FTO
Alpha-ketoglutarate-dependent dioxygenase FTO (Fat mass and obesity-associated protein) (U6 small nuclear RNA (2'-O-methyladenosine-N(6)-)-demethylase FTO) (EC 1.14.11.-) (U6 small nuclear RNA N(6)-methyladenosine-demethylase FTO) (EC 1.14.11.-) (mRNA (2'-O-methyladenosine-N(6)-)-demethylase FTO) (EC 1.14.11.-) (m6A(m)-demethylase FTO) (mRNA N(6)-methyladenosine demethylase FTO) (EC 1.14.11.53) (tRNA N1-methyl adenine demethylase FTO) (EC 1.14.11.-) [KIAA1752]
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N6-methyladenosine (m A) and demethylase fat mass and obesity-associated protein (FTO) were reported to be associated with oocyte development and maturation. But the relationship between FTO and ovarian aging was still unclear. This study was aimed at investigating the FTO expression level and the m A content during ovarian aging. The expression level of FTO and the content of m A RNA methylation in human follicular fluid (FF), granulosa cells (GCs) and mouse ovary from different age groups were studied by ELISA, WB, qRT-PCR, IHC and m A Colorimetric. Human FF ELISA quantified that the level of FTO protein decreased with age (P = 0.025). QRT-PCR results showed that the relative expression of FTO in human GCs was lower in the elderly group than in the young group (P = 0.012). FTO mRNA and protein expression levels were lower in the ovary of 32-week-old mice than in 3- and 8-week-old mice (P < 0.05). Immunohistochemistry showed FTO was relatively decreased in 32-week-old mice (P < 0.05). The m A content in total RNA from old human GCs and ovary from 32-week-old mice was significantly higher compared with the younger ones. In human FF, GCs and mouse ovary, the expression of FTO decreased while the content of m A increased with aging. However, the inner mechanism still needs further investigation.
Keywords
- Epigenetics
- FTO
- Ovarian aging
- Ovarian reserve
- m6A
ALKB-8 is a 2-oxoglutarate-dependent dioxygenase homologous to bacterial AlkB, which oxidatively demethylates DNA substrates. The mammalian AlkB family contains AlkB homologues denominated ALKBH1 to 8 and FTO. The C. elegans genome includes five AlkB-related genes, homologues of ALKBH1, 4, 6, 7, and 8, but lacks homologues of ALKBH2, 3, and 5 and FTO. ALKBH8 orthologues differ from other AlkB family members by possessing an additional methyltransferase module and an RNA binding N-terminal module. The ALKBH8 methyltransferase domain generates the wobble nucleoside 5-methoxycarbonylmethyluridine from its precursor 5-carboxymethyluridine and its (R)- and (S)-5-methoxycarbonylhydroxymethyluridine hydroxylated forms in tRNA Arg/UCG and tRNA Gly/UCC. The ALKBH8/ALKB-8 methyltransferase domain is highly similar to yeast TRM9, which selectively modulates translation of mRNAs enriched with AGA and GAA codons under both normal and stress conditions. In this report, we studied the role of alkb-8 in C. elegans. We show that downregulation of alkb-8 increases detection of lysosome-related organelles visualized by Nile red in vivo. Reversely, forced expression of alkb-8 strongly decreases the detection of this compartment. In addition, overexpression of alkb-8 applied in a pulse during the L1 larval stage increases the C. elegans lifespan.
MeSH Terms
- Aging
- AlkB Enzymes
- Animals
- Animals, Genetically Modified
- Caenorhabditis elegans
- Caenorhabditis elegans Proteins
- Dioxygenases
- Down-Regulation
- Embryo, Nonmammalian
- Gene Expression Regulation, Developmental
- Green Fluorescent Proteins
- Ketoglutaric Acids
- Larva
- Longevity
- Lysosomes
- Methyltransferases
- Operon
- Promoter Regions, Genetic
- RNA Interference
- S-Adenosylmethionine
During osteoporosis, the shift of bone mesenchymal stem cell (BMSC) lineage commitment to adipocyte leads to the imbalance between bone mass and fat, which increases the risk of fracture. The mechanism underlying this process is not fully understood. Fat mass and obesity-associated protein (FTO) is an RNA demethylase that demethylates various methylated nucleic acids and participates in various physiological and pathological processes. Here we identified FTO as a regulator for BMSC fate determination during osteoporosis. FTO was up-regulated in bone marrow during aging or osteoporosis in human and mice in a GDF11(growth differentiation factor 11)-C/EBPα-dependent mechanism. The expression of FTO was also up-regulated during adipocyte differentiation of BMSCs whereas its expression was down-regulated during osteoblast differentiation. Gain-of-function and loss-of-function experiments showed that FTO favored the BMSCs to differentiate to adipocytes rather than osteoblasts. Further mechanism study demonstrated that FTO bound and demethylated the mRNA of the Peroxisome proliferator-activated receptor gamma (Pparg), leading to the increase in the expression of Pparg mRNA. Reversely, Pparg knockdown blocked the function of GDF11-FTO during osteoblast differentiation of BMSCs. Furthermore, conditionally genetic knockout of Fto in osteoblasts inhibited the development of osteopenia in mice. Collectively, our findings demonstrated that GDF11-FTO-Pparg axis promoted the shift of osteoporotic BMSC fate to adipocyte and inhibited bone formation during osteoporosis.
