FTO gene

Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an is_associated_with::enzyme that in humans is encoded by the FTO is_associated_with::gene located on chromosome 16. As one homolog in the is_associated_with::AlkB family proteins, it is the first mRNA demethylase that has been identified. Certain variants of the FTO gene appear to be is_associated_with::correlated with is_associated_with::obesity in is_associated_with::humans.

Function
The is_associated_with::amino acid sequence of the transcribed FTO protein shows high similarity with the enzyme is_associated_with::AlkB which oxidatively demethylates is_associated_with::DNA. 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. The is_associated_with::nucleoside is_associated_with::N6-methyladenosine, an abundant modification in is_associated_with::RNA, was then found to be a major substrate of FTO. The FTO gene expression was also found to be significantly upregulated in the is_associated_with::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.

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

FTO demethylates m6A in mRNA
N6-methyladenosine''' is_associated_with::(m6A) is an abundant modification in is_associated_with::mRNA and is found within some viruses,  and most eukaryotes including mammals,    insects, plants,   and yeast. It is also found in is_associated_with::tRNA, is_associated_with::rRNA, and is_associated_with::small nuclear RNA (snRNA) as well as several is_associated_with::long non-coding RNA, such as is_associated_with::Xist. Adenosine methylation is directed by a large m6A methyltransferase complex containing is_associated_with::METTL3 as the SAM-binding sub-unit. In vitro, this methyltransferase complex preferentially methylates RNA oligonucleotides containing GGACU and a similar preference was identified in vivo in mapped m6A sites in Rous sarcoma virus genomic RNA and in bovine prolactin mRNA. In plants, the majority of the m6A is found within 150 nucleotides before the start of the is_associated_with::poly(A) tail.

Mapping of m6A in human and mouse RNA has identified over 18,000 m6A sites in the transcripts of more than 7,000 human genes with a is_associated_with::consensus sequence of [G/A/U][G>A]m6AC[U>A/C]<  consistent with the previously identified motif. Sites preferentially appear in two distinct landmarks—around is_associated_with::stop codons and within long internal is_associated_with::exons—and are highly conserved between is_associated_with::human and is_associated_with::mouse. A subset of stimulus-dependent, dynamically modulated sites has been identified. Silencing the m6A is_associated_with::methyltransferase significantly affects gene expression and alternative is_associated_with::RNA splicing patterns, resulting in modulation of the is_associated_with::p53 (also known as is_associated_with::TP53) signalling pathway and is_associated_with::apoptosis.

FTO demethylates m6A containing RNA efficiently in vitro. FTO knockdown with is_associated_with::siRNA led to increased amounts of m6A in polyA-RNA, whereas is_associated_with::overexpression of FTO resulted in decreased amounts of m6A in human cells. FTO partially co-localizes with is_associated_with::nuclear speckles, which supports the notion that m6A in nuclear RNA is a major physiological substrate of FTO. Function of FTO likely affects the processing of is_associated_with::pre-mRNA, other nuclear RNAs, or both. The discovery of the FTO-mediated oxidative is_associated_with::demethylation of m6A in nuclear RNA may initiate further investigations on biological regulation based on reversible chemical modification of RNA.

Tissue distribution
The FTO gene is widely expressed in both fetal and adult tissues.

Association with obesity
A study of 38,759 Europeans for variants of FTO identified an obesity risk is_associated_with::allele. In particular, carriers of one copy of the allele weighed on average 1.2 kg more than people with no copies. Carriers of two copies (16% of the subjects) weighed 3 kg 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 is_associated_with::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 (is_associated_with::rs1421085). 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 is_associated_with::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 is_associated_with::single nucleotide polymorphism in the first is_associated_with::intron of FTO called rs9939609. According to is_associated_with::HapMap, it has population frequencies of 45% in the West/Central Europeans, 52% in Yorubans (West African natives) and 14% in Chinese/Japanese. Furthermore is_associated_with::morbid obesity is associated with a combination of FTO and is_associated_with::INSIG2 is_associated_with::single nucleotide polymorphisms.

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

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). 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). 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. 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.

The obesity-associated noncoding region within the FTO gene interacts directly with the promoter of is_associated_with::IRX3, a homeobox gene. This noncoding region of FTO interacts with the promoters of IRX3 and FTO in human, mouse and zebrafish. Results suggest that IRX3 is linked with obesity and determines body mass and composition. This is further supported by the fact that obesity-associated is_associated_with::single nucleotide polymorphisms are involved in the expression of IRX3 (not FTO) in human brains.

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 and an impaired verbal fluency performance. Fittingly, a population-based study from Sweden found that carriers of the FTO rs9939609 A allele have an increased risk for incident Alzheimer disease.

Association with other diseases
The presence of the FTO rs9939609 A allele was also found to be positively correlated with other symptoms of the is_associated_with::metabolic syndrome, including higher fasting insulin, glucose, and triglycerides, and lower is_associated_with::HDL cholesterol. However all these effects appear to be secondary to weight increase since no association was found after correcting for increases in is_associated_with::body mass index. Similarly, the association of rs11076008 G allele with the increased risk for is_associated_with::degenerative disc disease was reported.

Model organisms
is_associated_with::Model organisms have been used in the study of FTO function. In contrast to the findings in humans deletion, analysis of the Fto gene in mice showed loss of function is associated with no differences in energy intake but greater energy expenditure and this results in a reduction of body weight and fatness. Another conditional is_associated_with::knockout mouse line, called Ftotm1a(EUCOMM)Wtsi was generated as part of the is_associated_with::International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals from this line underwent a standardized is_associated_with::phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on is_associated_with::mutant mice and only significant skeletal abnormalities were observed, including is_associated_with::kyphosis and abnormal vertebral is_associated_with::transverse processes, and only in female is_associated_with::homozygous mutant animals.

The reasons for the differences in FTO is_associated_with::phenotype between humans and different lines of mice is presently uncertain. However, many other genes involved in regulation of energy balance exert effects on both intake and expenditure.

Origin of name
By is_associated_with::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.