Obesity associated genetic variation in FTO is associated with diminished satiety

Context: Polymorphisms within the FTO gene have consistently been associated with obesity across multiple populations. However, to date, it is not known whether the association between genetic variation in FTO and obesity is mediated through effects on energy intake or energy expenditure. Objective: Our objective was to examine the association between alleles of FTO known to increase obesity risk and measures of habitual appetitive behavior. Methods: The intronic FTO single nucleotide polymorphism (rs9939609) was genotyped in 3337 United Kingdom children in whom measures of habitual appetitive behavior had been assessed using two scales (Satiety Responsiveness and Enjoyment of Food) from the Child Eating Behaviour Questionnaire, a psychometric tool that has been validated against objective measures of food intake. Associations of FTO genotype with indices of adiposity and appetite were assessed by ANOVA. Results: As expected, the A allele was associated with increased adiposity in this cohort and in an independent case-control replication study of United Kingdom children of similar age. AA homozygotes had significantly reduced Satiety Responsiveness scores (P = 0.008, ANOVA). Mediation analysis indicated that the association of the AA genotype with increased adiposity was explained in part through effects on Satiety Responsiveness. Conclusions: We have used a unique dataset to examine the relationship between a validated measure of children’s habitual appetitive behavior and FTO obesity risk genotype and conclude that the commonest known risk allele for obesity is likely to exert at least some of its effects by influencing appetite