The genetics of obesity: FTO leads the way
Authors: Katherine A. Fawcett, Inês Barroso
Journal: Trends in Genetics (2010)

In 2007, an association of single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated (FTO) gene region with body mass index (BMI) and risk of obesity was identified in multiple populations, making FTO the first locus unequivocally associated with adiposity. At the time, FTO was a gene of unknown function and it was not known whether these SNPs exerted their effect on adiposity by affecting FTO or neighboring genes. Therefore, this breakthrough association inspired a wealth of in silico, in vitro, and in vivo analyses in model organisms and humans to improve knowledge of FTO function. These studies suggested that FTO plays a role in controlling feeding behavior and energy expenditure. Here, we review the approaches taken that provide a blueprint for the study of other obesity-associated genes in the hope that this strategy will result in increased understanding of the biological mechanisms underlying body weight regulation. In 2007, an association of single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated (FTO) gene region with body mass index (BMI) and risk of obesity was identified in multiple populations, making FTO the first locus unequivocally associated with adiposity. At the time, FTO was a gene of unknown function and it was not known whether these SNPs exerted their effect on adiposity by affecting FTO or neighboring genes. Therefore, this breakthrough association inspired a wealth of in silico, in vitro, and in vivo analyses in model organisms and humans to improve knowledge of FTO function. These studies suggested that FTO plays a role in controlling feeding behavior and energy expenditure. Here, we review the approaches taken that provide a blueprint for the study of other obesity-associated genes in the hope that this strategy will result in increased understanding of the biological mechanisms underlying body weight regulation. Overweight and obesity, defined as body mass indices (BMI) >25 and >30, respectively, are associated with premature death through increased risk of many chronic diseases, including type 2 diabetes, cardiovascular disease and cancer [1Kopelman P. Health risks associated with overweight and obesity.Obes. Rev. 2007; 8: 13-17Crossref Scopus (502) Google Scholar]. Over the last three decades, the prevalence of overweight and obesity have increased rapidly and the latest World Health Organization (WHO) estimates suggest that 1.6 billion adults (aged 15 years and over) were overweight and 400 million were obese in 2005. These figures are predicted to rise to 2.3 billion overweight and over 700 million obese adults by 2015 (http://www.who.int/mediacentre/factsheets/fs311/en/index.html). Obesity is therefore a major international public health threat and economic burden. Although environmental factors, such as little physical activity and over-eating, have driven the recent rise in the numbers of people who are overweight or obese, genetic factors are estimated to account for 40–90% of the population variation in BMI [2Hjelmborg J.B. et al.Genetic influences on growth traits of BMI: a longitudinal study of adult twins.Obesity. 2008; 16: 847-852Crossref PubMed Scopus (90) Google Scholar, 3Maes H.H. et al.Genetic and environmental factors in relative body weight and human adiposity.Behav. Genet. 1997; 27: 325-351Crossref PubMed Scopus (1182) Google Scholar, 4Wardle J. et al.Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment.Am. J. Clin. Nutr. 2008; 87: 398-404Scopus (525) Google Scholar]. It is hoped that identifying the genetic factors underlying the heritable risk of obesity will contribute to our basic knowledge of the biology of energy balance, and might even highlight molecules and pathways that can be targeted for therapeutic intervention. In 2007, single nucleotide polymorphisms (SNPs) within the fat mass and obesity-associated gene (FTO) became the first to be associated reproducibly with human body mass. We review the implications of genetic association between SNPs in the FTO gene region and BMI in humans, the various studies undertaken and the challenges in progressing from a genetic association to new biological insight. We also provide an overview of possible future directions for research in this field. Before 2007, despite huge efforts using genome-wide linkage studies and candidate gene association studies, no genetic variation had been unequivocally associated with BMI and risk of obesity in population studies [5Saunders C.L. et al.Meta-analysis of genome-wide linkage studies in BMI and obesity.Obesity. 