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Wikipedia

FTO gene

January 01, 1970

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.[5] Certain alleles of the FTO gene appear to be correlated with obesity in humans.[6][7]

FTO
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFTO, ALKBH9, GDFD, BMIQ14, fat mass and obesity associated, alpha-ketoglutarate dependent dioxygenase
External IDsOMIM: 610966 MGI: 1347093 HomoloGene: 8053 GeneCards: FTO
Orthologs
SpeciesHumanMouse
Entrez

79068

26383

Ensembl

ENSG00000140718

ENSMUSG00000055932

UniProt

Q9C0B1

Q8BGW1

RefSeq (mRNA)

NM_001080432

NM_011936

RefSeq (protein)

NP_036066

Location (UCSC)Chr 16: 53.7 – 54.16 MbChr 8: 92.04 – 92.4 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function edit

The amino acid sequence of the transcribed FTO protein shows high similarity with the enzyme AlkB which oxidatively demethylates DNA.[8][9] 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.[8] The nucleoside N6-methyladenosine (m6A), an abundant modification in RNA, was then found to be a major substrate of FTO.[5][10] 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.[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 via fMRI.[13] However, rs9939609's association with FTO is controversial, and may actually affect another gene, called Iroquois homeobox protein 3 (IRX3).[14]

FTO demethylates RNA edit

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] 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.[10] 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.[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 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.[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]

Tissue distribution edit

The FTO gene is widely expressed in both fetal and adult tissues.[19]

Clinical significance edit

Obesity edit

 
Fat Mass and Obesity-Associated (FTO) Protein

38,759 Europeans were studied for variants of FTO obesity risk allele.[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 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.[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 of SNPs in the very same region of FTO (rs1421085).[21] 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.[22]

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).[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 normalised 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 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.[32] The transcription factor CUX1 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 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.[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 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.[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 proteine ARID5B, the single-nucleotide variant rs1421085, and the IRX3 and IRX5 genes.[40]

Alzheimer's disease edit

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]

Other diseases edit

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.[44] Similarly, the association of rs11076008 G allele with the increased risk for degenerative disc disease was reported.[45]

Origin of name edit

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.[46][47]

References edit

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External links edit

  • FTO protein, human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  • Catharine Paddock (2007-04-13). "Obesity Gene Discovered". Medical News Today. Retrieved 2008-03-22.
  • Overview of all the structural information available in the PDB for UniProt: Q9C0B1 (Alpha-ketoglutarate-dependent dioxygenase FTO) at the PDBe-KB.

