (FTO) and Variants near the Melanocortin-4 Receptor Gene (MC4R) Do Not Influence Dietary Intake. J Nutr. 2010;140:831–4.

    CAS  PubMed  Google Scholar 

  13. 13.

    Liu GF, Zhu HD, Lagou V, Gutin B, Stallmann-Jorgensen IS, Treiber FA, et al. FTO variant rs9939609 is associated with body mass index and waist circumference, but not with energy intake or physical activity in European- and African-American youth. BMC Med Genet. 2010;11:57.

    PubMed Central  PubMed  Google Scholar 

  14. 14.

    Hubacek JA, Pikhart H, Peasey A, Kubinova R, Bobak M. FTO Variant, Energy Intake, Physical Activity and Basal Metabolic Rate in Caucasians. The HAPIEE Study. Physiol Res. 2011;60:175–83.

    PubMed Central  CAS  PubMed  Google Scholar 

  15. 15.

    Harbron J, van der Merwe L, Zaahl MG, Kotze MJ, Senekal M. Fat Mass and Obesity-Associated (FTO) Gene Polymorphisms Are Associated with Physical Activity, Food Intake, Eating Behaviors, Psychological Health, and Modeled Change in Body Mass Index in Overweight/Obese Caucasian Adults. Nutrient. 2014;6:3130–52.

    CAS  Google Scholar 

  16. 16.

    Tanaka TN, van Rooij JS, et al. Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am J Clin Nutr. 2013;97:1395–402.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. 17.

    Park SL, Cheng I, Pendergrass SA, et al. Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations. Am J Epidemiol. 2013;178:780–90.

    PubMed Central  PubMed  Google Scholar 

  18. 18.

    McCaffery JM, Papandonatos GD, Peter I, Huggins GS, Raynor HA, Delahanty LM, et al. Obesity susceptibility loci and dietary intake in the Look AHEAD Trial. Am J Clin Nutr. 2012;95:1477–86.

    PubMed Central  CAS  PubMed  Google Scholar 

  19. 19.

    Qi, QB Chu, AY Kang, JH et al. (2014). Fried food consumption, genetic risk, and body mass index: gene-diet interaction analysis in three US cohort studies. Br Med J. 348: doi 10.1136/bmj.g1610

  20. 20.•

    Speakman JR, Rance KA, Johnstone AM. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity. 2008;16:1961–5. First study showing an effect of a variant in FTO on food intake in humans.

  21. 21.

    Sobczyk-Kopciol A, Broda G, Wojnar M, Kurjata P, Jakubczyk A, Klimkiewicz A, et al. Inverse association of the obesity predisposing FTO rs9939609 genotype with alcohol consumption and risk for alcohol dependence. Addiction. 2011;106:739–48.

    PubMed  Google Scholar 

  22. 22.

    Corella DO-A, Sorli C, et al. Statistical and Biological Gene-Lifestyle Interactions of MC4R and FTO with Diet and Physical Activity on Obesity: New Effects on Alcohol Consumption. PLoS One. 2012;7:e52344.

    PubMed Central  CAS  PubMed  Google Scholar 

  23. 23.

    Wang L, Liu XF, Luo XG, Zeng M, Zuo LJ, Wang KS. Genetic Variants in the Fat Mass- and Obesity-Associated (FTO) Gene are Associated with Alcohol Dependence. J Mol Neurosci. 2013;51:416–24.

    CAS  PubMed  Google Scholar 

  24. 24.

    Hubacek JA, Adamkova V, Dlouha D, et al. Fat mass and obesity associated gene (FTO) and alcohol intake. Addiction. 2012;107:1185–6.

    PubMed  Google Scholar 

  25. 25.

    Rzehak P, Scherag A, Grallert, the GINI & LISA Study Grps, et al. Associations between BMI and the FTO Gene Are Age Dependent: Results from the GINI and LISA Birth Cohort Studies up to Age 6 Years. Obes Facts. 2010;3:173–80.

    PubMed  Google Scholar 

  26. 26.

    Lopez-Bermejo A, Petry CJ, Diaz M, Sebastiani G, de Zegher F, Dunger DB, et al. The association between the FTO gene and fat mass in humans develops by the postnatal age of two weeks. J Clin Endocrinol Metab. 2008;93:1501–5.

    CAS  PubMed  Google Scholar 

  27. 27.

    Timpson NJ, Emmett PM, Frayling TM, Rogers I, Hattersley AT, McCarthy MI, et al. The fat mass- and obesity-associated locus and dietary intake in children. Am J Clin Nutr. 2008;88:971–8.

    CAS  PubMed  Google Scholar 

  28. 28.

