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1.  A Mouse Model for the Metabolic Effects of the Human Fat Mass and Obesity Associated FTO Gene 
PLoS Genetics  2009;5(8):e1000599.
Human FTO gene variants are associated with body mass index and type 2 diabetes. Because the obesity-associated SNPs are intronic, it is unclear whether changes in FTO expression or splicing are the cause of obesity or if regulatory elements within intron 1 influence upstream or downstream genes. We tested the idea that FTO itself is involved in obesity. We show that a dominant point mutation in the mouse Fto gene results in reduced fat mass, increased energy expenditure, and unchanged physical activity. Exposure to a high-fat diet enhances lean mass and lowers fat mass relative to control mice. Biochemical studies suggest the mutation occurs in a structurally novel domain and modifies FTO function, possibly by altering its dimerisation state. Gene expression profiling revealed increased expression of some fat and carbohydrate metabolism genes and an improved inflammatory profile in white adipose tissue of mutant mice. These data provide direct functional evidence that FTO is a causal gene underlying obesity. Compared to the reported mouse FTO knockout, our model more accurately reflects the effect of human FTO variants; we observe a heterozygous as well as homozygous phenotype, a smaller difference in weight and adiposity, and our mice do not show perinatal lethality or an age-related reduction in size and length. Our model suggests that a search for human coding mutations in FTO may be informative and that inhibition of FTO activity is a possible target for the treatment of morbid obesity.
Author Summary
Geneticists have identified many gene regions that cause human disease by using multiple genetic markers in large populations to find gene regions associated with disease. However, it is often not clear precisely which gene in any given region causes the disease or how the gene exerts its functional effect. For example, a gene variant in the non-coding region of FTO enhances obesity risk, but it is not clear if this is an effect of the FTO gene itself or another gene located nearby. We therefore tested whether FTO regulates body weight in the mouse. We found that a single change (mutation) in the sequence coding for the mouse FTO protein decreases the functional activity of FTO and causes reduced fat mass and body weight. Food intake and activity were normal, but the mutant mice had a higher metabolic rate. In addition, their fat mass was lower than that of normal mice when both were fed a high-fat diet. Our study provides direct evidence that FTO directly affects fat mass and thus is likely to have a role in human obesity. As reduced FTO function decreases body weight in mice, it is worth exploring if pharmaceutical agents that inhibit FTO activity might help reduce human obesity.
PMCID: PMC2719869  PMID: 19680540
2.  Adult Onset Global Loss of the Fto Gene Alters Body Composition and Metabolism in the Mouse 
PLoS Genetics  2013;9(1):e1003166.
The strongest BMI–associated GWAS locus in humans is the FTO gene. Rodent studies demonstrate a role for FTO in energy homeostasis and body composition. The phenotypes observed in loss of expression studies are complex with perinatal lethality, stunted growth from weaning, and significant alterations in body composition. Thus understanding how and where Fto regulates food intake, energy expenditure, and body composition is a challenge. To address this we generated a series of mice with distinct temporal and spatial loss of Fto expression. Global germline loss of Fto resulted in high perinatal lethality and a reduction in body length, fat mass, and lean mass. When ratio corrected for lean mass, mice had a significant increase in energy expenditure, but more appropriate multiple linear regression normalisation showed no difference in energy expenditure. Global deletion of Fto after the in utero and perinatal period, at 6 weeks of age, removed the high lethality of germline loss. However, there was a reduction in weight by 9 weeks, primarily as loss of lean mass. Over the subsequent 10 weeks, weight converged, driven by an increase in fat mass. There was a switch to a lower RER with no overall change in food intake or energy expenditure. To test if the phenotype can be explained by loss of Fto in the mediobasal hypothalamus, we sterotactically injected adeno-associated viral vectors encoding Cre recombinase to cause regional deletion. We observed a small reduction in food intake and weight gain with no effect on energy expenditure or body composition. Thus, although hypothalamic Fto can impact feeding, the effect of loss of Fto on body composition is brought about by its actions at sites elsewhere. Our data suggest that Fto may have a critical role in the control of lean mass, independent of its effect on food intake.
Author Summary
The fat mass and obesity (FTO) gene has one of the strongest links with body mass index (BMI) in the human population. One in six people have the “risk” alteration and weigh 3 kg more than those with the unaltered gene, but it is not understood how this gene influences BMI and obesity. We set out to understand how and where in the body FTO affects food intake, energy expenditure, and body composition using a mouse model that can be manipulated to lack FTO at particular times and/or places. Removing FTO everywhere from conception had a dramatic effect on body composition and resulted in stunted growth and some lethality. Removing FTO everywhere but only in adult animals resulted in better viability and normal growth but, surprisingly, reduced lean mass and increased fat mass with a change in the type of metabolic fuel being used. Finally, we removed FTO from the hypothalamus of adult animals, an important brain region involved in energy metabolism. These animals showed a mild reduction in food intake and weight gain. Our experiments show that FTO has an important role in body composition and that other brain areas outside of the hypothalamus are also important in determining its effects.
