Biology:FTO gene

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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. As one homolog in the AlkB family proteins, it is the first mRNA demethylase that has been identified.[1] Certain alleles of the FTO gene appear to be correlated with obesity in humans.[2][3]

Function

The amino acid sequence of the transcribed FTO protein shows high similarity with the enzyme AlkB which oxidatively demethylates DNA.[4][5] FTO is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylase, which are non-heme iron-containing proteins. Recombinant FTO protein was first discovered to catalyze demethylation of 3-methylthymine in single-stranded DNA, and 3-methyluridine in single-stranded RNA, with low efficiency.[4] The nucleoside N6-methyladenosine (m6A), an abundant modification in RNA, was then found to be a major substrate of FTO.[1][6] 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 orexigenic galanin-like peptide which is involved in the stimulation of food intake.[7]

Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward.[8]

People with two copies of the risk allele for the rs9939609 single nucleotide polymorphism (SNP) showed differing neural responses to food images via fMRI.[9] However, rs9939609's association with FTO is controversial, and may actually affect another gene, called Iroquois homeobox protein 3 (IRX3).[10]

FTO demethylates RNA

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 .[1][11] FTO knockdown with siRNA led to increased amounts of m6A in polyA-RNA, whereas overexpression of FTO resulted in decreased amounts of m6A in human cells.[6] FTO partially co-localizes with nuclear speckles, which supports the notion that in the nucleus, m6A can be a substrate of FTO. Function of FTO could affect the processing of pre-mRNA, other nuclear RNAs, or both. The discovery of the FTO-mediated oxidative demethylation 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.[1][6][11]

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.[12]

Plants do not carry orthologs of FTO and artificial introduction of an FTO transgene 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.[13] 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.[14]

Tissue distribution

The FTO gene is widely expressed in both fetal and adult tissues.[15]

Clinical significance

Obesity

Fat Mass and Obesity-Associated (FTO) Protein

38,759 Europeans were studied for variants of FTO obesity risk allele.[15] 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.[16]

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 of SNPs in the very same region of FTO (rs1421085).[17] 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.[18]

In 2009, variants in the FTO gene were further confirmed to associate with obesity in two very large genome wide association studies of body mass index (BMI).[19][20]

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).[21] 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).[22][23][24][25][26] 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.[27] 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 hypothalamic neurons derived from individuals carrying the obesity-risk variation at FTO SNPs rs1421085 or rs8050136 express lower levels of the adjacent gene RPGRIP1L compared to individuals carrying the protective variation.[28] The transcription factor CUX1 binds DNA at rs1421085 or rs8050136 in the presence of the protective variation and promotes RPGRIP1L expression[29][30] 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,[31][32][33] with no changes in energy expenditure, in agreement with data accumulated in human studies. RPGRIP1L is a protein found in primary cilia 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 hormone leptin that suppresses feeding, as well as alters the morphology of the hypothalamus that controls food consumption.[28][31][32] 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 of IRX3, a homeobox gene, and IRX5, 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-associated single 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 in mitochondrial thermogenesis by a factor of 5.[34][35] 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 proteine ARID5B, the single-nucleotide variant rs1421085, and the IRX3 and IRX5 genes.[36]

Alzheimer's disease

Recent studies revealed that carriers of common FTO gene polymorphisms show both a reduction in frontal lobe volume of the brain[37] and an impaired verbal fluency performance.[38] Fittingly, a population-based study from Sweden found that carriers of the FTO rs9939609 A allele have an increased risk for incident Alzheimer disease.[39]

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.[40] Similarly, the association of rs11076008 G allele with the increased risk for degenerative disc disease was reported.[41]

Origin of name

By exon 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.[42][43]