    Steemburgo T, Azevedo MJ, Gross JL, Milagro FI, Campion J, Martinez JA. The rs9939609 Polymorphism in the FTO Gene Is Associated with Fat and Fiber Intakes in Patients with Type 2 Diabetes. J Nutrigenet Nutrigenomics. 2013;6:97–106.

    CAS  PubMed  Google Scholar 

  29. 29.

    Haupt A, Thamer C, Staiger HT, Schritter O, Kirchhoff K, Machicao F, et al. Variation in the FTO Gene Influences Food Intake but not Energy Expenditure. Exp Clin Endocrinol Diabetes. 2009;117:194–7.

    CAS  PubMed  Google Scholar 

  30. 30.

    Lee HJ, Kim IK, Kang JH, Ahn Y, Han BG, Lee JY, et al. Effects of common FTO gene variants associated with BMI on dietary intake and physical activity in Koreans. Clin Chim Acta. 2010;411:1716–22.

    CAS  PubMed  Google Scholar 

  31. 31.

    Cecil JET, Watt R, Hetherington P, Palmer MM, CAN. An Obesity-Associated FTO Gene Variant and Increased Energy Intake in Children. N Engl J Med. 2008;359:2558–66.

    CAS  PubMed  Google Scholar 

  32. 32.

    Wardle J, Carnell S, Haworth CMA, Farooqi IS, O'Rahilly S, Plomin R. Obesity-associated genetic variation in FTO is associated with diminished satiety. J Clin Endocrinol Metab. 2008;93:3640–3.

    CAS  PubMed  Google Scholar 

  33. 33.

    Wardle J, Llewellyn C, Sanderson S, Plomin R. The FTO gene and measured food intake in children. Int J Obes. 2009;33:42–5.

    CAS  Google Scholar 

  34. 34.•

    den Hoed M, Westerterp-Plantenga MS, Bouwman FG, Mariman ECM, Westerterp KR. Postprandial responses in hunger and satiety are associated with the rs9939609 single nucleotide polymorphism in FTO. Am J Clin Nutr. 2009;90:1426–32. First study showing potential epistatic interactions between variant in FTO and other genes.

  35. 35.

    Tanofsky-Kraff M, Han JC, Anandalingam K, Shomaker LB, Columbo KM, Wolkoff LE, et al. The FTO gene rs9939609 obesity-risk allele and loss of control over eating. Am J Clin Nutr. 2009;90:1483–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  36. 36.

    Rutters F, Lemmens SGT, Born JM, Bouwman F, Nieuwenhuizen AG, Mariman E, et al. Genetic associations with acute stress-related changes in eating in the absence of hunger. Patient Educ Couns. 2010;79:367–71.

    PubMed  Google Scholar 

  37. 37.

    Dougkas A, Yaqoob P, Givens DI, Reynolds CK, Minihane AM. The impact of obesity-related SNP on appetite and energy intake. Br J Nutr. 2013;110:1151–6.

    CAS  PubMed  Google Scholar 

  38. 38.•

    Karra E, O'Daly OG, Choudhury, et al. A link between FTO, ghrelin, and impaired brain food-cue responsivity. J Clin Invest. 2013;123:3539–51. First study indicating a link between FTO and ghrelin that mediates the appetite and hence presumably the food intake effects of the variants.

    PubMed Central  CAS  PubMed  Google Scholar 

  39. 39.

    Scheid JL, Carr KA, Lin H, Fletcher KD, Sucheston L, Singh PK, et al. FTO polymorphisms moderate the association of food reinforcement with energy intake. Physiol Behav. 2014;132:51–6.

    CAS  PubMed  Google Scholar 

  40. 40.

    Peters U, North KE, Sethupathy P, et al. 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. 2013;9:e1003171.

    PubMed Central  CAS  PubMed  Google Scholar 

  41. 41.•

    Almen MS, Rask-Andersen M, Jacobsson JA, et al. Determination of the obesity-associated gene variants within the entire FTO gene by ultra-deep targeted sequencing in obese and lean children. Int J Obes. 2013;37:424–31. comprehensive survey of the SNP polymorphisms and their effects on BMI shows that the most significant SNPs linked to obesity in intron one of FTO do not include rs9939609 which is the most studied SNP.

  42. 42.•

    Sonestedt E, Roos C, Gullberg B, Ericson U, Wirfalt E, Orho-Melander M. Fat and carbohydrate intake modify the association between genetic variation in the FTO genotype and obesity. Am J Clin Nutr. 2009;90:1418–25. First demonstration that FTO effect on obesity interacts with dietary fat intake, being greater in those with elevated fat consumption.

  43. 43.