PMCID: PMC3536712  PMID: 23300482
3.  Hypothalamic-Specific Manipulation of Fto, the Ortholog of the Human Obesity Gene FTO, Affects Food Intake in Rats 
PLoS ONE  2010;5(1):e8771.
Sequence variants in the first intron of FTO are strongly associated with human obesity and human carriers of the risk alleles show evidence for increased appetite and food intake. Mice globally lacking Fto display a complex phenotype characterised by both increased energy expenditure and increased food intake. The site of action of FTO on energy balance is unclear. Fasting reduces levels of Fto mRNA in the arcuate nucleus (ARC) of the hypothalamus, a site where Fto expression is particularly high. In this study, we have extended this nutritional link by demonstrating that consumption of a high fat diet (45%) results in a 2.5 fold increase in Arc Fto expression. We have further explored the role of hypothalamic Fto in the control of food intake by using stereotactic injections coupled with AAV technology to bi-directionally modulate Fto expression. An over expression of Fto protein by 2.5-fold in the ARC results in a 14% decrease in average daily food intake in the first week. In contrast, knocking down Arc Fto expression by 40% increases food intake by 16%. mRNA levels of Agrp, Pomc and Npy, ARC-expressed genes classically associated with the control of food intake, were not affected by the manipulation of Fto expression. However, over expression of Fto resulted in a 4-fold increase in the mRNA levels of Stat3, a signalling molecule critical for leptin receptor signalling, suggesting a possible candidate for the mediation of Fto's actions. These data provide further support for the notion that FTO itself can influence key components of energy balance, and is therefore a strong candidate for the mediation of the robust association between FTO intronic variants and adiposity. Importantly, this provide the first indication that selective alteration of FTO levels in the hypothalamus can influence food intake, a finding consistent with the reported effects of FTO alleles on appetite and food intake in man.
PMCID: PMC2808248  PMID: 20098739
4.  Early Hypothalamic FTO Overexpression in Response to Maternal Obesity – Potential Contribution to Postweaning Hyperphagia 
PLoS ONE  2011;6(9):e25261.
Intrauterine and postnatal overnutrition program hyperphagia, adiposity and glucose intolerance in offspring. Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene have been linked to increased risk of obesity. FTO is highly expressed in hypothalamic regions critical for energy balance and hyperphagic phenotypes were linked with FTO SNPs. As nutrition during fetal development can influence the expression of genes involved in metabolic function, we investigated the impact of maternal obesity on FTO.
Female Sprague Dawley rats were exposed to chow or high fat diet (HFD) for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1 (PND1), some litters were adjusted to 3 pups (vs. 12 control) to induce postnatal overnutrition. At PND20, rats were weaned onto chow or HFD for 15 weeks. FTO mRNA expression in the hypothalamus and liver, as well as hepatic markers of lipid metabolism were measured.
At weaning, hypothalamic FTO mRNA expression was increased significantly in offspring of obese mothers and FTO was correlated with both visceral and epididymal fat mass (P<0.05); body weight approached significance (P = 0.07). Hepatic FTO and Fatty Acid Synthase mRNA expression were decreased by maternal obesity. At 18 weeks, FTO mRNA expression did not differ between groups; however body weight was significantly correlated with hypothalamic FTO. Postnatal HFD feeding significantly reduced hepatic Carnitine Palmitoyltransferase-1a but did not affect the expression of other hepatic markers investigated. FTO was not affected by chronic HFD feeding.
Maternal obesity significantly impacted FTO expression in both hypothalamus and liver at weaning. Early overexpression of hypothalamic FTO correlated with increased adiposity and later food intake of siblings exposed to HFD suggesting upregulation of FTO may contribute to subsequent hyperphagia, in line with some human data. No effect of maternal obesity was observed on FTO in adulthood.
PMCID: PMC3182187  PMID: 21980407
5.  Impaired hypothalamic Fto expression in response to fasting and glucose in obese mice 
Nutrition & Diabetes  2011;1(10):e19-.
Recent genome-wide association studies have identified a strong association between obesity and common variants in the fat mass and obesity associated (FTO) gene. FTO has been detected in the hypothalamus, but little is known about its regulation in that particular brain structure. The present study addressed the hypothesis that hypothalamic FTO expression is regulated by nutrients, specifically by glucose, and that its regulation by nutrients is impaired in obesity.