2007; 15: 2263-2275Crossref Scopus (118) Google Scholar]. In recent years, however, genome-wide association studies (GWAS), which test the correlation between SNPs across the entire genome and trait variation in a sample of individuals, have succeeded in identifying variants associated reproducibly with complex traits. GWAS for type 2 diabetes (T2D) detected strong association between common SNPs in the FTO region and risk of T2D [6Scuteri A. et al.Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.PLoS Genet. 2007; 3: e115Crossref PubMed Scopus (1346) Google Scholar, 7Frayling T.M. 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: 889-894Crossref PubMed Scopus (3468) Google Scholar, 8Scott L.J. et al.A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.Science. 2007; 316: 1341-1345Crossref PubMed Scopus (2296) Google Scholar]. However, subsequent analyses showed that the association between FTO SNPs and T2D was mediated by an association with BMI [7Frayling T.M. 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: 889-894Crossref PubMed Scopus (3468) Google Scholar]. The association between FTO SNPs and BMI and the risk of being overweight or obese has been confirmed in multiple populations [6Scuteri A. et al.Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.PLoS Genet. 2007; 3: e115Crossref PubMed Scopus (1346) Google Scholar, 7Frayling T.M. 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: 889-894Crossref PubMed Scopus (3468) Google Scholar, 9Dina C. et al.Variation in FTO contributes to childhood obesity and severe adult obesity.Nat. Genet. 2007; 39: 724-726Crossref PubMed Scopus (1281) Google Scholar, 10Andreasen C.H. et al.Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation.Diabetes. 2008; 57: 95-101Crossref PubMed Scopus (415) Google Scholar, 11Cecil J.E. et al.An obesity-associated FTO gene variant and increased energy intake in children.N. Engl. J. Med. 2008; 359: 2558-2566Crossref PubMed Scopus (546) Google Scholar, 12Loos R.J. et al.Common variants near MC4R are associated with fat mass, weight and risk of obesity.Nat. Genet. 2008; 40: 768-775Crossref PubMed Scopus (1047) Google Scholar, 13Do R. et al.Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study.Diabetes. 2008; 57: 1147-1150Crossref Scopus (198) Google Scholar, 14Freathy R.M. et al.Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI.Diabetes. 2008; 57: 1419-1426Crossref PubMed Scopus (265) Google Scholar, 15Grant S.F. et al.Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP.PloS ONE. 2008; 3: e1746Crossref PubMed Scopus (164) Google Scholar, 16Haupt A. et al.Impact of variation in the FTO gene on whole body fat distribution, ectopic fat, and weight loss.Obesity. 2008; 16: 1969-1972Crossref Scopus (104) Google Scholar, 17Hertel J.K. et al.Genetic analysis of recently identified type 2 diabetes loci in 1,638 unselected patients with type 2 diabetes and 1,858 control participants from a Norwegian population-based cohort (the HUNT study).Diabetologia. 2008; 51: 971-977Crossref Scopus (79) Google Scholar, 18Hinney A. et al.Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants.PloS ONE. 2007; 2: e1361Crossref PubMed Scopus (431) Google Scholar, 19Hotta K. et al.Variations in the FTO gene are associated with severe obesity in the Japanese.J. Hum. Genet. 2008; 53: 546-553Crossref PubMed Scopus (209) Google Scholar, 20Hubacek J.A. et al.The FTO gene and obesity in a large Eastern European population sample: the HAPIEE study.Obesity. 2008; 16: 2764-2766Crossref Scopus (64) Google Scholar, 21Hunt S.C. et al.Association of the FTO gene with BMI.Obesity. 2008; 16: 902-904Crossref Scopus (129) Google Scholar, 22Kring S.I. et al.FTO gene associated fatness in relation to body fat distribution and metabolic traits throughout a broad range of fatness.PloS ONE. 2008; 3: e2958Crossref Scopus (64) Google Scholar, 23Ng M.C. et al.Implication of genetic variants near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in type 2 diabetes and obesity in 6,719 Asians.Diabetes. 2008; 57: 2226-2233Crossref PubMed Scopus (308) Google Scholar, 24Pascoe L. et al.Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function.Diabetes. 2007; 56: 3101-3104Crossref Scopus (205) Google Scholar, 25Rampersaud E. et al.Physical activity and the association of common FTO gene variants with body mass index and obesity.Arch. Int. Med. 2008; 168: 1791-1797Crossref Scopus (222) Google Scholar, 26Tonjes A. et al.Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany.Eur. J. Hum. Genet. 2010; 18: 104-110Crossref PubMed Scopus (76) Google Scholar, 27Villalobos-Comparan M. et al.The FTO gene is associated with adulthood obesity in the Mexican population.Obesity. 2008; 16: 2296-2301Crossref PubMed Scopus (145) Google Scholar]. The effect of FTO SNPs on BMI is modest, with those individuals homozygous for the risk allele weighing, on average, 3 kg more than those homozygous for the protective allele [7Frayling T.M. 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: 889-894Crossref PubMed Scopus (3468) Google Scholar]. Association does not necessarily mean causation. BMI-associated SNPs lie within a 47 kilobase (kb) linkage disequilibrium (LD) block encompassing parts of the first two introns as well as exon 2 of FTO. Thus, the association signal could be due to correlation between FTO intronic SNPs and variation elsewhere in the gene or control elements of other genes. Indeed, the transcription start site of the retinitis pigmentosa GTPase regulator-interacting protein 1-like (RPGRIP1L) gene (homolog of murine Rpgrip1l, also known as Ftm) is in close proximity (∼400 bp) to the 5' end of FTO[7Frayling T.M. 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: 889-894Crossref PubMed Scopus (3468) Google Scholar]. It is therefore possible that SNPs in FTO are associated with obesity through an effect on RPGRIP1L. Efforts to fine-map the association signal to causative variant(s) are underway (Box 1).Box 1Fine-mapping association between FTO and obesityWhereas linkage disequilibrium (LD) aids the discovery of genetic associations, because the investigator does not need to test all variant(s) in a given genomic region to detect association signals, it is a hindrance to fine-mapping efforts. This is because high correlation between SNPs makes it difficult to distinguish between the effects of true causal variants and correlated non-causal variants. Consequently, it is not clear which causal variant(s) underlie the association between BMI and SNPs in FTO (which reside within a 47 kb LD block). So far, fine-mapping attempts have focused on selecting tagging SNPs within the associated genomic region and genotyping or imputing these in additional study populations of different ancestry [6Scuteri A. et al.Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.PLoS Genet. 2007; 3: e115Crossref PubMed Scopus (1346) Google Scholar, 9Dina C. et al.Variation in FTO contributes to childhood obesity and severe adult obesity.Nat. Genet. 2007; 39: 724-726Crossref PubMed Scopus (1281) Google Scholar, 15Grant S.F. et al.Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP.PloS ONE. 2008; 3: e1746Crossref PubMed Scopus (164) Google Scholar, 19Hotta K. et al.Variations in the FTO gene are associated with severe obesity in the Japanese.J. Hum. Genet. 2008; 53: 546-553Crossref PubMed Scopus (209) Google Scholar, 25Rampersaud E. et al.Physical activity and the association of common FTO gene variants with body mass index and obesity.Arch. Int. Med. 2008; 168: 1791-1797Crossref Scopus (222) Google Scholar, 26Tonjes A. et al.Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany.Eur. J. Hum. Genet. 2010; 18: 104-110Crossref PubMed Scopus (76) Google Scholar]. The advantage of using study cohorts of different ancestry lies in their varying patterns of LD. For example, LD is generally weaker in populations of African descent. Two recent studies attempted to refine the association signal from FTO in individuals of African ancestry, but none of the SNPs tested was associated with obesity in both cohorts [6Scuteri A. et al.Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.PLoS Genet. 2007; 3: e115Crossref PubMed Scopus (1346) Google Scholar, 15Grant S.F. et al.Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP.PloS ONE. 2008; 3: e1746Crossref PubMed Scopus (164) Google Scholar]. Fine-mapping studies have been done with Japanese [19Hotta K. et al.Variations in the FTO gene are associated with severe obesity in the Japanese.J. Hum. Genet. 