Obesity-associated genetic variation within the FTO gene likely to be associated with diminished satiety
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Polymorphisms within the FTO gene have been strongly and replicably linked to obesity (especially AA homozygosity for the high-risk allele rs9939609), with FTO increasingly considered a common obesity susceptibility gene in Caucasians. It is not yet known whether the association between FTO polymorphisms and obesity is mediated through effects on energy intake or energy expenditure. The former hypothesis is indirectly supported by findings of high expression of FTO mRNA in the hypothalamus. This study aimed to examine the association between alleles of the FTO gene known to increase obesity risk and measures of appetite behaviour. To this end, the intronic FTO SNP (rs9939609) was genotyped in 3337 children from the UK. For these children, measures of habitual appetitive behaviour had been assessed using two scales from the Child Eating Behaviour Questionnaire, a psychometric tool validated against objective measures of food intake. Data analysis revealed that the A allele was associated with increased adiposity in this study cohort as well as in an independent case-control replication study including UK children of the same age. Significantly reduced Satiety Responsiveness scores were observed in AA homozygotes. Moreover, mediation analysis revealed that the association between the AA genotype and increased adiposity was at least partly explained through effects on Satiety Responsiveness. In conclusion, this study used a unique dataset to investigate the relationship between a validated measure of children’s habitual appetite behaviour and FTO obesity-risk genotype. Data analysis demonstrated that the commonest known risk allele for obesity exerts at least some of its effects by influencing appetite.
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