Research design and methods:
The effect of intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of glucose on hypothalamic Fto mRNA levels was examined in fasted mice. Additionally, the effect of glucose on Fto mRNA levels was also investigated ex vivo using mouse hypothalamic explants. Lastly, the effect of i.p. glucose injection on hypothalamic Fto immunoreactivity and food intake was compared between lean wild-type and obese ob/ob mice.
In wild-type mice, fasting reduced both Fto mRNA levels and the number of Fto-immunoreactive cells in the hypothalamus, whereas i.p. glucose treatment reversed this effect of fasting. Furthermore, i.c.v. glucose treatment also increased hypothalamic Fto mRNA levels in fasted mice. Incubation of hypothalamic explants at high glucose concentration increased Fto mRNA levels. In ob/ob mice, both fasting and i.p. glucose treatment failed to alter the number of Fto-immunoreactive cells in the hypothalamus. Glucose-induced feeding suppression was abolished in ob/ob mice.
Reduction in hypothalamic Fto expression after fasting likely arises at least partly from reduced circulating glucose levels and/or reduced central action of glucose. Obesity is associated with impairments in glucose-mediated regulation of hypothalamic Fto expression and anorexia. Hypothalamic Fto-expressing neurons may have a role in the regulation of metabolism by monitoring metabolic states of the body.
PMCID: PMC3302139  PMID: 23154321
hypothalamus; obesity; nutrient; gene expression; feeding
6.  FTO Is a Relevant Factor for the Development of the Metabolic Syndrome in Mice 
PLoS ONE  2014;9(8):e105349.
The metabolic syndrome is a worldwide problem mainly caused by obesity. FTO was found to be a obesity-risk gene in humans and FTO deficiency in mice led to reduction in adipose tissue. Thus, FTO is an important factor for the development of obesity. Leptin-deficient mice are a well characterized model for analysing the metabolic syndrome. To determine the relevance of FTO for the development of the metabolic syndrome we analysed different parameters in combined homozygous deficient mice (Lepob/ob;Fto−/−). Lepob/ob;Fto−/− mice showed an improvement in analysed hallmarks of the metabolic syndrome in comparison to leptin-deficient mice wild type or heterozygous for Fto. Lepob/ob;Fto−/− mice did not develop hyperglycaemia and showed an improved glucose tolerance. Furthermore, extension of beta-cell mass was prevented in Lepob/ob;Fto−/−mice and accumulation of ectopic fat in the liver was reduced. In conclusion this study demonstrates that FTO deficiency has a protective effect not only on the development of obesity but also on the metabolic syndrome. Thus, FTO plays an important role in the development of metabolic disorders and is an interesting target for therapeutic agents.
PMCID: PMC4140775  PMID: 25144618
7.  Pharmacological Inhibition of FTO 
PLoS ONE  2015;10(4):e0121829.
In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells) and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO’s demethylase activity could be therapeutically useful for the treatment of obesity.
PMCID: PMC4382163  PMID: 25830347
8.  FTO influences adipogenesis by regulating mitotic clonal expansion 
Nature Communications  2015;6:6792.
The fat mass and obesity-associated (FTO) gene plays a pivotal role in regulating body weight and fat mass; however, the underlying mechanisms are poorly understood. Here we show that primary adipocytes and mouse embryonic fibroblasts (MEFs) derived from FTO overexpression (FTO-4) mice exhibit increased potential for adipogenic differentiation, while MEFs derived from FTO knockout (FTO-KO) mice show reduced adipogenesis. As predicted from these findings, fat pads from FTO-4 mice fed a high-fat diet show more numerous adipocytes. FTO influences adipogenesis by regulating events early in adipogenesis, during the process of mitotic clonal expansion. The effect of FTO on adipogenesis appears to be mediated via enhanced expression of the pro-adipogenic short isoform of RUNX1T1, which enhanced adipocyte proliferation, and is increased in FTO-4 MEFs and reduced in FTO-KO MEFs. Our findings provide novel mechanistic insight into how upregulation of FTO leads to obesity.
Mutations in the FTO gene have been linked to obesity. Here, Merkestein et al. provide in vitro and in vivo evidence that FTO directly regulates adipogenesis in mice at the stage of mitotic clonal expansion, likely by modulating the expression of the transcription factor RUNX1T1.
PMCID: PMC4410642  PMID: 25881961
9.  Prevalence of Loss-of-Function FTO Mutations in Lean and Obese Individuals 
Diabetes  2009;59(1):311-318.
Single nucleotide polymorphisms (SNPs) in intron 1 of fat mass– and obesity-associated gene (FTO) are strongly associated with human adiposity, whereas Fto−/− mice are lean and Fto+/− mice are resistant to diet-induced obesity. We aimed to determine whether FTO mutations are disproportionately represented in lean or obese humans and to use these mutations to understand structure-function relationships within FTO.
We sequenced all coding exons of FTO in 1,433 severely obese and 1,433 lean individuals. We studied the enzymatic activity of selected nonsynonymous variants.
