Fat mass and obesity-associated protein, also known asalpha-ketoglutarate-dependent dioxygenase FTO, is anenzyme that in humans is encoded by theFTOgene located onchromosome 16. As one homolog in theAlkB family proteins, it is the firstmessenger RNA (mRNA)demethylase that has been identified.[5] Certain alleles of theFTO gene appear to becorrelated withobesity inhumans.[6][7]
Theamino acidsequence of thetranscribed FTO protein shows high similarity with the enzymeAlkB which oxidativelydemethylatesDNA.[8][9] FTO is a member of the superfamily ofalpha-ketoglutarate-dependent hydroxylase, which are non-heme iron-containing proteins. Recombinant FTO protein was first discovered to catalyse demethylation of 3-methylthymine in single-stranded DNA, and3-methyluridine in single-stranded RNA, with low efficiency.[8] ThenucleosideN6-methyladenosine (m6A), an abundant modification inRNA, was then found to be a major substrate of FTO.[5][10] The FTO gene expression was also found to be significantly upregulated in thehypothalamus of rats after food deprivation and strongly negatively correlated with the expression of orexigenicgalanin-like peptide which is involved in the stimulation of food intake.[11]
Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward.[12]
People with two copies of the risk allele for the rs9939609 single-nucleotide polymorphism (SNP) showed differing neural responses to food images viafMRI.[13] However, rs9939609's association withFTO is controversial, and may actually affect another gene, called Iroquois homeobox protein 3 (IRX3).[14]
FTO has been demonstrated to efficiently demethylate the related modified ribonucleotide,N6,2'-O-dimethyladenosine, and to an equal or lesser extent, m6A, in vitro .[5][15] FTOknockdown withsiRNA led to increased amounts of m6A in polyA-RNA, whereasoverexpression of FTO resulted in decreased amounts of m6A in human cells.[10] FTO partially co-localizes withnuclear speckles, which supports the notion that in the nucleus, m6A can be asubstrate of FTO. The function of FTO could affect the processing ofpre-mRNA, other nuclear RNAs, or both. The discovery of the FTO-mediated oxidativedemethylation of RNA may initiate further investigations on biological regulation based on reversible chemical modification of RNA, and identification of RNA substrates for which FTO has the highest affinity.[5][10][15]
FTO can oxidize m6A to generate N6-hydroxymethyladenosine (hm6A) as an intermediate modification and N6 - formyladenosine(f6A) as a further oxidized product in mammalian cells.[16]
Plants do not carry orthologs ofFTO and artificial introduction of anFTOtransgene causes substantial and widespread RNA demethylation. Instead of causing catastrophic disregulation, the treated rice and potato plants show significant (50%) increases in yield and become more tolerant to drought.[17] In mESCs and during mouse development, FTO has been shown to mediated LINE1 RNA m6A demethylation and consequently affect local chromatin state and nearby gene transcription.[18]
A cohort consisting of 38,759 Europeans was studied for variants of the FTO obesity riskallele.[19] In particular,carriers of one copy of the allele weighed on average 1.2 kilograms (2.6 lb) more than people with no copies.Carriers of two copies (16% of the subjects) weighed 3 kilograms (6.6 lb) more and had a 1.67-fold higherrate of obesity than those with no copies. The association was observed in ages 7 and upwards. This gene is not directly associated with diabetes; however, increased body-fat also increases the risk of developingtype 2 diabetes.[20]
Simultaneously, a study of 2,900 affected individuals and 5,100 controls of French descent, together with 500 trios (confirming an association independent of population stratification) found association ofSNPs in the very same region of FTO (rs1421085).[21] The authors found that this variation, or a variation in strongLD with this variation explains 1% of the population BMI variance and 22% of the population attributable risk of obesity. The authors of this study claim that while obesity was already known to have a genetic component (fromtwin studies), noreplicated previous study has ever identified an obesity risk allele that was so common in the human population. The risk allele is a cluster of 10single nucleotide polymorphism in the firstintron of FTO called rs9939609. According toHapMap, it has population frequencies of 45% in the West/Central Europeans, 52% inYorubans (West African natives) and 14% in Chinese/Japanese. Furthermore,morbid obesity is associated with a combination of FTO andINSIG2single nucleotide polymorphisms.[22]
In 2009, variants in the FTO gene were further confirmed to associate withobesity in two very large genome wide association studies ofbody mass index (BMI).[23][24]
In adult humans, it was shown that adults bearing the at risk AT and AA alleles at rs9939609 consumed between 500 and 1250 kJ more each day than those carrying the protective TT genotype (equivalent to between 125 and 280 kcal per day more intake).[25] The same study showed that there was no impact of the polymorphism on energy expenditure. This finding of an effect of the rs9939609 polymorphism on food intake or satiety has been independently replicated in five subsequent studies (in order of publication).[26][27][28][29][30] Three of these subsequent studies also measured resting energy expenditure and confirmed the original finding that there is no impact of the polymorphic variation at the rs9939609 locus on energy expenditure. A different study explored the effects of variation in two different SNPs in the FTO gene (rs17817449 and rs1421085) and suggested there might be an effect on circulating leptin levels and energy expenditure, but this latter effect disappeared when the expenditure was normalized for differences in body composition.[31] The accumulated data across seven independent studies therefore clearly implicates the FTO gene in humans as having a direct impact on food intake but no effect on energy expenditure.