    Sonestedt E, Gullberg B, Ericson U, Wirfalt E, Hedblad B, Orho-Melander M. Association between fat intake, physical activity and mortality depending on genetic variation in FTO. Int J Obes. 2011;35:1041–9.

    CAS  Google Scholar 

  44. 44.

    Corella D, Arnett DK, Tucker KL, Kabagambe EK, Tsai M, Parnell LD, et al. A High Intake of Saturated Fatty Acids Strengthens the Association between the Fat Mass and Obesity-Associated Gene and BMI. J Nutr. 2011;141:2219–25.

    PubMed Central  CAS  PubMed  Google Scholar 

  45. 45.

    Phillips CM, Kesse-Guyot E, McManus R, Hercberg S, Lairon D, Planells R, et al. High Dietary Saturated Fat Intake Accentuates Obesity Risk Associated with the Fat Mass and Obesity-Associated Gene in Adults. J Nutr. 2012;142:824–31.

    CAS  PubMed  Google Scholar 

  46. 46.

    Moleres A, Ochoa MC, Rendo-Urteaga T, Martinez-Gonzalez MA, Julian MCAS, Martinez JA, et al. Dietary fatty acid distribution modifies obesity risk linked to the rs9939609 polymorphism of the fat mass and obesity-associated gene in a Spanish case–control study of children. Br J Nutr. 2012;107:533–8.

    CAS  PubMed  Google Scholar 

  47. 47.

    Ahmad T, Chasman DI, Mora S, Pare G, Cook NR, Buring JE, et al. The Fat-Mass and Obesity-Associated (FTO) gene, physical activity, and risk of incident cardiovascular events in white women. Am Heart J. 2011;160:1163–9.

    Google Scholar 

  48. 48.

    Hardy DS, Racette SB, Hoelscher DM. Macronutrient Intake as a Mediator with FTO to Increase Body Mass Index. J Am Coll Nutr. 2014;33:256–66.

    CAS  PubMed  Google Scholar 

  49. 49.

    Jaaskelainen A, Schwab U, Kolehmainen M, Kaakinen M, Savolainen MJ, Froguel P, et al. Meal Frequencies Modify the Effect of Common Genetic Variants on Body Mass Index in Adolescents of the Northern Finland Birth Cohort 1986. Plos One. 2013;8:e73802.

    PubMed Central  CAS  PubMed  Google Scholar 

  50. 50.

    Ortega-Azorin C, Sorli JV, Asensio EM, et al. Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low. Cardiovasc Diabetol. 2012;11:137.

    PubMed Central  CAS  PubMed  Google Scholar 

  51. 51.

    Lemas DJ, Klimentidis YC, Wiener HH, O'Brien DM, Hopkins SE, Allison DB, et al. Obesity polymorphisms identified in genome-wide association studies interact with n-3 polyunsaturated fatty acid intake and modify the genetic association with adiposity phenotypes in Yup'ik people. Genes Nutr. 2013;8:495–505.

    PubMed Central  CAS  PubMed  Google Scholar 

  52. 52.

    Lourenco BH, Qi L, Willett WC, Cardoso MA, the ACTION Study Team. FTO Genotype, Vitamin D Status, and Weight Gain During Childhood. Diabetes. 2014;63:808–14.

    PubMed Central  CAS  PubMed  Google Scholar 

  53. 53.

    Corella D, Carrasco P, Sorli JV, Coltell O, Ortega-Azorin C, Guillen M, et al. Education modulates the association of the FTO rs9939609 polymorphism with body mass index and obesity risk in the Mediterranean population. Nutr Metab Cardiovasc Dis. 2012;22:651–8.

    CAS  PubMed  Google Scholar 

  54. 54.

    Vimaleswaran KS, Angquist L, Hansen RD, et al. Association Between FTO Variant and Change in Body Weight and Its Interaction With Dietary Factors: The DiOGenes Study. Obesity. 2012;20:1669–74.

    CAS  PubMed  Google Scholar 

  55. 55.

    Speakman JR, Westerterp KR. Associations between energy demands, physical activity and body composition in humans between 18 and 96y of age. Am J Clin Nutr. 2010;92:826–34.

    CAS  PubMed  Google Scholar 

  56. 56.•

    Berentzen T, Kring SII, Holst C, Zimmermann E, Jess T, Hansen T, et al. Lack of association of fatness-related FTO gene variants with energy expenditure or physical activity. J Clin Endocrinol Metab. 2008;93:2904–8. First study to show lack of an association between FTO variants and physical activity levels.

  57. 57.