We identified 33 heterozygous nonsynonymous variants in lean (2.3%) and 35 in obese (2.4%) individuals, with 8 mutations unique to the obese and 11 unique to the lean. Two novel mutations replace absolutely conserved residues: R322Q in the catalytic domain and R96H in the predicted substrate recognition lid. R322Q was unable to catalyze the conversion of 2-oxoglutarate to succinate in the presence or absence of 3-methylthymidine. R96H retained some basal activity, which was not enhanced by 3-methylthymidine. However, both were found in lean and obese individuals.
Heterozygous, loss-of-function mutations in FTO exist but are found in both lean and obese subjects. Although intron 1 SNPs are unequivocally associated with obesity in multiple populations and murine studies strongly suggest that FTO has a role in energy balance, it appears that loss of one functional copy of FTO in humans is compatible with being either lean or obese. Functional analyses of FTO mutations have given novel insights into structure-function relationships in this enzyme.
PMCID: PMC2797938  PMID: 19833892
10.  FTO genotype is associated with exercise training-induced changes in body composition 
Obesity (Silver Spring, Md.)  2009;18(2):322-326.
The fat mass and obesity associated (FTO) gene is the first obesity-susceptibility gene identified by genome-wide association scans and confirmed in several follow-up studies. Homozygotes for the risk allele (A/A) have 1.67 times greater risk of obesity than those who do not have the allele. However, it is not known if regular exercise-induced changes in body composition are influenced by the FTO genotype. The purpose of our study was to test if the FTO genotype is associated with exercise-induced changes in adiposity. Body composition was derived from underwater weighing before and after a 20-week endurance training program in 481 previously sedentary white subjects of the HERITAGE Family Study. FTO SNP rs8050136 was genotyped using Illumina GoldenGate assay. In the sedentary state, the A/A homozygotes were significantly heavier and fatter than the heterozygotes and the C/C homozygotes in men (p=0.004) but not in women (p=0.331; gene-by-sex interaction p=0.0053). The FTO genotype was associated with body fat responses to regular exercise (p<0.005; adjusted for age, sex, and baseline value of response trait): carriers of the C-allele showed three times greater fat mass and %body fat losses than the A/A homozygotes. The FTO genotype explained 2% of the variance in adiposity changes. Our data suggest that the FTO obesity-susceptibility genotype influences the body fat responses to regular exercise. Resistance to exercise-induced reduction in total adiposity may represent one mechanism by which the FTO A allele promotes overweight and obesity.
PMCID: PMC2838609  PMID: 19543202
Adiposity; exercise; genotype; obesity; weight loss
11.  FTO, obesity and the adolescent brain 
Human Molecular Genetics  2012;22(5):1050-1058.
Genetic variations in fat mass- and obesity (FTO)-associated gene, a well-replicated gene locus of obesity, appear to be associated also with reduced regional brain volumes in elderly. Here, we examined whether FTO is associated with total brain volume in adolescence, thus exploring possible developmental effects of FTO. We studied a population-based sample of 598 adolescents recruited from the French Canadian founder population in whom we measured brain volume by magnetic resonance imaging. Total fat mass was assessed with bioimpedance and body mass index was determined with anthropometry. Genotype–phenotype associations were tested with Merlin under an additive model. We found that the G allele of FTO (rs9930333) was associated with higher total body fat [TBF (P = 0.002) and lower brain volume (P = 0.005)]. The same allele was also associated with higher lean body mass (P = 0.03) and no difference in height (P = 0.99). Principal component analysis identified a shared inverse variance between the brain volume and TBF, which was associated with FTO at P = 5.5 × 10−6. These results were replicated in two independent samples of 413 and 718 adolescents, and in a meta-analysis of all three samples (n = 1729 adolescents), FTO was associated with this shared inverse variance at P = 1.3 × 10−9. Co-expression networks analysis supported the possibility that the underlying FTO effects may occur during embryogenesis. In conclusion, FTO is associated with shared inverse variance between body adiposity and brain volume, suggesting that this gene may exert inverse effects on adipose and brain tissues. Given the completion of the overall brain growth in early childhood, these effects may have their origins during early development.
PMCID: PMC3606009  PMID: 23201753
12.  Obesity-associated variants within FTO form long-range functional connections with IRX3 
Nature  2014;507(7492):371-375.
Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type-2 diabetes (T2D) 1–3. While the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes 4–6. Yet, no direct connection between the obesity-associated variants and FTO expression or function has been made 7–9. Here, we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse, and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Supporting this, obesity-associated SNPs are associated with expression of IRX3, but not FTO, in human brains. Directly linking IRX3 expression with regulation of body mass and composition, Irx3-deficient mice exhibit a 25–30% reduction in body weight, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Furthermore, hypothalamic expression of a dominant negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data posit that IRX3 is a functional long-range target of obesity-associated variants within FTO, and represents a novel determinant of body mass and composition.
