FTO gene

Fat mass and obesity associated
Identifiers
Symbols FTO; KIAA1752; MGC5149
External IDs OMIM: 610966 MGI: 1347093 HomoloGene: 8053 GeneCards: FTO Gene
EC number 1.14.11.-
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 79068 26383
Ensembl ENSG00000140718 ENSMUSG00000055932
UniProt Q9C0B1 Q8BGW1
RefSeq (mRNA) NM_001080432.2 NM_011936.2
RefSeq (protein) NP_001073901.1 NP_036066.2
Location (UCSC) Chr 16:
53.74 – 54.16 Mb		 Chr 8:
93.84 – 94.19 Mb
PubMed search [1] [2]

Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO gene located on chromosome 16. Certain variants of the FTO gene appear to be correlated with obesity in humans.[1][2]

Contents

Tissue distribution

The FTO gene is widely expressed in both fetal and adult tissue.[1]

Function

The amino acid sequence of the transcribed FTO protein shows high homology with the enzyme AlkB which oxidatively demethylates DNA.[2][3] Furthermore recombinant FTO protein catalyzes demethylation of 3-methylthymine in single-stranded DNA.[2] The FTO gene expression was also found to be significantly upregulated in the hypothalamus of rats after food deprivation and strongly negatively correlated with the expression of orexogenic galanin like peptide which is involved in the stimulation of food intake.[4]

Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward.[5]

Clinical significance

Association with obesity

A study of 38,759 Europeans for variants of FTO identified an obesity risk allele.[1] 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 higher rate 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 developing Type 2 Diabetes.

Simultaneously, a study in 2,900 affected individuals and 5,100 controls of French descent, together with 500 trios (confirming an association independent of population stratification) found association of SNPs in the very same region of FTO (rs14210850) [6] The authors found that this variation, or a variation in strong LD 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 (from twin studies), no replicated previous study has ever identified an obesity risk allele that was so common in the human population. The risk allele is a cluster of 10 single nucleotide polymorphism in the first intron of FTO called rs9939609. According to HapMap, it has population frequencies of 45% in the West/Central Europeans, 52% in Yorubans (West African natives) and 14% in Chinese/Japanese. Furthermore morbid obesity is associated with a combination of FTO and INSIG2 single nucleotide polymorphisms.[7]

In 2009 variants in the FTO gene were further confirmed to associatate with obesity in two very large genome wide association studies of body mass index (BMI).[8][9]

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).[10] 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).[11][12][13][14][15] 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 normalised for differences in body composition.[16] 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. In contrast to the findings in humans deletion analysis of Fto gene in mice showed loss of function of FTO in mice is associated with no differences in energy intake but greater energy expenditure and this results in a reduction of body weight and fatness.[17] The reasons for the differences between humans and mice in the function of the FTO gene is presently uncertain. However, many other genes involved in regulation of energy balance exert effects on both intake and expenditure. It is perhaps not surprising therefore that the emphasis of action can vary between species with the effect in humans targeted on intake, and that in mice targeted on expenditure.

Association with Alzheimer's disease

Recent studies revealed that carriers of common FTO gene polymorphisms show both a reduction in frontal lobe volume of the brain [18] and an impaired verbal fluency performance. [19] Fittingly, a population-based study from Sweden found that carriers of the FTO rs9939609 A allele have an increased risk for incident Alzheimer disease. [20]

Association with other diseases

The presence of the FTO rs9939609 A allele was also found to be positively correlated with other symptoms of the metabolic syndrome, including higher fasting insulin, glucose, and triglycerides, and lower HDL-cholesterol. However all these effects appear to be secondary to weight increase since no association was found after correcting for increases in body mass index.[21]

Origin of name

The gene's abbreviation is FTO because it is one of 6 genes that lie in a deleted region in mice that results in a fused toes (FT) phenotype and other abnormalities.[22][23]