January 01, 1970
gene, mass, obesity, associated, protein, also, known, alpha, ketoglutarate, dependent, dioxygenase, enzyme, that, humans, encoded, located, chromosome, homolog, alkb, family, proteins, first, mrna, demethylase, that, been, identified, certain, alleles, appear. 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 5 Certain alleles of the FTO gene appear to be correlated with obesity in humans 6 7 FTOAvailable structuresPDBOrtholog search PDBe RCSBList of PDB id codes3LFM 4IDZ 4IE0 4IE4 4IE5 4IE6 4IE7 4CXW 4CXX 4CXY 4QHO 4QKN 4ZS3 4ZS2IdentifiersAliasesFTO ALKBH9 GDFD BMIQ14 fat mass and obesity associated alpha ketoglutarate dependent dioxygenaseExternal IDsOMIM 610966 MGI 1347093 HomoloGene 8053 GeneCards FTOGene location Human Chr Chromosome 16 human 1 Band16q12 2Start53 701 692 bp 1 End54 158 512 bp 1 Gene location Mouse Chr Chromosome 8 mouse 2 Band8 C5 8 44 34 cMStart92 040 153 bp 2 End92 395 067 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inbronchial epithelial cellBrodmann area 10middle frontal gyrusfrontal polecorpus callosumlactiferous ductinferior olivary nucleusBrodmann area 46postcentral gyrusentorhinal cortexTop expressed inventral tegmental areasuperior colliculusdorsal tegmental nucleusdorsomedial hypothalamic nucleushabenulapontine nucleisubiculuminferior colliculusparaventricular nucleus of hypothalamuslateral hypothalamusMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionoxidative DNA demethylase activity dioxygenase activity metal ion binding DNA N1 methyladenine dioxygenase activity oxidoreductase activity ferrous iron binding mRNA N6 methyladenosine dioxygenase activity oxidative RNA demethylase activityCellular componentnuclear speck nucleus nucleoplasmBiological processregulation of multicellular organism growth regulation of respiratory system process regulation of white fat cell proliferation cellular response to DNA damage stimulus oxidative demethylation oxidative single stranded RNA demethylation regulation of lipid storage RNA repair adipose tissue development DNA demethylation regulation of brown fat cell differentiation temperature homeostasis oxidative single stranded DNA demethylation DNA repair DNA dealkylation involved in DNA repairSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez7906826383EnsemblENSG00000140718ENSMUSG00000055932UniProtQ9C0B1Q8BGW1RefSeq mRNA NM 001080432NM 011936RefSeq protein NP 001073901NP 001350820NP 001350823NP 001350825NP 001350826NP 001350827NP 001350828NP 001350829NP 001350830NP 001350832NP 001350834NP 001350917NP 036066Location UCSC Chr 16 53 7 54 16 MbChr 8 92 04 92 4 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Function 2 FTO demethylates RNA 3 Tissue distribution 4 Clinical significance 4 1 Obesity 4 2 Alzheimer s disease 4 3 Other diseases 5 Origin of name 6 References 7 External linksFunction editThe amino acid sequence of the transcribed FTO protein shows high similarity with the enzyme AlkB which oxidatively demethylates DNA 8 9 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 8 The nucleoside N6 methyladenosine m6A an abundant modification in RNA was then found to be a major substrate of FTO 5 10 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 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 via fMRI 13 However rs9939609 s association with FTO is controversial and may actually affect another gene called Iroquois homeobox protein 3 IRX3 14 FTO demethylates RNA editFTO 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 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 10 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 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 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 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 Tissue distribution editThe FTO gene is widely expressed in both fetal and adult tissues 19 Clinical significance editObesity edit nbsp Fat Mass and Obesity Associated FTO Protein 38 759 Europeans were studied for variants of FTO obesity risk allele 