2008; 53: 546-553Crossref PubMed Scopus (209) Google Scholar] and Old Amish Order participants [25Rampersaud E. et al.Physical activity and the association of common FTO gene variants with body mass index and obesity.Arch. Int. Med. 2008; 168: 1791-1797Crossref Scopus (222) Google Scholar]. Some of the SNPs associated with BMI in these populations have overlapped with associated SNPs in Europeans but the SNPs most strongly associated with BMI vary between cohorts. For example, the strongest SNP (rs1861868) in the Old Amish Order study had not been previously associated with obesity. This might reflect interstudy differences in the causal variant(s) or differences in levels of LD between tested SNPs and the same causal variant(s). It is worth mentioning that in a European fine-mapping study cohort, three of the four most significantly associated SNPs (rs17817449, rs3751812 and rs1421085) were in putative functional regions (based on conservation and predicted impact on regulatory domains) but these SNPs were highly correlated with each other and their effects could not be distinguished [9Dina C. et al.Variation in FTO contributes to childhood obesity and severe adult obesity.Nat. Genet. 2007; 39: 724-726Crossref PubMed Scopus (1281) Google Scholar]. Interestingly, despite an earlier demonstration that associated SNPs in the FTO region were likely to be tagging the same signal rather than multiple, independent signals [6Scuteri A. et al.Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.PLoS Genet. 2007; 3: e115Crossref PubMed Scopus (1346) Google Scholar], Tonjes et al. discovered an independent association with BMI from SNPs in FTO introns 2 and 3, downstream of the original signal, in Sorbian individuals [26Tonjes A. et al.Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany.Eur. J. Hum. Genet. 2010; 18: 104-110Crossref PubMed Scopus (76) Google Scholar]. This suggests that this genomic region might harbor multiple variants that influence susceptibility to obesity, which might complicate future fine-mapping attempts. Whereas linkage disequilibrium (LD) aids the discovery of genetic associations, because the investigator does not need to test all variant(s) in a given genomic region to detect association signals, it is a hindrance to fine-mapping efforts. This is because high correlation between SNPs makes it difficult to distinguish between the effects of true causal variants and correlated non-causal variants. Consequently, it is not clear which causal variant(s) underlie the association between BMI and SNPs in FTO (which reside within a 47 kb LD block). So far, fine-mapping attempts have focused on selecting tagging SNPs within the associated genomic region and genotyping or imputing these in additional study populations of different ancestry [6Scuteri A. et al.Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.PLoS Genet. 2007; 3: e115Crossref PubMed Scopus (1346) Google Scholar, 9Dina C. et al.Variation in FTO contributes to childhood obesity and severe adult obesity.Nat. Genet. 2007; 39: 724-726Crossref PubMed Scopus (1281) Google Scholar, 15Grant S.F. et al.Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP.PloS ONE. 2008; 3: e1746Crossref PubMed Scopus (164) Google Scholar, 19Hotta K. et al.Variations in the FTO gene are associated with severe obesity in the Japanese.J. Hum. Genet. 2008; 53: 546-553Crossref PubMed Scopus (209) Google Scholar, 25Rampersaud E. et al.Physical activity and the association of common FTO gene variants with body mass index and obesity.Arch. Int. Med. 2008; 168: 1791-1797Crossref Scopus (222) Google Scholar, 26Tonjes A. et al.Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany.Eur. J. Hum. Genet. 2010; 18: 104-110Crossref PubMed Scopus (76) Google Scholar]. The advantage of using study cohorts of different ancestry lies in their varying patterns of LD. For example, LD is generally weaker in populations of African descent. Two recent studies attempted to refine the association signal from FTO in individuals of African ancestry, but none of the SNPs tested was associated with obesity in both cohorts [6Scuteri A. et al.Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.PLoS Genet. 2007; 3: e115Crossref PubMed Scopus (1346) Google Scholar, 15Grant S.F. et al.Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP.PloS ONE. 2008; 3: e1746Crossref PubMed Scopus (164) Google Scholar]. Fine-mapping studies have been done with Japanese [19Hotta K. et al.Variations in the FTO gene are associated with severe obesity in the Japanese.J. Hum. Genet. 