References

  1. ^ a b c Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI (2007). "A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity". Science 316 (5826): 889–94. doi:10.1126/science.1141634. PMC 2646098. PMID 17434869. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2646098. 
  2. ^ a b c Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O'Rahilly S, Schofield CJ (2007). "The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase". Science 318 (5855): 1469–72. doi:10.1126/science.1151710. PMC 2668859. PMID 17991826. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2668859. 
  3. ^ Sanchez-Pulido L, Andrade-Navarro MA (2007). "The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily". BMC Biochem. 8: 23. doi:10.1186/1471-2091-8-23. PMC 2241624. PMID 17996046. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2241624. 
  4. ^ Fredriksson R, Hägglund M, Olszewski PK, Stephansson O, Jacobsson JA, Olszewska AM, Levine AS, Lindblom J, Schiöth HB (2008). "The obesity gene, FTO, is of ancient origin, upregulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain". Endocrinology 149 (5): 2062. doi:10.1210/en.2007-1457. PMID 18218688. 
  5. ^ Olszewski PK, Fredriksson R, Olszewska AM, Stephansson O, Alsio J, Radomska KJ, Levine AS, Schioth HB (October 2009). "Hypothalamic FTO is associated with the regulation of energy intake not feeding reward". BMC Neurosci 10: 129. doi:10.1186/1471-2202-10-129. PMC 2774323. PMID 19860904. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2774323. 
  6. ^ Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, Carlsson LM, Kiess W, Vatin V, Lecoeur C, Delplanque J, Vaillant E, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, Le Stunff C, Bougnères P, Kovacs P, Marre M, Balkau B, Cauchi S, Chèvre JC, Froguel P. (2007). "Variation in FTO contributes to childhood obesity and severe adult obesity.". Nature Genetics 39 (6): 724–6. doi:10.1038/ng2048. PMID 17496892. 
  7. ^ Chu X, Erdman R, Susek M, Gerst H, Derr K, Al-Agha M, Wood GC, Hartman C, Yeager S, Blosky MA, Krum W, Stewart WF, Carey D, Benotti P, Still CD, Gerhard GS (2008). "Association of morbid obesity with FTO and INSIG2 allelic variants". Arch Surg 143 (3): 235–40; discussion 241. doi:10.1001/archsurg.2007.77. PMID 18347269. 
  8. ^ Thorleifsson G, Walters GB, Gudbjartsson DF, et al. (January 2009). "Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.". Nat. Genet. 41 (1): 18–24. doi:10.1038/ng.274. PMID 19079260. 
  9. ^ Willer CJ, Speliotes EK, Loos RJ, et al. (January 2009). "Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.". Nat. Genet. 41 (1): 24–34. doi:10.1038/ng.287. PMC 2695662. PMID 19079261. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2695662. 
  10. ^ Speakman JR, Rance KA, Johnstone AM (August 2008). "Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure". Obesity (Silver Spring) 16 (8): 1961–5. doi:10.1038/oby.2008.318. PMID 18551109. 
  11. ^ Wardle J, Carnell S, Haworth CM, Farooqi IS, O'Rahilly S, Plomin R (September 2008). "Obesity associated genetic variation in FTO is associated with diminished satiety". J. Clin. Endocrinol. Metab. 93 (9): 3640–3. doi:10.1210/jc.2008-0472. PMID 18583465. 
  12. ^ Timpson NJ, Emmett PM, Frayling TM, Rogers I, Hattersley AT, McCarthy MI, Davey Smith G (October 2008). "The fat mass- and obesity-associated locus and dietary intake in children". Am. J. Clin. Nutr. 88 (4): 971–8. PMID 18842783. 
  13. ^ Haupt A, Thamer C, Staiger H, Tschritter O, Kirchhoff K, Machicao F, Häring HU, Stefan N, Fritsche A (April 2009). "Variation in the FTO gene influences food intake but not energy expenditure". Exp. Clin. Endocrinol. Diabetes 117 (4): 194–7. doi:10.1055/s-0028-1087176. PMID 19053021. 
  14. ^ Wardle J, Llewellyn C, Sanderson S, Plomin R (January 2009). "The FTO gene and measured food intake in children". Int J Obes (Lond) 33 (1): 42–5. doi:10.1038/ijo.2008.174. PMID 18838977. 
  15. ^ Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CN (December 2008). "An obesity-associated FTO gene variant and increased energy intake in children". N. Engl. J. Med. 359 (24): 2558–66. doi:10.1056/NEJMoa0803839. PMID 19073975. 
  16. ^ Do R, Bailey SD, Desbiens K, Belisle A, Montpetit A, Bouchard C, Pérusse L, Vohl MC, Engert JC (April 2008). "Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study". Diabetes 57 (4): 1147–50. doi:10.2337/db07-1267. PMID 18316358. 
  17. ^ Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Brüning JC, Rüther U (April 2009). "Inactivation of the Fto gene protects from obesity". Nature 458 (7240): 894–8. doi:10.1038/nature07848. PMID 19234441. 
  18. ^ Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD, Dinov ID, Toga AW, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN, Corneveaux JJ, Stephan DA, DeCarli CS, DeChairo BM, Potkin SG, Jack CR Jr, Weiner MW, Raji CA, Lopez OL, Becker JT, Carmichael OT, Thompson PM; Alzheimer's Disease Neuroimaging Initiative. (2010). "A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly.". Proc Natl Acad Sci U S A 107 (18): 8404–9. doi:10.1073/pnas.0910878107. PMC 2889537. PMID 20404173. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2889537. 
  19. ^ Benedict C, Jacobsson JA, Rönnemaa E, Almén MS, Brooks S, Schultes B, Fredriksson R, Lannfelt L, Kilander L, Schiöth HS. (2011). "The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men.". Neurobiology of Aging. doi:10.1016/j.neurobiolaging.2011.02.006. 
  20. ^ 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.". J Alzheimers Dis. 23 (3): 461–9. PMID 21098976. 
  21. ^ Freathy RM, Timpson NJ, Lawlor DA, Pouta A, Ben-Shlomo Y, Ruokonen A, Ebrahim S, Shields B, Zeggini E, Weedon MN, Lindgren CM, Lango H, Melzer D, Ferrucci L, Paolisso G, Neville MJ, Karpe F, Palmer CN, Morris AD, Elliott P, Jarvelin MR, Smith GD, McCarthy MI, Hattersley AT, Frayling TM (2008). "Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected, given its effect on BMI". Diabetes 57 (5): 1419. doi:10.2337/db07-1466. PMID 18346983. 
  22. ^ Peters T, Ausmeier K, Rüther U (1999). "Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation". Mamm. Genome 10 (10): 983–6. doi:10.1007/s003359901144. PMID 10501967. 
  23. ^ Kim B, Kim Y, Cooke PS, Rüther U, Jorgensen JS (2011). "The fused toes locus is essential for somatic-germ cell interactions that foster germ cell maturation in developing gonads in mice.". Biol Reprod 84 (5): 1024–32. doi:10.1095/biolreprod.110.088559. PMID 21293032. http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21293032. 

External links