    Goossens GH, Petersen L, Blaak EE, the NUGENOB Consortium, et al. Several obesity- and nutrient-related gene polymorphisms but not FTO and UCP variants modulate postabsorptive resting energy expenditure and fat-induced thermogenesis in obese individuals: the NUGENOB Study. Int J Obes. 2009;33:669–79.

    CAS  Google Scholar 

  58. 58.

    Arrizabalaga M, Larrarte E, Margareto J, Maldonado-Martin S, Barrenechea L, Labayen I. Preliminary findings on the influence of FTO rs9939609 and MC4R rs17782313 polymorphisms on resting energy expenditure, leptin and thyrotropin levels in obese non-morbid premenopausal women. J Physiol Biochem. 2014;70:255–62.

    CAS  PubMed  Google Scholar 

  59. 59.

    Speakman JR. Doubly-labelled water: Theory and practice. Berlin: Springer; 1997.

    Google Scholar 

  60. 60.•

    Andreasen CH, Stender-Petersen KL, Mogensen MS, et al. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes. 2008;57:95–101. First study to show that the impact of the FTO variants interacts with physical activity levels with the effects being lower in those with greater activity.

  61. 61.

    Rampersaud E, Mitchell BD, Pollin TI, Fu M, Shen H, O'Connell JR, et al. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch Intern Med. 2008;168:1791–7.

    PubMed Central  PubMed  Google Scholar 

  62. 62.

    Vimaleswaran KSL, Zhao SX, Luan JH, Bingham JA, Khaw SA, Ekelund KT, et al. Physical activity attenuates the body mass index-increasing influence of genetic variation in the FTO gene. Am J Clin Nutr. 2009;90:425–8.

    CAS  PubMed  Google Scholar 

  63. 63.

    Ruiz JR, Labayen I, Ortega FB, the HELENA Study Grp, et al. Attenuation of the Effect of the FTO rs9939609 Polymorphism on Total and Central Body Fat by Physical Activity in Adolescents The HELENA Study. Arch Pediatr Adolesc Med. 2010;164:328–33.

    PubMed  Google Scholar 

  64. 64.

    Scott RA, Bailey MES, Moran CN, Wilson RH, Fuku N, Tanaka M, et al. FTO genotype and adiposity in children: physical activity levels influence the effect of the risk genotype in adolescent males. Eur J Hum Genet. 2011;18:1339–43.

    Google Scholar 

  65. 65.

    Xi B, Wang CY, Wu LJ, Zhang MX, Shen Y, Zhao XY, et al. Influence of Physical Inactivity on Associations Between Single Nucleotide Polymorphisms and Genetic Predisposition to Childhood Obesity. Am J Epidemiol. 2011;173:1256–62.

    PubMed  Google Scholar 

  66. 66.

    Zhu JW, Loos RJF, Lu L, Zong G, Gan W, Ye XW, et al. Associations of Genetic Risk Score with Obesity and Related Traits and the Modifying Effect of Physical Activity in a Chinese Han Population. PLoS One. 2014;9:e91442.

    PubMed Central  PubMed  Google Scholar 

  67. 67.

    Yang J, Loos RJF, Powell JE, et al. FTO genotype is associated with phenotypic variability of body mass index. Nature. 2012;490:267–70.

    PubMed Central  CAS  PubMed  Google Scholar 

  68. 68.

    Gustavsson J, Mehlig K, Leander K, Lissner L, Bjorck L, Rosengren A, et al. FTO Genotype, Physical Activity, and Coronary Heart Disease Risk in Swedish Men and Women. Circ Cardiovasc Genet. 2014;7:171–7.

    CAS  PubMed  Google Scholar 

  69. 69.

    Arch JRS, Hislop D, Wang SJY, Speakman JR. Some mathematical and technical issues in the measurement and interpretation of open-circuit calorimetry in small animals. Int J Obes. 2006;30:1322–31.

    CAS  Google Scholar 

  70. 70.

    Tschöp MH, Speakman JR, Arch JRS, et al. A guide to analysis of mouse energy metabolism. Nat Methods. 2012;9:57–63.

    Google Scholar 

  71. 71.

    Speakman JR. FTO effect on energy demand versus food intake. Nature. 2010;464:E1.

    CAS  PubMed  Google Scholar 

  72. 72.

    Church C, Lee S, Bagg EAL, 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:e1000599.

    PubMed Central  PubMed  Google Scholar 

  73. 73.•

    McMurray F, Church CD, Larder R, et al. Adult Onset Global Loss of the Fto Gene Alters Body Composition and Metabolism in the Mouse. PLoS Genet. 2013;9:e1003166. Mouse study reconciling many of the discrepancies in the literature between mouse and human impacts of FTO.

  74. 74.