Human hypothalamicneurons derived from individuals carrying the obesity-risk variation at FTO SNPs rs1421085 or rs8050136 express lower levels of the adjacent geneRPGRIP1L compared to individuals carrying the protective variation.[32] The transcription factorCUX1 binds DNA at rs1421085 or rs8050136 in the presence of the protective variation and promotes RPGRIP1L expression[33][34] suggesting a potential molecular mechanism by which FTO obesity-associates SNPs alter the expression of nearby genes. Reduced expression of RPGRIP1L in mice results in increased body weight due to increased food intake,[35][36][37] with no changes in energy expenditure, in agreement with data accumulated in human studies. RPGRIP1L is a protein found in primarycilia that are cellular organelles important for body weight regulation. Decreased RPGRIP1L expression in the mouse brain, or cells derived from humans, results in lower sensitivity for the hormoneleptin that suppresses feeding, as well as alters the morphology of the hypothalamus that controls food consumption.[32][35][36] These studies provide a potential mechanism by which obesity-risk variations in FTO SNPs promote increased food intake by influencing the function of genes in the vicinity.
The obesity-associated noncoding region within the FTO gene interacts directly with the promoter ofIRX3, a homeobox gene, andIRX5, another homeobox gene. The noncoding region of FTO interacts with the promoters of IRX3 and FTO in human, mouse and zebrafish, and with IRX5. Results suggest that IRX3 and IRX5 are linked with obesity and determine body mass and composition. This is further supported by the fact that obesity-associatedsingle nucleotide polymorphisms, in which cytosine is substituted for thymine, are involved in the expression of IRX3 and IRX5 (not FTO) in human brains. The enhanced expression of IRX3 and IRX5 resulting from this single nucleotide alteration promoted a shift from energy-dissipating beige adipocytes to energy-storing white adipocytes and a subsequent reduction inmitochondrial thermogenesis by a factor of 5.[38][39] Another study found indications that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner, and that there is a pathway for adipocyte thermoregulation which involves the proteineARID5B, the single-nucleotide variant rs1421085, and the IRX3 and IRX5 genes.[40]
Recent studies revealed that carriers of common FTO gene polymorphisms show both a reduction in frontal lobe volume of the brain[41] and an impaired verbal fluency performance.[42] Fittingly, a population-based study from Sweden found that carriers of the FTO rs9939609 A allele have an increased risk for incident Alzheimer disease.[43]
The presence of the FTO rs9939609 A allele was also found to be positively correlated with other symptoms of themetabolic syndrome, including higher fasting insulin, glucose, and triglycerides, and lowerHDL cholesterol. However all these effects appear to be secondary to weight increase since no association was found after correcting for increases inbody mass index.[44] Similarly, the association of rs11076008 G allele with the increased risk fordegenerative disc disease was reported.[45]
Byexon trapping, Peters et al. (1999) cloned a novel gene from a region of several hundred kb deleted by the mouse 'fused toes' (FT) mutation. They named the gene 'fatso' (Fto) due to its large size.[46][47]
^Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, et al. (June 2007). "Variation in FTO contributes to childhood obesity and severe adult obesity".Nature Genetics.39 (6):724–726.doi:10.1038/ng2048.PMID17496892.S2CID3248168.
^Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, et al. (January 2009). "Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity".Nature Genetics.41 (1):18–24.doi:10.1038/ng.274.PMID19079260.S2CID764409.
^Haupt A, Thamer C, Staiger H, Tschritter O, Kirchhoff K, Machicao F, et al. (April 2009). "Variation in the FTO gene influences food intake but not energy expenditure".Experimental and Clinical Endocrinology & Diabetes.117 (4):194–197.doi:10.1055/s-0028-1087176.PMID19053021.
^Benedict C, Jacobsson JA, Rönnemaa E, Sällman-Almén M, Brooks S, Schultes B, et al. (June 2011). "The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men".Neurobiology of Aging.32 (6): 1159.e1–1159.e5.doi:10.1016/j.neurobiolaging.2011.02.006.PMID21458110.S2CID20051507.
^Keller L, Xu W, Wang HX, Winblad B, Fratiglioni L, Graff C (2011). "The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study".Journal of Alzheimer's Disease.23 (3):461–469.doi:10.3233/JAD-2010-101068.PMID21098976.
^Peters T, Ausmeier K, Rüther U (October 1999). "Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation".Mammalian Genome.10 (10):983–986.doi:10.1007/s003359901144.PMID10501967.S2CID20362657.
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