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 messenger RNA (mRNA) demethylase that has been identified. [5] Certain alleles of the FTO gene appear to be correlated with obesity in humans. [6] [7]
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 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]
The FTO gene is widely expressed in both fetal and adult tissues. [19]
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]
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]
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]
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]
In genetics and bioinformatics, a single-nucleotide polymorphism is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently large fraction of the population, many publications do not apply such a frequency threshold.
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.
Nutritional genomics, also known as nutrigenomics, is a science studying the relationship between human genome, human nutrition and health. People in the field work toward developing an understanding of how the whole body responds to a food via systems biology, as well as single gene/single food compound relationships. Nutritional genomics or Nutrigenomics is the relation between food and inherited genes, it was first expressed in 2001.
Perilipin, also known as lipid droplet-associated protein, perilipin 1, or PLIN, is a protein that, in humans, is encoded by the PLIN gene. The perilipins are a family of proteins that associate with the surface of lipid droplets. Phosphorylation of perilipin is essential for the mobilization of fats in adipose tissue.
Agouti-signaling protein is a protein that in humans is encoded by the ASIP gene. It is responsible for the distribution of melanin pigment in mammals. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte produces phaeomelanin, or eumelanin. This interaction is responsible for making distinct light and dark bands in the hairs of animals such as the agouti, which the gene is named after. In other species such as horses, agouti signalling is responsible for determining which parts of the body will be red or black. Mice with wildtype agouti will be grey-brown, with each hair being partly yellow and partly black. Loss of function mutations in mice and other species cause black fur coloration, while mutations causing expression throughout the whole body in mice cause yellow fur and obesity.
Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or mesenchyme fork head protein 1 (MFH1) is a protein that in humans is encoded by the FOXC2 gene. FOXC2 is a member of the fork head box (FOX) family of transcription factors.
AlkB (Alkylation B) is a protein found in E. coli, induced during an adaptive response and involved in the direct reversal of alkylation damage. AlkB specifically removes alkylation damage to single stranded (SS) DNA caused by SN2 type of chemical agents. It efficiently removes methyl groups from 1-methyl adenines, 3-methyl cytosines in SS DNA. AlkB is an alpha-ketoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. It oxidatively demethylates the DNA substrate. Demethylation by AlkB is accompanied with release of CO2, succinate, and formaldehyde.
Taste receptor 2 member 38 is a protein that in humans is encoded by the TAS2R38 gene. TAS2R38 is a bitter taste receptor; varying genotypes of TAS2R38 influence the ability to taste both 6-n-propylthiouracil (PROP) and phenylthiocarbamide (PTC). Though it has often been proposed that varying taste receptor genotypes could influence tasting ability, TAS2R38 is one of the few taste receptors shown to have this function.
Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
Melanocortin 3 receptor (MC3R) is a protein that in humans is encoded by the MC3R gene.
RPGRIP1L is a human gene.
Transmembrane protein 18 also known as TMEM18 is a protein which in humans is encoded by the TMEM18 gene.
Like many other medical conditions, obesity is the result of an interplay between environmental and genetic factors. Studies have identified variants in several genes that may contribute to weight gain and body fat distribution; although, only in a few cases are genes the primary cause of obesity.
Iroquois-class homeodomain protein IRX-3, also known as Iroquois homeobox protein 3, is a protein that in humans is encoded by the IRX3 gene.
Most cases of type 2 diabetes involved many genes contributing small amount to the overall condition. As of 2011 more than 36 genes have been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total genetic component of the disease.
N6-Methyladenosine (m6A) was originally identified and partially characterised in the 1970s, and is an abundant modification in mRNA and DNA. It is found within some viruses, and most eukaryotes including mammals, insects, plants and yeast. It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist.
In recent years it has become apparent that the environment and underlying mechanisms affect gene expression and the genome outside of the central dogma of biology. It has been found that many epigenetic mechanisms are involved in the regulation and expression of genes such as DNA methylation and chromatin remodeling. These epigenetic mechanisms are believed to be a contributing factor to pathological diseases such as type 2 diabetes. An understanding of the epigenome of diabetes patients may help to elucidate otherwise hidden causes of this disease.
Within the field of molecular biology, the epitranscriptome includes all the biochemical modifications of the RNA within a cell. In analogy to epigenetics that describes "functionally relevant changes to the genome that do not involve a change in the nucleotide sequence", epitranscriptomics involves all functionally relevant changes to the transcriptome that do not involve a change in the ribonucleotide sequence. Thus, the epitranscriptome can be defined as the ensemble of such functionally relevant changes.
A variant of uncertainsignificance (VUS) is a genetic variant that has been identified through genetic testing but whose significance to the function or health of an organism is not known. Two related terms are "gene of uncertain significance" (GUS), which refers to a gene that has been identified through genome sequencing but whose connection to a human disease has not been established, and "insignificant mutation", referring to a gene variant that has no impact on the health or function of an organism. The term "variant' is favored in clinical practice over "mutation" because it can be used to describe an allele more precisely. When the variant has no impact on health, it is called a "benign variant". When it is associated with a disease, it is called a "pathogenic variant". A "pharmacogenomic variant" has an effect only when an individual takes a particular drug and therefore is neither benign nor pathogenic.
Chuan He is a Chinese-American chemical biologist. He currently serves as the John T. Wilson Distinguished Service Professor at the University of Chicago, and an Investigator of the Howard Hughes Medical Institute. He is best known for his work in discovering and deciphering reversible RNA methylation in post-transcriptional gene expression regulation. He was awarded the 2023 Wolf Prize in Chemistry for his work in discovering and deciphering reversible RNA methylation in post-transcriptional gene expression regulation in addition to his contributions to the invention of TAB-seq, a biochemical method that can map 5-hydroxymethylcytosine (5hmC) at base-resolution genome-wide, as well as hmC-Seal, a method that covalently labels 5hmC for its detection and profiling.