PMCID: PMC4113484  PMID: 24646999
13.  FTO is necessary for the induction of leptin resistance by high-fat feeding 
Molecular Metabolism  2015;4(4):287-298.
Loss of function FTO mutations significantly impact body composition in humans and mice, with Fto-deficient mice reported to resist the development of obesity in response to a high-fat diet (HFD). We aimed to further explore the interactions between FTO and HFD and determine if FTO can influence the adverse metabolic consequence of HFD.
We studied mice deficient in FTO in two well validated models of leptin resistance (HFD feeding and central palmitate injection) to determine how Fto genotype may influence the action of leptin. Using transcriptomic analysis of hypothalamic tissue to identify relevant pathways affected by the loss of Fto, we combined data from co-immunoprecipitation, yeast 2-hybrid and luciferase reporter assays to identify mechanisms through which FTO can influence the development of leptin resistant states.
Mice deficient in Fto significantly increased their fat mass in response to HFD. Fto+/− and Fto−/− mice remained sensitive to the anorexigenic effects of leptin, both after exposure to a HFD or after acute central application of palmitate. Genes encoding components of the NFкB signalling pathway were down-regulated in the hypothalami of Fto-deficient mice following a HFD. When this pathway was reactivated in Fto-deficient mice with a single low central dose of TNFα, the mice became less sensitive to the effect of leptin. We identified a transcriptional coactivator of NFкB, TRIP4, as a binding partner of FTO and a molecule that is required for TRIP4 dependent transactivation of NFкB.
Our study demonstrates that, independent of body weight, Fto influences the metabolic outcomes of a HFD through alteration of hypothalamic NFкB signalling. This supports the notion that pharmacological modulation of FTO activity might have the potential for therapeutic benefit in improving leptin sensitivity, in a manner that is influenced by the nutritional environment.
PMCID: PMC4354923  PMID: 25830092
Fto; Leptin resistance; High-fat diet; NFкB; TRIP4; Hypothalamus; SOCS3; GWAS, Genome-wide association studies; SNPs, single nucleotide polymorphisms; FTO, FaT mass and Obesity related; HFD, high-fat diet; MEF, Mouse embryonic fibroblasts; Y2H, Yeast two-hybrid; Irx3, Iroquois Homeobox 3; ICV, intracerebroventricular injection; Ob-R, leptin receptor; SOCS3, suppressor of cytokine signalling; Tlr4, Toll-like receptor 4; PTPs, protein-tyrosine phosphatase; WAT, white adipose tissue
14.  Reproducibility and accuracy of body composition assessments in mice by dual energy x-ray absorptiometry and time domain nuclear magnetic resonance 
To assess the accuracy and reproducibility of dual-energy absorptiometry (DXA; PIXImus™) and time domain nuclear magnetic resonance (TD-NMR; Bruker Optics) for the measurement of body composition of lean and obese mice.
Subjects and measurements
Thirty lean and obese mice (body weight range 19–67 g) were studied. Coefficients of variation for repeated (x 4) DXA and NMR scans of mice were calculated to assess reproducibility. Accuracy was assessed by comparing DXA and NMR results of ten mice to chemical carcass analyses. Accuracy of the respective techniques was also assessed by comparing DXA and NMR results obtained with ground meat samples to chemical analyses. Repeated scans of 10–25 gram samples were performed to test the sensitivity of the DXA and NMR methods to variation in sample mass.
In mice, DXA and NMR reproducibility measures were similar for fat tissue mass (FTM) (DXA coefficient of variation [CV]=2.3%; and NMR CV=2.8%) (P=0.47), while reproducibility of lean tissue mass (LTM) estimates were better for DXA (1.0%) than NMR (2.2%) (

DXA and NMR provide comparable levels of reproducibility in measurements of body composition lean and obese mice. While DXA and NMR measures are highly correlated with chemical analysis measures, DXA consistently overestimates LTM and FTM (by ~8% and ~46%, respectively), while NMR only slightly underestimates LTM (by ~0.2%) and overestimates FTM (~15%.) The NMR method also has practical advantages compared to DXA, such as speed of measurement and the ability to scan unanesthetized animals.
PMCID: PMC3169293  PMID: 21909234
DXA; NMR; adiposity; obesity
European Journal of Human Genetics  2013;21(12):1417-1422.