    Church, C Moir, L McMurray, F et al.: (2011) Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet. 42: 1086-U147

  75. 75.••

    Gerken T, Girard CA, Tung YC, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318:1469–72. First demonstration of what FTOs function is, showing that it is a nucleic acid demethylase.

  76. 76.••

    Han ZF, Niu TH, Chang JB, Lei XG, Zhao MY, Wang Q, et al. Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature. 2010;464:1205–U129. Demonstration from crystal structure of how FTO exerts its substrate specificity towards RNA.

  77. 77.

    Rask-Andersen M, Almen MS, Olausen HR, Olszewski PK, Eriksson J, Chavan RA, et al. Functional coupling analysis suggests link between the obesity gene FTO and the BDNF-NTRK2 signaling pathway. BMC Neurosci. 2011;12:117.

    PubMed Central  CAS  PubMed  Google Scholar 

  78. 78.

    Olszewski PK, Fredriksson R, Eriksson JD, Mitra A, Radomska KJ, Gosnell BA, et al. Fto colocalizes with a satiety mediator oxytocin in the brain and upregulates oxytocin gene expression. Biochem Biophys Res Commun. 2011;408:422–6.

    CAS  PubMed  Google Scholar 

  79. 79.

    Olszewski PK, Fredriksson R, Olszewska AM, Stephansson O, Alsio J, Radomska KJ, et al. Hypothalamic FTO is associated with the regulation of energy intake not feeding reward. BMC Neurosci. 2009;10:129.

    PubMed Central  PubMed  Google Scholar 

  80. 80.

    Poritsanos, NJ Lew, PS Fischer, J Mobbs, CV Nagy, JI Wong, D Ruther, U Mizuno, TM (2011) Impaired hypothalamic Fto expression in response to fasting and glucose in obese mice. Nutr Diabetes. 1: 10.1038/nutd.2011.15

  81. 81.

    Cheung MKG, O'Rahilly P, Yeo S, GSH. FTO expression is regulated by availability of essential amino acids. Int J Obes. 2013;37:744–7.

    CAS  Google Scholar 

  82. 82.

    Caruso V, Bahari H, Morris MJ. The Beneficial Effects of Early Short-Term Exercise in the Offspring of Obese Mothers are Accompanied by Alterations in the Hypothalamic Gene Expression of Appetite Regulators and FTO (Fat Mass and Obesity Associated) Gene. J Neuroendocrinol. 2013;25:742–52.

    CAS  PubMed  Google Scholar 

  83. 83.

    Tung YCLA, Shan E, Bosch XY, O'Rahilly F, Coll S, Yeo AP, et al. Hypothalamic-Specific Manipulation of Fto, the Ortholog of the Human Obesity Gene FTO, Affects Food Intake in Rats. PLoS One. 2010;5:e8771.

    PubMed Central  PubMed  Google Scholar 

  84. 84.

    Pitman RT, Fong JT, Billman P, Puri N. Knockdown of the Fat Mass and Obesity Gene Disrupts Cellular Energy Balance in a Cell-Type Specific Manner. PLoS One. 2012;7:e38444.

    PubMed Central  CAS  PubMed  Google Scholar 

  85. 85.

    Labayen I, Ruiz JR, Ortega FB, et al. Association between the FTO rs9939609 polymorphism and leptin in European adolescents: a possible link with energy balance control. The HELENA study. Int J Obes. 2011;35:66–71.

    CAS  Google Scholar 

  86. 86.

    Wang P, Yang FJ, Du H, Guan YF, Xu TY, Xu XW, et al. Involvement of Leptin Receptor Long Isoform (LepRb)-STAT3 Signaling Pathway in Brain Fat Mass- and Obesity-Associated (FTO) Downregulation during Energy Restriction. Mol Med. 2011;17:523–32.

    PubMed Central  CAS  PubMed  Google Scholar 

  87. 87.

    Lin L, Hales CM, Garber K, Jin P. Fat mass and obesity-associated (FTO) protein interacts with CaMKII and modulates the activity of CREB signaling pathway. Hum Mol Genet. 2014;23:3299–306.

    CAS  PubMed  Google Scholar 

  88. 88.

    Hess ME, Hess S, Meyer KD, et al. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci. 2013;126:1042–U96.

    Google Scholar 

  89. 89.

    McTaggart JS, Lee S, Iberl M, Church C, Cox RD, Ashcroft FM. FTO Is Expressed in Neurones throughout the Brain and Its Expression Is Unaltered by Fasting. PLoS One. 2011;6:e27968.

    PubMed Central  CAS  PubMed  Google Scholar 

  90. 90.