References

  1. ↑ 1.0 1.1 1.2 1.3 "N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO". Nature Chemical Biology 7 (12): 885–7. October 2011. doi:10.1038/nchembio.687. PMID 22002720. 
  2. ↑ "The bigger picture of FTO: the first GWAS-identified obesity gene". Nature Reviews. Endocrinology 10 (1): 51–61. January 2014. doi:10.1038/nrendo.2013.227. PMID 24247219. 
  3. ↑ "FTO Obesity Variant Circuitry and Adipocyte Browning in Humans". The New England Journal of Medicine 373 (10): 895–907. September 2015. doi:10.1056/NEJMoa1502214. PMID 26287746. 
  4. ↑ 4.0 4.1 "The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase". Science 318 (5855): 1469–72. November 2007. doi:10.1126/science.1151710. PMID 17991826. Bibcode: 2007Sci...318.1469G. 
  5. ↑ "The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily". BMC Biochemistry 8: 23. November 2007. doi:10.1186/1471-2091-8-23. PMID 17996046. 
  6. ↑ 6.0 6.1 6.2 "Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons". Cell 149 (7): 1635–46. June 2012. doi:10.1016/j.cell.2012.05.003. PMID 22608085. 
  7. ↑ "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 149 (5): 2062–71. May 2008. doi:10.1210/en.2007-1457. PMID 18218688. 
  8. ↑ "Hypothalamic FTO is associated with the regulation of energy intake not feeding reward". BMC Neuroscience 10: 129. October 2009. doi:10.1186/1471-2202-10-129. PMID 19860904. 
  9. ↑ "An obesity-associated risk allele within the FTO gene affects human brain activity for areas important for emotion, impulse control and reward in response to food images". The European Journal of Neuroscience 43 (9): 1173–80. May 2016. doi:10.1111/ejn.13177. PMID 26797854. http://researchonline.ljmu.ac.uk/9287/3/EJN-2015-09-23036_revizdManuscript.pdf. 
  10. ↑ "Scrutinizing the FTO locus: compelling evidence for a complex, long-range regulatory context". Human Genetics 134 (11–12): 1183–93. November 2015. doi:10.1007/s00439-015-1599-5. PMID 26340902. 
  11. ↑ 11.0 11.1 "Reversible methylation of m6Am in the 5' cap controls mRNA stability" (in En). Nature 541 (7637): 371–375. January 2017. doi:10.1038/nature21022. PMID 28002401. Bibcode: 2017Natur.541..371M. 
  12. ↑ "FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA". Nature Communications 4: 1798. 2013. doi:10.1038/ncomms2822. PMID 23653210. Bibcode: 2013NatCo...4.1798F. 
  13. ↑ "RNA demethylation increases the yield and biomass of rice and potato plants in field trials". Nature Biotechnology 39 (12): 1581–1588. July 2021. doi:10.1038/s41587-021-00982-9. PMID 34294912. *Lay summary in: "Researchers Transfer a Human Protein Into Plants to Supersize Them". August 17, 2021. https://www.smithsonianmag.com/innovation/researchers-transfer-human-protein-plants-supersize-them-180978443/. 
  14. ↑ Wei, Jiangbo; Yu, Xianbin; Yang, Lei; Liu, Xuelian; Gao, Boyang; Huang, Boxian; Dou, Xiaoyang; Liu, Jun et al. (2022-05-27). "FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development". Science 376 (6596): 968–973. doi:10.1126/science.abe9582. ISSN 1095-9203. PMID 35511947. Bibcode: 2022Sci...376..968W. 
  15. ↑ 15.0 15.1 "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. May 2007. doi:10.1126/science.1141634. PMID 17434869. Bibcode: 2007Sci...316..889F. 
  16. ↑ "Beyond the fourth wave of genome-wide obesity association studies". Nutrition & Diabetes 2 (7): e37. July 2012. doi:10.1038/nutd.2012.9. PMID 23168490. 
  17. ↑ "Variation in FTO contributes to childhood obesity and severe adult obesity". Nature Genetics 39 (6): 724–6. June 2007. doi:10.1038/ng2048. PMID 17496892. 
  18. ↑ "Association of morbid obesity with FTO and INSIG2 allelic variants". Archives of Surgery 143 (3): 235–40; discussion 241. March 2008. doi:10.1001/archsurg.2007.77. PMID 18347269. 
  19. ↑ "Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity". Nature Genetics 41 (1): 18–24. January 2009. doi:10.1038/ng.274. PMID 19079260. 
  20. ↑ "Six new loci associated with body mass index highlight a neuronal influence on body weight regulation". Nature Genetics 41 (1): 25–34. January 2009. doi:10.1038/ng.287. PMID 19079261. 
  21. ↑ "Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure". Obesity 16 (8): 1961–5. August 2008. doi:10.1038/oby.2008.318. PMID 18551109. 
