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FLASH GENE
Symbol FTO contributors: mct/pgu - updated : 21-05-2015
HGNC name fat mass and obesity associated
HGNC id 24678
Corresponding disease
GRDED growth retardation, psychomotor delay, early death
OBS2 severe obesity
Location 16q12.2      Physical location : 53.737.874 - 54.148.378
Synonym name
  • fused-toe murine homolog
  • protein FATSO
  • alpha-ketoglutarate-dependent dioxygenase FTO
  • AlkB homolog 9
    • Synonym symbol(s) KIAA1752, MGC5149, FATSO, ALKBH9
    EC.number 1.14.11.-
    DNA
    TYPE functioning gene
    STRUCTURE 410.50 kb     9 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Binding site
    text structure
  • first intron of FTO contains common single nucleotide polymorphisms associated with body weight and adiposity
    • MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 - 4313 - 505 - 2007 17991826
    EXPRESSION
    Rna function high FTO mRNA levels are observed in the brain, including the cerebellum, hippocampus and hypothalamus
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Endocrineadrenal gland   highly
     neuroendocrinepituitary  highly
    Hearing/Equilibriumearinnercochlea highly
    Nervousbraindiencephalonhypothalamus highly Homo sapiens
     brainforebraincerebral cortex highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  highly Homo sapiens
    Muscularstriatumskeletal highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    Text ubiquitous in embryo
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • DSBH fold of FTO contains four conserved residues characteristic of Fe(II) and 2OG binding sites
    • secondary structure a double-stranded beta-helix (DSBH) fold homologous to those of Fe(II) and 2-oxoglutarate (2OG) oxygenases
    HOMOLOGY
    intraspecies homolog to to the DNA repair ALKBH1 protein
    Homologene
    FAMILY
  • non-heme dioxygenase (Fe(II)- and 2-oxoglutarate-dependent dioxygenases) superfamily
  • FTO family
  • FTO family
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
    intracellular,nucleus,nucleolus
    text may be in mitochondria (not confirmed)
    basic FUNCTION
  • nucleic acid demethylase that may work on DNA or RNA
  • may have an important role for gender specific development of severe obesity and insulin resistance in children
  • could participate in the central control of energy homeostasis
  • implicated in the regulation of lipolysis
  • functionally involved in energy homeostasis by the control of energy expenditure
  • playing an essential role for normal development of the central nervous and cardiovascular systems
  • effect of FTO on BMI may be mediated through impaired responsiveness to satiety
  • directly involved in the regulation of energy intake and metabolism
  • FTO and/or RPGRIP1L may participate in the leptin signaling pathway
  • FTO and RPGRIP1L participate in the control of food intake by modulating leptin sensitivity in the arcuate hypothalamic
  • proposed transcription co-factor, influencing expression of the gene encoding a satiety mediator, OXT
  • may influence body composition through playing a role in cellular nutrient sensing
  • FTO status can influence the central sensing of dietary macronutrient composition
  • regulates activity of the dopaminergic midbrain circuitry
  • is a protein-regulator of the balanced activation between canonical and non-canonical branches of the Wnt pathway
  • plays a role in development and cilia formation/function
  • may potentially facilitate weight gain in humans by shifting the endocrine balance from the satiety hormone leptin toward the hunger-promoting hormone ghrelin
  • FTO regulates fatty acid mobilization in adipocytes and thus body weight in part through posttranscriptional regulation of ANGPTL4
  • ALKBH1, ALKBH5, ALKBH8 and FTO act as RNA demethylases
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • FTO and RPGRIP1L (a ciliary gene located in close proximity to the transcriptional start site of FTO) are regulated by isoforms P200 and P110 of the transcription factor, CUX1
  • relationship between FTO and OXT could thus be an important mechanism through which FTO exerts its effect on energy balance
  • interactions between genetic variants of FTO and GNB3 influence clinical parameters to augment hypertension
  • FTO modulates circadian rhythms and inhibits the CLOCK-ARNTL-induced transcription
  • FTO bound to ANGPTL4, which encodes an adipokine that stimulates intracellular lipolysis in adipocytes
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) OBS2 , GRDED
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    altered FTO demethylase activity underlies the enhanced fat mass associated with the FTO gene variant and this alteration in activity is associated with increased food intake, decreased energy expenditure, or both
    constitutional   amplification   gain of function
    increased FTO expression results in increased food intake, leading to increased adiposity
    constitutional     --over  
    leads to increased fat mass and obesity through hyperphagia
    constitutional       loss of function
    has a protective effect not only on the development of obesity but also on the metabolic syndrome
    constitutional       loss of function
    affects the 3-methyluridine/uridine and pseudouridine/uridine ratios in total brain RNA
    Susceptibility
  • to type 2 diabetes
  • to childhood and adult obesity, associated with reduced brain volume in the healthy elderly
  • to metabolic syndrome
  • to variation of onset age and survival odds of overweight in younger adults
  • to Polycystic ovary syndrome (PCOS)
    • Variant & Polymorphism SNP , other
  • risk allele increasing odds of obesity
  • variants might lead to an up- or dysregulation of FTO expression, thus rendering individuals more susceptible to obesity
  • interaction between common variants of FTO and MC4R is associated with risk of PCOS
  • two SNPs, rs1421085 and rs17817449, have been previously identified as significantly and reliably associated with obesity
  • variations influence the risk of metabolic syndrome
  • a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly
  • SNPs (including rs9939609, rs17817449, rs3751812, rs1421085 and rs9930506) in intron 1 of FTO are associated with an increased risk of obesity
  • SNP rs8050136 in intron 1 of FTO, within a binding site for the transcription factor CUX1, plays a role in the control of FTO and RPGRIP1L expression and implies that functional consequences of the allelic variation at rs8050136 could be, in part or exclusively, responsible for the association of this region of linkage disequilibrium with adiposity
  • risk genetic variants at FTO gene can accelerate the onset age and influence the survival odds of overweight in younger adults
  • SNP rs7202116 at the FTO gene locus, which is known to be associated with obesity, is also associated with phenotypic variability
  • rs57103849 located in the fourth intron of FTO showed BMI independent association with younger age at diagnosis of T2Diabetes
    • Candidate gene candidate gene involved in processes such as programmed cell death, craniofacial development, and establishment of left-right asymmetry
    Marker
    Therapy target may be a target for subsequent functional analyses
    SystemTypeDisorderPubmed
    obesity  
    anti-obesity drugs targeted to FTO should be designed to reduce FTO expression or activity and predict that their effects in vivo will largely act by reducing appetite
    ANIMAL & CELL MODELS
  • leanness of Fto-deficient mice develops as a consequence of increased energy expenditure and systemic sympathetic activation, despite decreased spontaneous locomotor activity and relative hyperphagia
  • Fto-null mice have reduced fat mass
  • mice with increased Fto expression on a high-fat diet develop glucose intolerance
  • mice lacking FTO in adipocytes fed a normal diet or adipocytes from these mice revealed alterations in triglyceride metabolism that would be expected to favor increased fatty acid storage by adipose tissue