    Vujovic P, Stamenkovic S, Jasnic N, Lakic I, Djurasevic S, Cvijic G, et al. Fasting Induced Cytoplasmic Fto expression in Some Neurons of Rat Hypothalamus. PLos One. 2013;8:e63694.

    PubMed Central  CAS  PubMed  Google Scholar 

  91. 91.•

    Ma MH, O'Rahilly HP, Ron S, Yeo D, GSH. Kinetic analysis of FTO (fat mass and obesity-associated) reveals that it is unlikely to function as a sensor for 2-oxoglutarate. Biochem J. 2012;444:83–187. Demonstration that it is unlikely FTO acts as a sensor of flux in the TCA cycle. Negative result but an important thing to be eliminated.

  92. 92.

    Gulati P, Yeo GSH. The biology of FTO: from nucleic acid demethylase to amino acid sensor. Diabetologia. 2013;56:2113–21.

    PubMed Central  CAS  PubMed  Google Scholar 

  93. 93.•

    Gulati P, Cheung MK, Antrobus R, Church CD, Harding HP, Tung YCL, et al. Role for the obesity-related FTO gene in the cellular sensing of amino acids. PNAS. 2013;110:2557–62. First suggestion that FTO is an amino acid sensor.

    PubMed Central  CAS  PubMed  Google Scholar 

  94. 94.

    Huang T, Qi QB, Li YP, Hu FB, Bray GA, Sacks FM, et al. FTO genotype, dietary protein, and change in appetite: the Preventing Overweight Using Novel Dietary Strategies trial. Am J Clin Nutr. 2014;99:1126–30.

    CAS  PubMed  Google Scholar 

  95. 95.

    Yang M, Xu YY, Liang L, et al. The Effects of Genetic Variation in FTO rs9939609 on Obesity and Dietary Preferences in Chinese Han Children and Adolescents. PLoS One. 2014;9:e104574.

    PubMed Central  PubMed  Google Scholar 

  96. 96.

    Stratigopoulos G, LeDuc CA, Cremona ML, Chung WK, Leibel RL. 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. 2011;286:2155–70.

    PubMed Central  CAS  PubMed  Google Scholar 

  97. 97.

    Stratigopoulos G, Padilla SL, Leduc CA, Watson E, Hattersley AT, McCarthy MI, et al. Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol. 2008;294:R1185–96.

    CAS  Google Scholar 

  98. 98.•

    Stratigopoulos G, Carli JFM, O'Day DR, et al. Hypomorphism for RPGRIP1L, a Ciliary Gene Vicinal to the FTO Locus, Causes Increased Adiposity in Mice. Cell Metab. 2014;19:767–79. Indication that FTO variants may actually impact adjacent gene RPGRIP1L.

    CAS  PubMed  Google Scholar 

  99. 99.••

    Smemo S, Tena JJ, Kim KH, et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature. 2014;507:371–5. Demonstration that FTO variants may exert their action via effects on the nearby IRX3 gene.

    PubMed Central  CAS  PubMed  Google Scholar 

  100. 100.

    Bravard A, Vial G, Chauvin MA, Rouille Y, Bailleul B, Vidal H, et al. FTO contributes to hepatic metabolism regulation through regulation of leptin action and STAT3 signalling in liver. Cell Commun Signal. 2014;12:4.

    PubMed Central  PubMed  Google Scholar 

  101. 101.

    Wahlen K, Sjolin E, Hoffstedt J. The common rs9939609 gene variant of the fat mass- and obesity-associated gene FTO is related to fat cell lipolysis. J Lipid Res. 2008;49:607–11.

    PubMed  Google Scholar 

  102. 102.

    Berulava T, Ziehe M, Klein-Hitpass L, Mladenov E, Thomale J, Ruther U, et al. FTO levels affect RNA modification and the transcriptome. Eur J Hum Genet. 2013;21:317–23.

    PubMed Central  CAS  PubMed  Google Scholar 

  103. 103.

    Jia GF, Fu Y, He C. Reversible RNA adenosine methylation in biological regulation. Trends Genet. 2013;29:108–15.

    PubMed Central  CAS  PubMed  Google Scholar 

  104. 104.

    Jia GF, Fu Y, Zhao X, Dai Q, Zheng GQ, Yang Y, et al. N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7:885–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  105. 105.

    Fu Y, Jia GF, Pang XQ, Wang RN, Wang X, Li CJ, et al. FTO-mediated formation of N-6-hydroxymethyladenosine and N-6-formyladenosine in mammalian RNA. Nat Commun. 2013;4:1798.

    PubMed Central  PubMed  Google Scholar 

  106. 106.