  22. ↑ "Obesity associated genetic variation in FTO is associated with diminished satiety". The Journal of Clinical Endocrinology and Metabolism 93 (9): 3640–3. September 2008. doi:10.1210/jc.2008-0472. PMID 18583465. 
  23. ↑ "The fat mass- and obesity-associated locus and dietary intake in children". The American Journal of Clinical Nutrition 88 (4): 971–8. October 2008. doi:10.1093/ajcn/88.4.971. PMID 18842783. 
  24. ↑ "Variation in the FTO gene influences food intake but not energy expenditure". Experimental and Clinical Endocrinology & Diabetes 117 (4): 194–7. April 2009. doi:10.1055/s-0028-1087176. PMID 19053021. 
  25. ↑ "The FTO gene and measured food intake in children". International Journal of Obesity 33 (1): 42–5. January 2009. doi:10.1038/ijo.2008.174. PMID 18838977. 
  26. ↑ "An obesity-associated FTO gene variant and increased energy intake in children". The New England Journal of Medicine 359 (24): 2558–66. December 2008. doi:10.1056/NEJMoa0803839. PMID 19073975. 
  27. ↑ "Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study". Diabetes 57 (4): 1147–50. April 2008. doi:10.2337/db07-1267. PMID 18316358. 
  28. ↑ 28.0 28.1 "Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development". JCI Insight 4 (3). February 2019. doi:10.1172/jci.insight.123337. PMID 30728336. 
  29. ↑ "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". The Journal of Biological Chemistry 286 (3): 2155–70. January 2011. doi:10.1074/jbc.m110.188482. PMID 21037323. 
  30. ↑ "Regulation of Fto/Ftm gene expression in mice and humans". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 294 (4): R1185-96. April 2008. doi:10.1152/ajpregu.00839.2007. PMID 18256137. 
  31. ↑ 31.0 31.1 "Hypomorphism for RPGRIP1L, a ciliary gene vicinal to the FTO locus, causes increased adiposity in mice". Cell Metabolism 19 (5): 767–79. May 2014. doi:10.1016/j.cmet.2014.04.009. PMID 24807221. 
  32. ↑ 32.0 32.1 "Hypomorphism of Fto and Rpgrip1l causes obesity in mice". The Journal of Clinical Investigation 126 (5): 1897–910. May 2016. doi:10.1172/JCI85526. PMID 27064284. 
  33. ↑ "Mks6 mutations reveal tissue- and cell type-specific roles for the cilia transition zone". FASEB Journal 33 (1): 1440–1455. January 2019. doi:10.1096/fj.201801149R. PMID 30133325. 
  34. ↑ "Obesity-associated variants within FTO form long-range functional connections with IRX3". Nature 507 (7492): 371–5. March 2014. doi:10.1038/nature13138. PMID 24646999. Bibcode: 2014Natur.507..371S. 
  35. ↑ "Obesity Genetics: New Insights Might Mean New Therapies". Medscape. 19 August 2015. http://www.medscape.com/viewarticle/849799. 
  36. ↑ "FTO Obesity Variant Circuitry and Adipocyte Browning in Humans". The New England Journal of Medicine 373 (10): 895–907. September 2015. doi:10.1056/NEJMoa1502214. PMID 26287746. 
  37. ↑ "A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly". Proceedings of the National Academy of Sciences of the United States of America 107 (18): 8404–9. May 2010. doi:10.1073/pnas.0910878107. PMID 20404173. Bibcode: 2010PNAS..107.8404H. 
  38. ↑ "The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men". Neurobiology of Aging 32 (6): 1159.e1–5. June 2011. doi:10.1016/j.neurobiolaging.2011.02.006. PMID 21458110. 
  39. ↑ "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): 461–9. 2011. doi:10.3233/JAD-2010-101068. PMID 21098976. 
  40. ↑ "Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI". Diabetes 57 (5): 1419–26. May 2008. doi:10.2337/db07-1466. PMID 18346983. 
  41. ↑ "A preliminary association study of fat mass and obesity associated gene polymorphisms and degenerative disc disease in a Chinese Han population". The Journal of International Medical Research 42 (1): 205–12. February 2014. doi:10.1177/0300060513503761. PMID 24304927. 
  42. ↑ "Cloning of Fatso (Fto), a novel gene deleted by the Fused toes (Ft) mouse mutation". Mammalian Genome 10 (10): 983–6. October 1999. doi:10.1007/s003359901144. PMID 10501967. 
  43. ↑ "The fused toes locus is essential for somatic-germ cell interactions that foster germ cell maturation in developing gonads in mice". Biology of Reproduction 84 (5): 1024–32. May 2011. doi:10.1095/biolreprod.110.088559. PMID 21293032. 

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