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 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 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 of SNPs in the very same region of FTO rs1421085 21 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 22 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 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 normalised 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 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 32 The transcription factor CUX1 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 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 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 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 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 proteine ARID5B the single nucleotide variant rs1421085 and the IRX3 and IRX5 genes 40 Alzheimer s disease edit 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 Other diseases edit 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 44 Similarly the association of rs11076008 G allele with the increased risk for degenerative disc disease was reported 45 Origin of name editBy 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 46 47 References edit a b c GRCh38 Ensembl release 89 ENSG00000140718 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000055932 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine a b c d Jia G Fu Y Zhao X Dai Q Zheng G Yang Y Yi C Lindahl T Pan T Yang YG He C October 2011 N6 methyladenosine in nuclear RNA is a major substrate of the obesity associated FTO Nature Chemical Biology 7 12 885 7 doi 10 1038 nchembio 687 PMC 3218240 PMID 22002720 Loos RJ Yeo GS January 2014 The bigger picture of FTO the first GWAS identified obesity gene Nature Reviews Endocrinology 10 1 51 61 doi 10 1038 nrendo 2013 227 PMC 4188449 PMID 24247219 Claussnitzer M Dankel SN Kim KH Quon G Meuleman W Haugen C et al September 2015 FTO Obesity Variant Circuitry and Adipocyte Browning in Humans The New England Journal of Medicine 373 10 895 907 doi 10 1056 NEJMoa1502214 PMC 4959911 PMID 26287746 a b 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 November 2007 The obesity associated FTO gene encodes a 2 oxoglutarate dependent nucleic acid demethylase Science 318 5855 1469 72 Bibcode 2007Sci 318 1469G doi 10 1126 science 1151710 PMC 2668859 PMID 17991826 Sanchez Pulido L Andrade Navarro MA November 2007 The FTO fat mass and obesity associated gene codes for a novel member of the non heme dioxygenase superfamily BMC Biochemistry 8 23 doi 10 1186 1471 2091 8 23 PMC 2241624 PMID 17996046 a b c Meyer KD Saletore Y Zumbo P Elemento O Mason CE Jaffrey SR June 2012 Comprehensive analysis of mRNA methylation reveals enrichment in 3 UTRs and near stop codons Cell 149 7 1635 46 doi 10 1016 j cell 2012 05 003 PMC 3383396 PMID 22608085 Fredriksson R Hagglund M Olszewski PK Stephansson O Jacobsson JA Olszewska AM Levine AS Lindblom J Schioth HB May 2008 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 doi 10 1210 en 2007 1457 PMID 18218688 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 Neuroscience 10 129 doi 10 1186 1471 2202 10 129 PMC 2774323 PMID 19860904 Wiemerslage L Nilsson EK Solstrand Dahlberg L Ence Eriksson F Castillo S Larsen AL Bylund SB Hogenkamp PS Olivo G Bandstein M Titova OE Larsson EM Benedict C Brooks SJ Schioth HB May 2016 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 PDF The European Journal of Neuroscience 43 9 1173 80 doi 10 1111 ejn 13177 PMID 26797854 S2CID 4538964 Rask Andersen M Almen MS Schioth HB November 2015 Scrutinizing the FTO locus compelling evidence for a complex long range regulatory context Human Genetics 134 11 12 1183 93 doi 10 1007 s00439 015 1599 5 PMID 26340902 S2CID 16199296 a b Mauer J Luo X Blanjoie A Jiao X Grozhik AV Patil DP Linder B Pickering BF Vasseur JJ Chen Q Gross SS Elemento O Debart F Kiledjian M Jaffrey SR January 2017 Reversible methylation of m6Am in the 5 cap controls mRNA stability Nature 541 7637 371 375 Bibcode 2017Natur 541 371M