    Fu Y, He CA. Nucleic acid modifications with epigenetic significance. Curr Opin Chem Biol. 2012;16:516–24.

    PubMed Central  CAS  PubMed  Google Scholar 

  107. 107.

    Liu J, Jia GF. Methylation Modifications in Eukaryotic Messenger RNA. J Genet Genom. 2014;41:21–33.

    CAS  Google Scholar 

  108. 108.

    Merkestein M, McTaggart JS, Lee S, Kramer HB, McMurray F, Lafond M, et al. Changes in Gene Expression Associated with FTO Overexpression in Mice. PLoS One. 2014;9:e97162.

    PubMed Central  PubMed  Google Scholar 

  109. 109.

    Pan T. N6-methyl-adenosine modification in messenger and long non-coding RNA. Trends Biochem Sci. 2013;38:204–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  110. 110.

    Wu Q, Saunders RA, Szkudlarek-Mikho M, de la Serna I, Chin KV. The obesity-associated Fto gene is a transcriptional coactivator. Biochem Biophys Res Commun. 2010;401:390–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  111. 111.

    Johnson L, van Jaarsveld CHM, Emmett PM, Rogers IS, Ness AR, Hattersley AT, et al. Dietary Energy Density Affects Fat Mass in Early Adolescence and Is NotModified by FTO Variants. PLos One. 2009;4:e4594.

    PubMed Central  PubMed  Google Scholar 

  112. 112.

    Hakanen M, Raitakari OT, Lehtimaki T, Peltonen N, Pahkala K, Sillanmaki L, et al. FTO Genotype Is Associated with Body Mass Index after the Age of Seven Years But Not with Energy Intake or Leisure-Time Physical Activity. J Clin Endocrinol Metab. 2009;94:1281–7.

    CAS  PubMed  Google Scholar 

  113. 113.

    Papathanasopoulos A, Camilleri M, Carlson PJ, Vella A, Nord SJL, Burton DD, et al. A Preliminary Candidate Genotype-Intermediate Phenotype Study of Satiation and Gastric Motor Function in Obesity. Obesity. 2010;18:1201–11.

    PubMed Central  PubMed  Google Scholar 

  114. 114.

    Jonassaint CR, Szatkiewicz JP, Bulik CM, et al. Absence of Association Between Specific Common Variants of the Obesity-Related FTO Gene and Psychological and Behavioral Eating Disorder Phenotypes. Am J Med Genet B Neuropsychiatr Genet. 2011;1568:454–61.

    Google Scholar 

  115. 115.

    Lear SA, Deng WQ, Pare G, Sulistyoningrum DC, Loos RJF, Devlin A. Associations of the FTO rs9939609 variant with discrete body fat depots and dietary intake in a multi-ethnic cohort. Genet Res. 2011;93:419–26.

    Google Scholar 

  116. 116.

    Müller TD, Greene BH, Bellodi L, et al. Fat Mass and Obesity-Associated Gene (FTO) in Eating Disorders: Evidence for Association of the rs9939609 Obesity Risk Allele with Bulimia nervosa and Anorexia nervosa. Obes Facts. 2012;5:408–19.

    PubMed  Google Scholar 

  117. 117.

    Lappalainen T, Lindstrom J, Paananen J, Eriksson JG, Karhunen L, Tuomilehto J, et al. Association of the fat mass and obesity-associated (FTO) gene variant (rs9939609) with dietary intake in the Finnish Diabetes Prevention Study. Br J Nutr. 2012;108:1859–65.

    CAS  PubMed  Google Scholar 

  118. 118.

    Velders FP, De Wit JE, Jansen PW, Jaddoe VWV, Hofman A, Verhulst FC, et al. FTO at rs9939609, Food Responsiveness, Emotional Control and Symptoms of ADHD in Preschool Children. PLoS One. 2012;7:e49131.

    PubMed Central  CAS  PubMed  Google Scholar 

  119. 119.

    Brunkwall, L Ericson, U Hellstrand, S Gullberg, B Orho-Melander, M Sonestedt, E (2013) Genetic variation in the fat mass and obesity-associated gene (FTO) in association with food preferences in healthy adults. Food Nutr Res. 57: 10.3402/fnr.v57i0.20028

  120. 120.

    Chu AY, Workalemahu T, Paynter NP, CHARGE Nutr Working Grp DietGen Consortium, et al. Novel locus including FGF21 is associated with dietary macronutrient intake. Hum Mol Genet. 2013;22:1895–902.

    PubMed Central  CAS  PubMed  Google Scholar 

  121. 121.

    Ibba A, Pilia S, Zavattari P, Loche A, Guzzetti C, Casini MR, et al. The role of FTO genotype on eating behavior in obese Sardinian children and adolescents. J Pediatr Endocrinol Metab. 2013;26:539–44.