MeSH Terms
- Adipocytes
- Adult
- Aged
- Aged, 80 and over
- Aging
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Animals
- Bone Morphogenetic Proteins
- Female
- Growth Differentiation Factors
- Humans
- Male
- Mesenchymal Stem Cells
- Mice, Inbred C57BL
- Middle Aged
- Osteogenesis
- Osteoporosis
- PPAR gamma
- Signal Transduction
- Young Adult
Keywords
- Adipocyte
- FTO
- GDF11
- Osteoblast
- Osteoporosis
- PPARγ
Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10 ) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.
MeSH Terms
- Aged
- Aging
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Cohort Studies
- Energy Intake
- European Continental Ancestry Group
- Female
- Fibroblast Growth Factors
- Genetic Loci
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Genomics
- Genotype
- Heart Diseases
- Humans
- Male
- Membrane Proteins
- Middle Aged
- Nutrients
- Obesity
- Polymorphism, Single Nucleotide
- Receptors, Retinoic Acid
Diabetes and obesity are commonly associated with Alzheimer's disease (AD). Accumulating evidence show that insulin signaling defects are protentional upstream driver of AD. However, the mechanism by which diabetes and insulin signaling defects contribute to AD remains unknown. Here we show that Fat mass and obesity-associated protein (FTO) is involved the insulin defects-associated AD. Defective insulin signaling in diabetes and obesity in human and mice activated Fto in the brain tissues. Lentivirus-mediated knockdown of Fto reduced the phosphorylation of Tau protein whereas overexpression of FTO promoted the level of phosphorylated Tau in neurons. Mechanism study demonstrated that FTO activated the phosphorylation of Tau in a mTOR-dependent manner because FTO activated mTOR and its downstream signaling and rapamycin blocked FTO-mediated phosphorylation of Tau. FTO promoted the activation of mTOR by increasing the mRNA level of TSC1 but not TSC2, the upstream inhibitor of mTOR. Finally, we found that conditional knockout of Fto in the neurons reduced the cognitive deficits in 3xTg AD mice. Collectively, our evidence demonstrated that FTO is critically involved in insulin defects-related AD.
MeSH Terms
- Aging
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Alzheimer Disease
- Animals
- Brain
- Diabetes Mellitus
- Male
- Mice, Knockout
- Obesity
- Phosphorylation
- Signal Transduction
- TOR Serine-Threonine Kinases
- Tuberous Sclerosis Complex 1 Protein
- Tumor Suppressor Proteins
- tau Proteins
Keywords
- AD
- Diabetes
- FTO
- Insulin resistance
- TSC1
- Tau
- mTOR
The fat mass and obesity associated gene (FTO) was the first gene identified by genome-wide association studies to correlate with higher body mass index (BMI) and increased odds of obesity. FTO remains the locus with the largest and most replicated effect on body weight, but the mechanism whereby FTO affects body weight and the development of obesity is not fully understood. Here we tested whether FTO is associated with differences in food cravings and a key aspect of dopamine function that has been hypothesized to influence food reward mechanisms. Moreover, as food cravings and dopamine function are known to decline with age, we explored effects of age on relations between FTO and food cravings and dopamine function. Seven-eight healthy subjects between 22 and 83years old completed the Food Cravings Questionnaire and underwent genotyping for FTO rs9939609, the first FTO single nucleotide polymorphism associated with obesity. Compared to TT homozygotes, individuals carrying the obesity-susceptible A allele had higher total food cravings, which correlated with higher BMI. Additionally, food cravings declined with age, but this age effect differed across variants of FTO rs9939609: while TT homozygotes showed the typical age-related decline in food cravings, there was no such decline among A carriers. All subjects were scanned with [18F]fallypride PET to assess a recent proposal that at the neurochemical level FTO alters dopamine D2-like receptor (DRD2) function to influence food reward related mechanisms. However, we observed no evidence of FTO effects on DRD2 availability.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Benzamides
