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The FTO gene rs9939609 obesity-risk allele and loss of control over eating

Unit on Growth and Obesity, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
American Journal of Clinical Nutrition (Impact Factor: 6.92). 10/2009; 90(6):1483-8. DOI: 10.3945/ajcn.2009.28439
Source: PubMed

ABSTRACT Children with rs9939609 FTO variant alleles (homozygous = AA and heterozygous = AT) are predisposed to greater adiposity than are those with 2 wild-type alleles (TT).
Because FTO is highly expressed in hypothalamic regions that are important for appetite, FTO genotype may affect energy balance by influencing eating behavior. Loss of control (LOC) eating, a behavior commonly reported by overweight youth, predicts excessive weight gain in children. However, the relation between FTO genotype and LOC eating has not been previously examined.
Two-hundred eighty-nine youth aged 6-19 y were genotyped for rs9939609, underwent body-composition measurements, and were interviewed to determine the presence or absence of LOC eating. A subset (n = 190) participated in a lunch buffet test meal designed to model an LOC eating episode. Subjects with AA and AT genotypes were grouped together for comparison with wild-type TT subjects.
Subjects with at least one A allele (67.7%) had significantly greater body mass indexes, body mass index z scores (P < 0.01), and fat mass (P < 0.05). Of the AA/AT subjects, 34.7% reported LOC compared with 18.2% of the TT subjects (P = 0.002). Although total energy intake at the test meal did not differ significantly by genotype (P = 0.61), AA/AT subjects consumed a greater percentage of energy from fat than did the TT subjects (P < 0.01).
Children and adolescents with 1 or 2 FTO rs9939609 obesity-risk alleles report more frequent LOC eating episodes and select foods higher in fat at a buffet meal. Both LOC eating and more frequent selection of energy-dense, palatable foods may be mechanisms through which variant FTO alleles lead to excess body weight.

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    • "FTO mRNA was widely expressed in fetal and adult tissues, especially in the brain, and in particular the hypothalamus, which is involved in energy balance (Dina et al., 2007; Frayling et al., 2007; Gerken et al., 2007). Moreover, several studies suggested that risk-allele carriers had greater food intake in human subjects (Cecil et al., 2008; Speakman et al., 2008), but not all (Tanofsky-Kraff et al., 2009). The risk-allele in human FTO may enhance the expression and/or activity of the FTO (Church et al., 2010). "
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    ABSTRACT: To investigate whether gene polymorphism of the fat mass and obesity associated gene (FTO) is associated with metabolic syndrome (MS), we used two MS criteria, the National Cholesterol Education Program-Adult Treatment panel III (NCEP-ATPIII) definition in 2003 and the Japanese definition in 2005. Subjects were respectively 859 and 865 Japanese workers at a company in Shimane Prefecture, Japan. They were non-MS individuals in 1998 and had regular health checkups between 1998 and 2006. The Cox proportional hazard regression was used to predict MS. Three SNPs in the FTO, rs9939609, rs1121980 and rs1558902, were genotyped by the TaqMan PCR assay and a retrospective study was performed. The three SNPs in the FTO were significantly associated with body mass index, and rs1121980 and rs1558902 were associated with fasting plasma glucose. MS defined by the NCEP-ATPIII definition was significantly associated with additive and dominant models of rs9939609 and rs1121980, and the dominant model of rs1558902, even after adjusting for confounding factors such as age, sex and lifestyle. MS defined by the Japanese definition was significantly associated with the additive model of rs1121980 and additive and dominant models of rs1558902 in multivariate analysis. These results suggested that FTO gene polymorphisms, rs9939609, rs1121980 and rs1558902, were associated with an increased risk of MS among Japanese workers.
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    • "This weight gain is likely due to the gene's involvement in the regulation of energy intake. According to recent studies, individuals carrying the at-risk allele prefer energy dense food [14], have reduced feelings of satiety [15], display loss of control over eating [16], consume more fat and calories (even after adjusting for BMI) [17], and display a greater tendency towards consuming palatable foods after eating a meal [18]. Thus, FTO seems to predispose individuals to greater caloric intake and reduced feelings of satiety. "
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    ABSTRACT: There is an emerging body of work indicating that genes, epigenetics, and the in utero environment can impact whether or not a child is obese. While certain genes have been identified that increase one's risk for becoming obese, other factors such as excess gestational weight gain, gestational diabetes mellitus, and smoking can also influence this risk. Understanding these influences can help to inform which behaviors and exposures should be targeted if we are to decrease the prevalence of obesity. By helping parents and young children change certain behaviors and exposures during critical time periods, we may be able to alter or modify one's genetic predisposition. However, further research is needed to determine which efforts are effective at decreasing the incidence of obesity and to develop new methods of prevention. In this paper, we will discuss how genes, epigenetics, and in utero influences affect the development of obesity. We will then discuss current efforts to alter these influences and suggest future directions for this work.
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    • "These results are in agreement with those from a large questionnaire study [8]. However, in another study where food intake was measured, FTO genotype was not associated with total energy intake, but rather with altered food preference; individuals with the A allele consumed a greater proportion of calories from fat [9]. These results suggest that FTO may affect body weight by influencing food intake and dietary composition. "
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    ABSTRACT: Single-nucleotide polymorphisms in the first intron of the ubiquitously expressed FTO gene are associated with obesity. Although the physiological functions of FTO remain unclear, food intake is often altered when Fto expression levels are manipulated. Furthermore, deletion of FTO from neurones alone has a similar effect on food intake to deletion of FTO in all tissues. These results indicate that FTO expression in the brain is particularly important. Considerable focus has been placed on the dynamic regulation of Fto mRNA expression in the hypothalamus after short-term (16-48 hour) fasting, but results have been controversial. There are no studies that quantify FTO protein levels across the brain, and assess its alteration following short-term fasting. Using immunohistochemistry, we found that FTO protein is widely expressed in mouse brain, and present in the majority of neurones. Using quantitative Western blotting and RT-qPCR we show that FTO protein and mRNA levels in the hypothalamus, cerebellum and rostral brain are relatively uniform, and levels in the brain are higher than in skeletal muscles of the lower limbs. Fasting for 18 hours does not alter the expression pattern, or levels, of FTO protein and mRNA. We further show that the majority of POMC neurones, which are critically involved in food intake regulation, also express FTO, but that the percentage of FTO-positive POMC neurones is not altered by fasting. In summary, we find no evidence that Fto/FTO expression is regulated by short-term (18-hour) fasting. Thus, it is unlikely that the hunger and increased post-fasting food intake caused by such food deprivation is driven by alterations in Fto/FTO expression. The widespread expression of FTO in neurones also suggests that physiological studies of this protein should not be limited to the hypothalamus.
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