    CAS  PubMed  Google Scholar 

  122. 122.

    Kjeldahl K, Rasmussen MA, Hasselbalch AL, Kyvik KO, Christiansen L, Rezzi S, et al. No genetic footprints of the fat mass and obesity associated (FTO) gene in human plasma H-1 CPMG NMR metabolic profiles. Metabolomics. 2014;10:132–40.

    CAS  Google Scholar 

  123. 123.

    Wahl S, Krug S, Then C, et al. Comparative analysis of plasma metabolomics response to metabolic challenge tests in healthy subjects and influence of the FTO obesity risk allele. Metabolomics. 2014;10:386–401.

    CAS  Google Scholar 

  124. 124.

    Roswall N, Angquist L, Ahluwalia TS, et al. Association between Mediterranean and Nordic diet scores and changes in weight and waist circumference: influence of FTO and TCF7L2 loci. Am J Clin Nutr. 2014;100:1188–97.

    CAS  PubMed  Google Scholar 

  125. 125.

    Grunnet LG, Brons C, Jacobsen S, Nilsson E, Astrup A, Hansen T, et al. Increased Recovery Rates of Phosphocreatine and Inorganic Phosphate after Isometric Contraction in Oxidative Muscle Fibers and Elevated Hepatic Insulin Resistance in Homozygous Carriers of the A-allele of FTOrs9939609. J Clin Endocrinol Metab. 2009;94:596–602.

    CAS  PubMed  Google Scholar 

  126. 126.

    Corpeleijn E, Petersen L, Holst C, Saris WH, Astrup A, Langin D, et al. Obesity-related Polymorphisms and Their Associations With the Ability to Regulate Fat Oxidation in Obese Europeans: The NUGENOB Study. Obesity. 2010;18:1369–77.

    CAS  PubMed  Google Scholar 

  127. 127.

    Zavattari P, Loche A, Pilia S, Ibba A, Moi L, Guzzetti C, et al. rs9939609 in the FTO Gene is Associated with Obesity but not with Several Biochemical Parameters in Sardinian Obese Children. Ann Hum Genet. 2014;75:648–54.

    Google Scholar 

  128. 128.

    Kowalska I, Adamska A, Malecki MT, Karczewska-Kupczewska M, Nikolajuk A, Szopa M, et al. Impact of the FTO gene variation on fat oxidation and its potential influence on body weight in women with polycystic ovary syndrome. Clin Endocrinol. 2012;77:120–5.

    CAS  Google Scholar 

  129. 129.

    Huuskonen A, Lappalainen J, Oksala N, Santtila M, Hakkinen K, Kyrolainen H, et al. Aerobic Fitness Does Not Modify the Effect of FTO Variation on Body Composition Traits. PLoS One. 2012;7:e51635.

    PubMed Central  CAS  PubMed  Google Scholar 

  130. 130.

    Prats-Puig A, Grau-Cabrera P, Riera-Perez E, Cortes-Marina R, Fortea E, Soriano-Rodriguez P, et al. Variations in the obesity genes FTO, TMEM18 and NRXN3 influence the vulnerability of children to weight gain induced by short sleep duration. Int J Obes. 2013;37:182–7.

    CAS  Google Scholar 

  131. 131.

    Eynon N, Nasibulina ES, Banting LK, et al. The FTO A/T Polymorphism and Elite Athletic Performance: A Study Involving Three Groups of European Athletes. PLos One. 2013;8:e60570.

    PubMed Central  CAS  PubMed  Google Scholar 

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John R. Speakman declares that he has no conflict of interest.

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This article is part of the Topical Collection on Psychological Issues

Appendix 1

Appendix 1

Table 3

Table 3 Effects of variants of the FTO SNPs on food and macronutrient intakes and related parameters (ordered by date of publication)

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Speakman, J.R. The ‘Fat Mass and Obesity Related’ (FTO) gene: Mechanisms of Impact on Obesity and Energy Balance. Curr Obes Rep 4, 73–91 (2015). https://doi.org/10.1007/s13679-015-0143-1

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Keywords

  • FTO
  • GWAS
  • BMI
  • Body composition
  • Adiposity
  • Fatness
  • Obesity
  • Food intake
  • Energy expenditure
  • Physical activity
  • 2-oxoglutarate
  • Demethylation
  • DNA
  • RNA
  • Leptin
  • Ghrelin
  • Hypothalamus
  • Amino acid sensor
  • mTOR
  • Protein intake
  • Macronutrient intake
  • IRX3
  • RPGRIP1L
  • FTM