- Body Mass Index
- Brain
- Craving
- Feeding Behavior
- Female
- Food
- Genetic Association Studies
- Humans
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Positron-Emission Tomography
- Pyrrolidines
- Radiopharmaceuticals
- Receptors, Dopamine D2
- Young Adult
Keywords
- Aging
- Dopamine receptor availability
- FTO
- Food cravings
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in developed countries. This study aimed to confirm the effect of common putative CVD-associated gene variants (FTO rs17817449, KIF6 rs20455, 9p21 rs10757274 and 2q36.3 rs2943634) on CVD manifestation, and determine whether this effect differs between younger (< 50 years) and older CVD patients. 1191 controls and 1889 MI patients were analyzed. All participants were Caucasian Czech males aged <65 years (532 were <50 years) who were examined at cardiology clinics in Prague, Czech Republic. Variants of FTO, 9p21, 2q36.3, and KIF-6 were genotyped using PCR-RFLP or TaqMan assay. Variants of FTO (OR 1.48; 95% CI, 1.19-1.84 in a TT vs. GG comparison, p=0.0005); 9p21 (OR 1.74; 95% CI, 1.41-2.14 in an AA vs. GG comparison, p=0.0001); and 2q36.3 (OR 1.34; 95%CI, 1.09-1.65 in an AA vs. C comparison, p=0.006) were significantly associated with MI in the male Czech population. In contrast, genotype frequencies of KIF-6 (rs20455) were the same in patients and controls (P=1.00). Nearly identical results were observed when a subset of young MI patients (N=532, aged <50 years) was analyzed. We confirmed the importance of determining FTO, 9p21, and 2q36.3 variants as part of the genetic determination of MI risk in the Czech male population.
MeSH Terms
- Age Factors
- Aging
- Body Mass Index
- Chromosomes, Human, Pair 2
- Chromosomes, Human, Pair 9
- Czech Republic
- Genetic Variation
- Genotype
- Humans
- Male
- Middle Aged
- Myocardial Infarction
- Polymorphism, Single Nucleotide
- Risk Factors
Keywords
- Cardiovascular disease
- Polymorphism
- Slavic population
- Young
A longitudinal study was conducted to examine sex-specific associations between changes in adiposity over a 10-year period, the FTO rs9939609 polymorphism, and leukocyte telomere length (LTL). A population-based cohort including 2128 middle-aged and older Korean men (n = 1087) and women (n = 1041) participated in a prospective study. Anthropometric measurements of weight, height, and waist and hip circumference were taken at baseline (from 2001 to 2003) and at the 10-year follow-up period (from 2011 to 2012). The FTO rs9939609 polymorphism was genotyped using DNA samples collected at baseline and LTL was assessed at the 10-year follow-up period. Multiple linear regression analysis was used with adjustments for age, baseline body mass index, and other potential confounders. Presence of the FTO rs9939609 polymorphism risk allele was inversely associated with LTL (p < 0.01) in all participants, with a significant association seen only in women when the genders were modeled separately. Conversely, a significant inverse association between changes in waist circumference and LTL was found in men (p < 0.001) but not in women. No significant interaction between adiposity measures and the FTO polymorphism in association with LTL was identified for either sex. These data suggest that biological aging in men may be accelerated by increasing waist circumference, whereas in women, aging may be affected by genetic variations in FTO regardless of adiposity changes over time.