2008; 53: 546-553Crossref PubMed Scopus (209) Google Scholar] and Old Amish Order participants [25Rampersaud E. et al.Physical activity and the association of common FTO gene variants with body mass index and obesity.Arch. Int. Med. 2008; 168: 1791-1797Crossref Scopus (222) Google Scholar]. Some of the SNPs associated with BMI in these populations have overlapped with associated SNPs in Europeans but the SNPs most strongly associated with BMI vary between cohorts. For example, the strongest SNP (rs1861868) in the Old Amish Order study had not been previously associated with obesity. This might reflect interstudy differences in the causal variant(s) or differences in levels of LD between tested SNPs and the same causal variant(s). It is worth mentioning that in a European fine-mapping study cohort, three of the four most significantly associated SNPs (rs17817449, rs3751812 and rs1421085) were in putative functional regions (based on conservation and predicted impact on regulatory domains) but these SNPs were highly correlated with each other and their effects could not be distinguished [9Dina C. et al.Variation in FTO contributes to childhood obesity and severe adult obesity.Nat. Genet. 2007; 39: 724-726Crossref PubMed Scopus (1281) Google Scholar]. Interestingly, despite an earlier demonstration that associated SNPs in the FTO region were likely to be tagging the same signal rather than multiple, independent signals [6Scuteri A. et al.Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.PLoS Genet. 2007; 3: e115Crossref PubMed Scopus (1346) Google Scholar], Tonjes et al. discovered an independent association with BMI from SNPs in FTO introns 2 and 3, downstream of the original signal, in Sorbian individuals [26Tonjes A. et al.Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany.Eur. J. Hum. Genet. 2010; 18: 104-110Crossref PubMed Scopus (76) Google Scholar]. This suggests that this genomic region might harbor multiple variants that influence susceptibility to obesity, which might complicate future fine-mapping attempts. Since the discovery of the FTO signal, additional GWAS have succeeded in identifying many additional novel obesity loci [12Loos R.J. et al.Common variants near MC4R are associated with fat mass, weight and risk of obesity.Nat. Genet. 2008; 40: 768-775Crossref PubMed Scopus (1047) Google Scholar, 28Cotsapas C. et al.Common body mass index-associated variants confer risk of extreme obesity.Hum. Mol. Genet. 2009; 18: 3502-3507Crossref PubMed Scopus (86) Google Scholar, 29Heard-Costa N.L. et al.NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.PLoS Genet. 2009; 5: e1000539Crossref PubMed Scopus (218) Google Scholar, 30Liu Y.J. et al.Genome-wide association scans identified CTNNBL1 as a novel gene for obesity.Hum. Mol. Genet. 2008; 17: 1803-1813Crossref Scopus (142) Google Scholar, 31Meyre D. et al.Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations.Nat. Genet. 2009; 41: 157-159Crossref PubMed Scopus (522) Google Scholar, 32Thorleifsson G. et al.Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.Nat. Genet. 2009; 41: 18-24Crossref PubMed Scopus (1093) Google Scholar, 33Willer C.J. et al.Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.Nat. Genet. 2009; 41: 25-34Crossref PubMed Scopus (1407) Google Scholar]. Before these findings can be converted into clinical benefits, however, it is necessary to determine the biological mechanisms by which confirmed obesity susceptibility variants impact BMI. When associations between SNPs at FTO and BMI were first discovered [6Scuteri A. et al.Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.PLoS Genet. 2007; 3: e115Crossref PubMed Scopus (1346) Google Scholar, 7Frayling T.M. 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: 889-894Crossref PubMed Scopus (3468) Google Scholar, 9Dina C. et al.Variation in FTO contributes to childhood obesity and severe adult obesity.Nat. Genet. 2007; 39: 724-726Crossref PubMed Scopus (1281) Google Scholar], little was known about the function of the FTO gene product. Fto was first identified in the mouse by positional cloning [34Peters T. et al.Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation.Mamm. Genome. 1999; 10: 983-986Crossref Scopus (139) Google Scholar] as one of the genes within a 1.6 megabase deletion on chromosome 8 responsible for the Fused toes (Ft) phenotype [35van der Hoeven F. et al.Programmed cell death is affected in the novel mouse mutant Fused toes (Ft).Development. 1994; 120: 2601-2607Google Scholar]. Mice homozygous for the deletion died mid-gestation and exhibited severe malformations of the head and face, central nervous system (CNS) developmental defects [36Anselme I. et al.Defects in brain patterning and head morphogenesis in the mouse mutant Fused toes.Dev. Biol. 2007; 304: 208-220Crossref Scopus (51) Google Scholar, 37Gotz K. et al.Homozygous Ft embryos are affected in floor plate maintenance and ventral neural tube patterning.Dev. Dyn. 2005; 233: 623-630Crossref Scopus (16) Google Scholar], randomized left–right asymmetry [38Heymer J. et al.The expression pattern of nodal and lefty in the mouse mutant Ft suggests a function in the establishment of handedness.Mech. Dev. 1997; 66: 5-11Crossref Scopus (60) Google Scholar], polydactyly and growth retardation. Heterozygotes displayed fused toes and enlargement of the thymus [34Peters T. et al.Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation.Mamm. Genome. 1999; 10: 983-986Crossref Scopus (139) Google Scholar, 35van der Hoeven F. et al.Programmed cell death is affected in the novel mouse mutant Fused toes (Ft).Development. 1994; 120: 2601-2607Google Scholar]. However, no obesity or thinness was reported in these mice. Nevertheless, as Fto was only one of six genes deleted in the Ft mouse (the others were the Iroquois B cluster of genes, Irx3, Irx5 and Irx6, and two other genes, Fts and Rpgrip1l), it was not known which, if any, of these phenotypic manifestations were due to Fto deficiency. Interestingly, a phenotype similar to that of Ft mice was seen in a human patient harboring a small chromosomal duplication on 16q12.2, a region that includes the FTO gene [39Stratakis C.A. et al.Anisomastia associated with interstitial duplication of chromosome 16, mental retardation, obesity, dysmorphic facies, and digital anomalies: molecular mapping of a new syndrome by fluorescent in situ hybridization and microsatellites to 16q13 (D16S419-D16S503).J. Clin. Endocrinol. Metab. 2000; 85: 3396-3401Google Scholar]. Clues from the Ft mouse and human chromosomal duplication were not sufficient to shed light on the specific effects of FTO. Moreover, FTO was not annotated in the public databases as having homology to any other known gene. The discovery that this mysterious gene was associated with human obesity [6Scuteri A. et al.Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.PLoS Genet. 2007; 3: e115Crossref PubMed Scopus (1346) Google Scholar, 7Frayling T.M. 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: 889-894Crossref PubMed Scopus (3468) Google Scholar, 9Dina C. et al.Variation in FTO contributes to childhood obesity and severe adult obesity.Nat. Genet. 2007; 39: 724-726Crossref PubMed Scopus (1281) Google Scholar] inspired further research aimed at elucidating its functional properties. In silico analyses of the human FTO sequence revealed homologs in other vertebrates (from fish to mammals) and marine algae (from unicellular photosynthetic picoplankton to multicellular seaweed) [40Fredriksson R. et al.The obesity gene, FTO, is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain.Endocrinology. 2008; 149: 2062-2071Crossref PubMed Scopus (304) Google Scholar, 41Gerken T. et al.The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.Science. 2007; 318: 1469-1472Crossref PubMed Scopus (1204) Google Scholar, 42Robbens S. et al.The FTO gene, implicated in human obesity, is found only in vertebrates and marine algae.J. Mol. Evol. 2008; 66: 80-84Crossref PubMed Scopus (53) Google Scholar, 43Sanchez-Pulido L. Andrade-Navarro M.A. The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily.BMC Biochem. 2007; 8: 23Crossref Scopus (162) Google Scholar]. Sequence analysis showed that FTO shares features with Fe (II) and 2-oxoglutarate (2OG) oxygenases [41Gerken T. et al.The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.Science. 2007; 318: 1469-1472Crossref PubMed Scopus (1204) Google Scholar, 43Sanchez-Pulido L. Andrade-Navarro M.A. The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily.BMC Biochem. 2007; 8: 23Crossref Scopus (162) Google Scholar]. These enzymes catalyze oxidative reactions on multiple substrates using non-heme iron as a co-factor and 2OG as a co-substrate [41Gerken T. et al.The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.Science. 2007; 318: 1469-1472Crossref PubMed Scopus (1204) Google Scholar, 43Sanchez-Pulido L. Andrade-Navarro M.A. The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily.BMC Biochem. 2007; 8: 23Crossref Scopus (162) Google Scholar]. Within this superfamily, FTO is most similar to the Escherichia coli enzyme AlkB and its eukaryotic homologs, which can repair DNA methylation damage by hydroxylating methyl groups on the DNA leading to their removal [44Trewick S.C. et al.Methylation: lost in hydroxylation?.EMBO Rep. 2005; 6: 315-320Crossref PubMed Scopus (162) Google Scholar]. These data suggest that FTO might act as a demethylase. Sequence analysis also predicted that human