doi 10 1038 nature21022 PMC 5513158 PMID 28002401 Fu Y Jia G Pang X Wang RN Wang X Li CJ et al 2013 FTO mediated formation of N6 hydroxymethyladenosine and N6 formyladenosine in mammalian RNA Nature Communications 4 1798 Bibcode 2013NatCo 4 1798F doi 10 1038 ncomms2822 PMC 3658177 PMID 23653210 Yu Q Liu S Yu L Xiao Y Zhang S Wang X et al July 2021 RNA demethylation increases the yield and biomass of rice and potato plants in field trials Nature Biotechnology 39 12 1581 1588 doi 10 1038 s41587 021 00982 9 PMID 34294912 S2CID 236197910 Lay summary in Kim SE August 17 2021 Researchers Transfer a Human Protein Into Plants to Supersize Them Smithsonian Magazine Wei Jiangbo Yu Xianbin Yang Lei Liu Xuelian Gao Boyang Huang Boxian Dou Xiaoyang Liu Jun Zou Zhongyu Cui Xiao Long Zhang Li Sheng Zhao Xingsen Liu Qinzhe He P Cody Sepich Poore Caraline 2022 05 27 FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development Science 376 6596 968 973 Bibcode 2022Sci 376 968W doi 10 1126 science abe9582 ISSN 1095 9203 PMC 9746489 PMID 35511947 a b Frayling TM Timpson NJ Weedon MN Zeggini E Freathy RM Lindgren CM et al May 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 Bibcode 2007Sci 316 889F doi 10 1126 science 1141634 PMC 2646098 PMID 17434869 Sandholt CH Hansen T Pedersen O July 2012 Beyond the fourth wave of genome wide obesity association studies Nutrition amp Diabetes 2 7 e37 doi 10 1038 nutd 2012 9 PMC 3408643 PMID 23168490 Dina C Meyre D Gallina S Durand E Korner 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 Bougneres P Kovacs P Marre M Balkau B Cauchi S Chevre JC Froguel P June 2007 Variation in FTO contributes to childhood obesity and severe adult obesity Nature Genetics 39 6 724 6 doi 10 1038 ng2048 PMID 17496892 S2CID 3248168 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 March 2008 Association of morbid obesity with FTO and INSIG2 allelic variants Archives of Surgery 143 3 235 40 discussion 241 doi 10 1001 archsurg 2007 77 PMID 18347269 Thorleifsson G Walters GB Gudbjartsson DF Steinthorsdottir V Sulem P Helgadottir A Styrkarsdottir U Gretarsdottir S Thorlacius S Jonsdottir I Jonsdottir T Olafsdottir EJ Olafsdottir GH Jonsson T Jonsson F Borch Johnsen K Hansen T Andersen G Jorgensen T Lauritzen T Aben KK Verbeek AL Roeleveld N Kampman E Yanek LR Becker LC Tryggvadottir L Rafnar T Becker DM Gulcher J Kiemeney LA Pedersen O Kong A Thorsteinsdottir U Stefansson K 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 PMID 19079260 S2CID 764409 Willer CJ Speliotes EK Loos RJ Li S Lindgren CM Heid IM et al January 2009 Six new loci associated with body mass index highlight a neuronal influence on body weight regulation Nature Genetics 41 1 25 34 doi 10 1038 ng 287 PMC 2695662 PMID 19079261 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 16 8 1961 5 doi 10 1038 oby 2008 318 PMID 18551109 S2CID 33151950 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 The Journal of Clinical Endocrinology and Metabolism 93 9 3640 3 doi 10 1210 jc 2008 0472 PMID 18583465 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 The American Journal of Clinical Nutrition 88 4 971 8 doi 10 1093 ajcn 88 4 971 PMC 4773885 PMID 18842783 Haupt A Thamer C Staiger H Tschritter O Kirchhoff K Machicao F Haring HU Stefan N Fritsche A April 2009 Variation in the FTO gene influences food intake but not energy expenditure Experimental and Clinical Endocrinology amp Diabetes 117 4 194 7 doi 10 1055 s 0028 1087176 PMID 19053021 Wardle J Llewellyn C Sanderson S Plomin R January 2009 The FTO gene and measured food intake in children International Journal of Obesity 33 1 42 5 doi 10 1038 ijo 2008 174 PMID 18838977 Cecil JE Tavendale R Watt P Hetherington MM Palmer CN December 2008 An obesity associated FTO gene variant and increased energy intake in children The New England Journal of Medicine 359 24 2558 66 doi 10 1056 NEJMoa0803839 PMID 19073975 Do R Bailey SD Desbiens K Belisle A Montpetit A Bouchard C Perusse 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 a b Wang L De Solis AJ Goffer Y