MeSH Terms
- Adiposity
- Adult
- Aged
- Aging
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Female
- Humans
- Leukocytes
- Longitudinal Studies
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Sex Factors
- Telomere
Keywords
- FTO polymorphism
- adiposity
- biological aging
- leukocyte telomere length
- longitudinal study
Type 2 diabetes mellitus (T2D) is highly prevalent in Middle-Eastern and North African Arab populations, but the molecular basis for this susceptibility is unknown. Altered DNA methylation levels were reported in insulin-secreting and responding tissues, but whether methylation in accessible tissues such as peripheral blood is associated with T2D risk remains an open question. Age-related alteration of DNA methylation level was reported in certain methylation sites, but no association with T2D has been shown. Here we report on a population-based study of 929 men and women representing the East Jerusalem Palestinian (EJP) Arab population and compare with the findings among Israeli Ashkenazi Jews. This is the first reported epigenetic study of an Arab population with a characteristic high prevalence of T2D. We found that DNA methylation of a prespecified regulatory site in peripheral blood leukocytes (PBLs) is associated with impaired glucose metabolism and T2D independent of sex, body mass index, and white blood cell composition. This CpG site (Chr16: 53,809,231-2; hg19) is located in a region within an intron of the FTO gene, suspected to serve as a tissue-specific enhancer. The association between PBL hypomethylation and T2D varied by age, revealing differential patterns of methylation aging in healthy and diabetic individuals and between ethnic groups: T2D patients displayed prematurely low methylation levels, and this hypomethylation was greater and occurred earlier in life among Palestinian Arabs than Ashkenazi Jews. Our study suggests that premature DNA methylation aging is associated with increased risk of T2D. These findings should stimulate the search for more such sites and may pave the way to improved T2D risk prediction within and between human populations.
Keywords
- Ashkenazi Jews
- DNA methylation
- East Jerusalem Palestinians
- Epigenetic aging
- Ethnic groups
- Leukocytes
- Population epigenetics
- Type 2 diabetes
Although overweight and obesity are associated with poor health outcomes in the elderly, the biological bases of obesity-related behaviors during aging are poorly understood. Common variants in the FTO gene are associated with adiposity in children and younger adults as well as with adverse mental health in older individuals. However, it is unclear whether FTO influences longitudinal trajectories of adiposity and other intermediate phenotypes relevant to mental health during aging. We examined whether a commonly carried obesity-risk variant in the FTO gene (rs1421085 single-nucleotide polymorphism) influences adiposity and is associated with changes in brain function in participants within the Baltimore Longitudinal Study of Aging, one of the longest-running longitudinal aging studies in the United States. Our results show that obesity-related risk allele carriers of FTO gene show dose-dependent increments in body mass index during aging. Moreover, the obesity-related risk allele is associated with reduced medial prefrontal cortical function during aging. Consistent with reduced brain function in regions intrinsic to impulse control and taste responsiveness, risk allele carriers of FTO exhibit dose-dependent increments in both impulsivity and intake of fatty foods. We propose that a common neural mechanism may underlie obesity-associated impulsivity and increased consumption of high-calorie foods during aging.
MeSH Terms
- Adiposity
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Body Mass Index
- Brain
- Diet
- Eating
- Feeding Behavior
- Female
- Genotype
- Humans
- Impulsive Behavior
- Longitudinal Studies
- Male
- Middle Aged
- Obesity
- Polymorphism, Single Nucleotide
- Proteins
- Radionuclide Imaging
- United States
- Young Adult
It is becoming increasingly recognized that early-life nutritional, metabolic and environmental factors can have a long-term impact on the early onset of obesity, type 2 diabetes and cardiovascular diseases. Numerous experimental and epidemiological observations support the concept that an individual's response to their adult lifestyle and nutritional environment depends not only on their genetic susceptibility but also on their previous early-life experiences. The current research challenge is to determine the primary pathways contributing to 'non- or epi-genetic' causes of excess adult weight gain and adiposity. Evidence from the fields of genetic epidemiology, life course modelling and diet-induced foetal programming all support a role for the FTO gene in this complex biological interaction. It may provide a missing link in the developmental regulation of energy metabolism. Our review therefore considers the role of the FTO gene in the early-life determination of body weight, body composition and energy balance. We will summarize current knowledge on FTO biology combining human genetic epidemiology, molecular models and findings from animal studies. Notably, we will focus on the role of FTO in energy balance in humans, the importance of FTO polymorphisms in childhood growth and the impact of foetal nutrition. Ultimately, we propose a new hypothesis for future research designed to understand the role of FTO in setting gene expression in metabolically active tissues.
MeSH Terms
- Adipose Tissue
- Adiposity
- Aging
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Animals
- Epigenesis, Genetic
- Humans
- Models, Genetic
- Obesity
- Polymorphism, Single Nucleotide
- Proteins
Keywords
- FTO
- animal models
- early life
- foetal programming
- genetic epidemiology
- obesity
Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26-49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m², respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Body Mass Index
- Cohort Studies
- Cross-Sectional Studies
- European Continental Ancestry Group
- Female
- Genetic Association Studies
- Health Surveys
- Humans
- Male
- Middle Aged
- Obesity
- Polymorphism, Single Nucleotide
- Proteins
- United States
- Young Adult