FTO gene
Encyclopedia
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 human
s.
sequence
of the transcribed
FTO protein shows high homology
with the enzyme AlkB
which oxidatively demethylates
DNA
. Furthermore recombinant FTO protein catalyzes demethylation of 3-methylthymine in single-stranded DNA. 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.
Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward.
. 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) 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 polymorphism
s.
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).
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.
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. 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.
, 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
.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the FTO gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
located on chromosome 16
Chromosome 16 (human)
125px|rightChromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs and represents just under 3 % of the total DNA in cells.Identifying genes on each chromosome is an active area of genetic...
. Certain variants of the FTO gene appear to be correlated with obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
in human
Human
Humans are the only living species in the Homo genus...
s.
Function
The amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence
Sequence (biology)
A sequence in biology is the one-dimensional ordering of monomers, covalently linked within in a biopolymer; it is also referred to as the primary structure of the biological macromolecule.-See also:* Protein sequence* DNA sequence...
of the transcribed
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
FTO protein shows high homology
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
with the enzyme AlkB
AlkB
AlkB protein is a protein induced during an adaptive response and is involved in the direct reversal of alkylation damage [1]. AlkB specifically removes alkylation damage to single stranded DNA caused by SN2 type of chemical agents [2]. It efficiently removes methyl groups from 1-methyl...
which oxidatively demethylates
Demethylation
Demethylation is the chemical process resulting in the removal a of methyl group from a molecule.A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen atoms....
DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. Furthermore recombinant FTO protein catalyzes demethylation of 3-methylthymine in single-stranded DNA. The FTO gene expression was also found to be significantly upregulated in the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
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.
Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward.
Association with obesity
A study of 38,759 Europeans for variants of FTO identified an obesity risk alleleAllele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
. In particular, carriers of one copy
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
of the allele weighed on average 1.2 kilograms (2.6 lb) more than people with no copies. Carriers of two copies
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
(16% of the subjects) weighed 3 kilograms (6.6 lb) more and had a 1.67-fold higher rate
Rate
In mathematics, a rate is a ratio between two measurements, often with different units. If the unit or quantity in respect of which something is changing is not specified, usually the rate is per unit time. However, a rate of change can be specified per unit time, or per unit of length or mass or...
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) 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
Repeatability
Repeatability or test-retest reliability is the variation in measurements if they would have been taken by a single person or instrument on the same item and under the same conditions. A less-than-perfect test-retest reliability causes test-retest variability. Such variability can be caused by, for...
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
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
in the first intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
of FTO called rs9939609. According to HapMap, it has population frequencies of 45% in the West/Central Europeans, 52% in Yorubans
Yoruba people
The Yoruba people are one of the largest ethnic groups in West Africa. The majority of the Yoruba speak the Yoruba language...
(West African natives) and 14% in Chinese/Japanese. Furthermore morbid obesity is associated with a combination of FTO and INSIG2
INSIG2
Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene.- Regulation :Insulin activates the human INSIG2 promoter in a process mediated by phosphorylated SAP1a....
single nucleotide polymorphism
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
s.
In 2009 variants in the FTO gene were further confirmed to associatate with obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
in two very large genome wide association studies of body mass index
Body mass index
The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...
(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.
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. 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 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 metabolic syndromeMetabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
, 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
Body mass index
The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...
.