Common intronic SNPs in the human fat mass and obesity associated (FTO) gene are strongly associated with body mass index (BMI). In mouse models, inactivation of the Fto gene results in a lean phenotype, whereas overexpression of Fto leads to increased food intake and obesity. The latter finding suggests that copy number variants at the FTO locus might be associated with extremes of adiposity. To address this question, we searched for rare, private or de novo copy number variation in a cohort of 985 obese and 869 lean subjects of European ancestry drawn from the extremes of the BMI distribution, genotyped on Affymetrix 6.0 arrays. A ∼680 kb duplication, confirmed by real-time PCR and G-to-FISH analyses, was observed between ∼rs11859825 and rs9932411 in a 68-year-old male with severe obesity. The duplicated region on chromosome 16 spans the entire genome-wide association studies risk locus for obesity, and further encompasses RBL2, AKTIP, RPGRIP1L and all but the last exon of the FTO gene. Affected family members exhibit a unique obesity phenotype, characterized by increased fat distribution in the shoulders and neck with a significantly increased neck circumference. This phenotype was accompanied by increased peripheral blood expression of RBL2 with no alteration in expression of FTO or other genes in the region. No other duplications or deletions in this region were identified in the cohort of obese and lean individuals or in a further survey of 4778 individuals, suggesting that large rare copy number variants surrounding the FTO gene are not a frequent cause of obesity.
PMCID: PMC3831078  PMID: 23591406
FTO; RBL2; CNV; obesity
PLoS ONE  2014;9(5):e97162.
Single nucleotide polymorphisms in the first intron of the fat-mass-and-obesity-related gene FTO are associated with increased body weight and adiposity. Increased expression of FTO is likely underlying this obesity phenotype, as mice with two additional copies of Fto (FTO-4 mice) exhibit increased adiposity and are hyperphagic. FTO is a demethylase of single stranded DNA and RNA, and one of its targets is the m6A modification in RNA, which might play a role in the regulation of gene expression. In this study, we aimed to examine the changes in gene expression that occur in FTO-4 mice in order to gain more insight into the underlying mechanisms by which FTO influences body weight and adiposity. Our results indicate an upregulation of anabolic pathways and a downregulation of catabolic pathways in FTO-4 mice. Interestingly, although genes involved in methylation were differentially regulated in skeletal muscle of FTO-4 mice, no effect of FTO overexpression on m6A methylation of total mRNA was detected.
PMCID: PMC4026227  PMID: 24842286
PLoS ONE  2010;5(11):e14005.
FTO (fat mass and obesity associated) was identified as an obesity-susceptibility gene by several independent large-scale genome association studies. A cluster of SNPs (single nucleotide polymorphism) located in the first intron of FTO was found to be significantly associated with obesity-related traits, such as body mass index, hip circumference, and body weight. FTO encodes a protein with a novel C-terminal α-helical domain and an N-terminal double-strand β-helix domain which is conserved in Fe(II) and 2-oxoglutarate-dependent oxygenase family. In vitro, FTO protein can demethylate single-stranded DNA or RNA with a preference for 3-methylthymine or 3-methyluracil. Its physiological substrates and function, however, remain to be defined. Here we report the generation and analysis of mice carrying a conditional deletion allele of Fto. Our results demonstrate that Fto plays an essential role in postnatal growth. The mice lacking Fto completely display immediate postnatal growth retardation with shorter body length, lower body weight, and lower bone mineral density than control mice, but their body compositions are relatively normal. Consistent with the growth retardation, the Fto mutant mice have reduced serum levels of IGF-1. Moreover, despite the ubiquitous expression of Fto, its specific deletion in the nervous system results in similar phenotypes as the whole body deletion, indicating that Fto functions in the central nerve system to regulate postnatal growth.
PMCID: PMC2982835  PMID: 21103374
Fat mass and obesity associated gene (FTO) plays an important role in appetite control and energy consumption in human and mice. In order to examine FTO expression influence on fat deposition in Suzhong pigs, FTO mRNA expression was detected in 16 tissues by RT-PCR, FTO protein expression was detected in 5 tissues by western blot, and association of FTO polymorphism with meat quality traits was analyzed in Suzhong populations with 714 records. RT-PCR results revealed that FTO mRNA was expressed in all sixteen tissues with significant differences (p<0.05), expression in backfat was significantly higher than that of any other tissue (p<0.05), and expression in longissimus dorsi muscle had the second highest significance level (p<0.05). Western blot results demonstrated that FTO protein was highly expressed in backfat and longissimus dorsi muscle. Furthermore, FTO mRNA and protein expression in tissues of high-fat pigs was significantly higher than that of low-fat pigs (p<0.05), suggesting FTO expression had advantageous effects on fat deposition. FTO polymorphism results evidenced that at A227G locus, G allele seemed to have advantageous effects on fat deposition, indicating it could be a significant candidate gene for improving pork quality in Suzhong pigs.
PMCID: PMC4093081  PMID: 25049719
FTO; Fat Deposition; Expression; Polymorphism; Suzhong Pig
Nature genetics  2010;42(12):1086-1092.