Birkenbach KE Engle SE Tanis R et al February 2019 Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development JCI Insight 4 3 doi 10 1172 jci insight 123337 PMC 6413800 PMID 30728336 Stratigopoulos G LeDuc CA Cremona ML Chung WK Leibel RL January 2011 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 doi 10 1074 jbc m110 188482 PMC 3023512 PMID 21037323 Stratigopoulos G Padilla SL LeDuc CA Watson E Hattersley AT McCarthy MI et al April 2008 Regulation of Fto Ftm gene expression in mice and humans American Journal of Physiology Regulatory Integrative and Comparative Physiology 294 4 R1185 96 doi 10 1152 ajpregu 00839 2007 PMC 2808712 PMID 18256137 a b Stratigopoulos G Martin Carli JF O Day DR Wang L Leduc CA Lanzano P et al May 2014 Hypomorphism for RPGRIP1L a ciliary gene vicinal to the FTO locus causes increased adiposity in mice Cell Metabolism 19 5 767 79 doi 10 1016 j cmet 2014 04 009 PMC 4131684 PMID 24807221 a b Stratigopoulos G Burnett LC Rausch R Gill R Penn DB Skowronski AA et al May 2016 Hypomorphism of Fto and Rpgrip1l causes obesity in mice The Journal of Clinical Investigation 126 5 1897 910 doi 10 1172 JCI85526 PMC 4855930 PMID 27064284 Lewis WR Bales KL Revell DZ Croyle MJ Engle SE Song CJ et al January 2019 Mks6 mutations reveal tissue and cell type specific roles for the cilia transition zone FASEB Journal 33 1 1440 1455 doi 10 1096 fj 201801149R PMC 6355093 PMID 30133325 Smemo S Tena JJ Kim KH Gamazon ER Sakabe NJ Gomez Marin C Aneas I Credidio FL Sobreira DR Wasserman NF Lee JH Puviindran V Tam D Shen M Son JE Vakili NA Sung HK Naranjo S Acemel RD Manzanares M Nagy A Cox NJ Hui CC Gomez Skarmeta JL Nobrega MA March 2014 Obesity associated variants within FTO form long range functional connections with IRX3 Nature 507 7492 371 5 Bibcode 2014Natur 507 371S doi 10 1038 nature13138 PMC 4113484 PMID 24646999 Harrison P 19 August 2015 Obesity Genetics New Insights Might Mean New Therapies Medscape Claussnitzer M Dankel SN Kim KH Quon G Meuleman W Haugen C Glunk V Sousa IS Beaudry JL Puviindran V Abdennur NA Liu J Svensson PA Hsu YH Drucker DJ Mellgren G Hui CC Hauner H Kellis M September 2015 FTO Obesity Variant Circuitry and Adipocyte Browning in Humans The New England Journal of Medicine 373 10 895 907 doi 10 1056 NEJMoa1502214 PMC 4959911 PMID 26287746 Ho AJ Stein JL Hua X Lee S Hibar DP Leow AD et al May 2010 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 Bibcode 2010PNAS 107 8404H doi 10 1073 pnas 0910878107 PMC 2889537 PMID 20404173 Benedict C Jacobsson JA Ronnemaa E Sallman Almen M Brooks S Schultes B Fredriksson R Lannfelt L Kilander L Schioth HB 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 5 doi 10 1016 j neurobiolaging 2011 02 006 PMID 21458110 S2CID 20051507 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 9 doi 10 3233 JAD 2010 101068 PMID 21098976 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 May 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 26 doi 10 2337 db07 1466 PMC 3073395 PMID 18346983 Lao L Zhong G Li X Liu Z February 2014 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 doi 10 1177 0300060513503761 PMID 24304927 Peters T Ausmeier K Ruther U October 1999 Cloning of Fatso Fto a novel gene deleted by the Fused toes Ft mouse mutation Mammalian Genome 10 10 983 6 doi 10 1007 s003359901144 PMID 10501967 S2CID 20362657 Kim B Kim Y Cooke PS Ruther U Jorgensen JS May 2011 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 doi 10 1095 biolreprod 110 088559 PMID 21293032 External links editFTO protein human at the U S National Library of Medicine Medical Subject Headings MeSH Catharine Paddock 2007 04 13 Obesity Gene Discovered Medical News Today Retrieved 2008 03 22 Overview of all the structural information available in the PDB for UniProt Q9C0B1 Alpha ketoglutarate dependent dioxygenase FTO at the PDBe KB Portal nbsp Biology Retrieved from https en wikipedia org w index php title FTO gene amp oldid 1215824546, wikipedia, wiki, book, books, library,

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