Genome-wide association studies have identified SNPs within the human FTO gene that display a strong association with obesity. Individuals homozygous for the at-risk rs9939609 A allele weigh ~3kg more. Loss of function and/or expression of FTO in mice leads to increased energy expenditure and a lean phenotype. We show here that ubiquitous overexpression of Fto leads to a dose-dependent increase in body and fat mass, irrespective of whether mice are fed a standard or high fat diet. The increased body mass results primarily from increased food intake. Glucose intolerance develops with increased Fto expression on a high fat diet. This study provides the first direct evidence that increased Fto expression causes obesity in mice.
PMCID: PMC3018646  PMID: 21076408
Obesity (Silver Spring, Md.)  2008;16(Suppl 3):S33-S39.
The genetics of human body fat content (obesity) are clearly complex. Genetic and physiological analysis of rodents have helped enormously in pointing to critical molecules and cells in central nervous system and “peripheral” pathways mediating the requisite fine control over the defense of body fat. Human and animal studies are consistent with inferences from evolutionary considerations that the strengths of defenses against fat loss are greater than those against gain. Many of the genes participating in these pathways have reciprocal effects on both energy intake and expenditure, though different genes may have primary roles in respective responses to weight gain or loss. Such distinctions have important consequences for both research and treatment strategies. The body mass index (BMI) is a useful gross indicator of adiposity, but more refined measurements of body composition and energy homeostasis will be required to understand the functional consequences of allelic variation in genes of interest. Phenotypes related to energy intake and expenditure—which clearly are the major determinants of net adipose tissue storage—are not salient when individuals are in energy balance (weight stable); measurements obtained during weight perturbation studies are likely to provide more revealing phenotypes for genetic analysis. The advent of high-density genome-wide scans in large numbers of human subjects for association analysis will revolutionize the study of the genetics of complex traits such as obesity by generating substantial numbers of powerful linkage signals from smaller genetic intervals. Many of the genes implicated will not have been previously related to energy homeostasis (e.g., recent experience with FTO/FTM as described below), and will have relatively small effects on the associated phenotype(s). The mouse will again prove useful in determining the relevant physiology of these new genes. New analytic tools will have to be developed to permit the necessary analysis of the gene × gene interactions that must ultimately convey aggregate genetic effects on adiposity.
PMCID: PMC2682366  PMID: 19037210
Diabetes  2009;58(10):2402-2408.
Common variants in FTO (the fat mass– and obesity-associated gene) associate with obesity and type 2 diabetes. The regulation and biological function of FTO mRNA expression in target tissue is unknown. We investigated the genetic and nongenetic regulation of FTO mRNA in skeletal muscle and adipose tissue and their influence on in vivo glucose and fat metabolism.
The FTO rs9939609 polymorphism was genotyped in two twin cohorts: 1) 298 elderly twins aged 62–83 years with glucose tolerance ranging from normal to type 2 diabetes and 2) 196 young (25–32 years) and elderly (58–66 years) nondiabetic twins examined by a hyperinsulinemic-euglycemic clamp including indirect calorimetry. FTO mRNA expression was determined in subcutaneous adipose tissue (n = 226) and skeletal muscle biopsies (n = 158).
Heritability of FTO expression in both tissues was low, and FTO expression was not influenced by FTO rs9939609 genotype. FTO mRNA expression in skeletal muscle was regulated by age and sex, whereas age and BMI were predictors of adipose tissue FTO mRNA expression. FTO mRNA expression in adipose tissue was associated with an atherogenic lipid profile. In skeletal muscle, FTO mRNA expression was negatively associated to fat and positively to glucose oxidation rates as well as positively correlated with expression of genes involved in oxidative phosphorylation including PGC1α.
The heritability of FTO expression in adipose tissue and skeletal muscle is low and not influenced by obesity-associated FTO genotype. The age-dependent decline in FTO expression is associated with peripheral defects of glucose and fat metabolism.
PMCID: PMC2750213  PMID: 19587359
Scientific Reports  2015;5:9233.
Common variants of human fat mass- and obesity-associated gene Fto have been linked with higher body mass index, but the biological explanation for the link has remained obscure. Recent findings suggest that these variants affect the homeobox protein IRX3. Here we report that FTO has a role in white adipose tissue which modifies its response to high-fat feeding. Wild type and Fto-deficient mice were exposed to standard or high-fat diet for 16 weeks after which metabolism, behavior and white adipose tissue morphology were analyzed together with adipokine levels and relative expression of genes regulating white adipose tissue adipogenesis and Irx3. Our results indicate that Fto deficiency increases the expression of genes related to adipogenesis preventing adipocytes from becoming hypertrophic after high-fat diet. In addition, we report a novel finding of increased Irx3 expression in Fto-deficient mice after high-fat feeding indicating a complex link between FTO, IRX3 and fat metabolism.
PMCID: PMC4363842  PMID: 25782772
The fat mass and obesity associated, FTO, gene has been shown to be associated with obesity in human in several genome-wide association scans. In vitro studies suggest that Fto may function as a single-stranded DNA demethylase. In addition, homologous recombination-targeted knockout of Fto in mice resulted in growth retardation, loss of white adipose tissue, and increase energy metabolism and systemic sympathetic activation. Despite these intense investigations, the exact function of Fto remains unclear. We show here that Fto is a transcriptional coactivator that enhances the transactivation potential of the CCAAT/enhancer binding proteins (C/EBPs) from unmethylated as well as methylation-inhibited gene promoters. Fto also exhibits nuclease activity. We showed further that Fto enhances the binding C/EBP to unmethylated and methylated DNA. The coactivator role of FTO in modulating the transcriptional regulation of adipogenesis by C/EBPs is consistent with the temporal progressive loss of adipose tissue in the Fto-deficient mice, thus suggesting a role for Fto in the epigenetic regulation of the development and maintenance of fat tissue. How FTO reactivates transcription from methyl-repressed gene needs to be further investigated.
PMCID: PMC2963669  PMID: 20858458
Obesity; adipogenesis; transcriptional coactivator; Fto; CCAAT/enhancer binding protein; DNA methylation
PLoS ONE  2012;7(12):e51082.
Fat mass and obesity associated gene (FTO) is the first gene associated with body mass index (BMI) and risk for diabetes. FTO is highly expressed in the brain and pancreas, and is involved in regulating dietary intake and energy expenditure. To investigate the transcriptional regulation of FTO expression, we created 5′-deletion constructs of the FTO promoter to determine which transcription factors are most relevant to FTO expression. The presence of an activation region at −201/+34 was confirmed by luciferase activity analysis. A potential Foxa2 (called HNF-3β) binding site and an upstream stimulatory factor (USF)-binding site was identified in the −100 bp fragment upstream of the transcription start site (TSS). Furthermore, using mutagenesis, we identified the Foxa2 binding sequence (−26/−14) as a negative regulatory element to the activity of the human FTO promoter. The USF binding site did not affect the FTO promoter activity. Chromatin immunoprecipitation (ChIP) assays were performed to confirm Foxa2 binding to the FTO promoter. Overexpression of Foxa2 in HEK 293 cells significantly down-regulated FTO promoter activity and expression. Conversely, knockdown of Foxa2 by siRNA significantly up-regulated FTO expression. These findings suggest that Foxa2 negatively regulates the basal transcription and expression of the human FTO gene.
PMCID: PMC3517585  PMID: 23236435
PLoS ONE  2014;9(6):e98984.
Previous studies have suggested that fat mass-and obesity-associated (FTO) gene is associated with body mass index (BMI) and the risk of obesity. This study aims to assess the association of five FTO polymorphisms (rs9939609, rs8050136, rs1558902, rs3751812 and rs6499640) with obesity and relative parameters in Han Chinese adolescents.
We examined a total of 401 adolescents, 223 normal weights (58.7% boys, 41.3% girls), 178 overweight (60.1% boys, 39.9% girls), aging from 14 to 18-years-old, recruited randomly from public schools in the central region of Wuxi, a southern city of China. DNA samples were genotyped for the five polymorphisms by Sequenom Plex MassARRAY. Association of the FTO polymorphisms with BMI, serum fasting plasm glucose (FPG), fasting insulin (FIns), triglyceride (TG) and cholesterol (TC) were investigated.
1) Serum FPG, FIns, TG and TC were statistically significant higher than that in normal control group. 2) We found that BMI was higher in the rs9939609 TA+AA, rs8050136 AC+AA, rs1558902 TA+AA and rs3751812 GT+TT genotypes than in wild TT genotypes (rs9939609: P = 0.038; rs1558902: P = 0.038;), CC genotypes(rs8050136: P = 0.024) and GG genotypes (rs3751812: P = 0.024), which were not significant on adjusting for multiple testing. 3) In case-control studies, five polymorphisms were not significantly associated with overweight (p>0.05), haplotype analyses showed non-haplotype is significantly associated with a higher risk of being overweight (p>0.05). 4) There existed no significant statistical difference about FPG, FIns, TG and TC in genotype model for any SNP.
Our study has conducted a genetic association study of the FTO polymorphisms with BMI, serum fasting plasm glucose (FPG), fasting insulin (FIns), triglyceride (TG) and cholesterol (TC). Our study found BMI of subjects with A allele of FTO rs9939609 is higher than that with T allele. Further studies on other polymorphisms from FTO and increasing the sample size are needed.
PMCID: PMC4049598  PMID: 24911064

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