Studies have consistently shown that FTO SNPs are not associated with physical activity levels,43,100,110-114 which has been convincingly confirmed in a large-scale meta-analysis of published and unpublished data of 218,166 adults and 19,268 children.115 Although physical activity does not seem to mediate the association between FTO and obesity-susceptibility, this meta-analysis showed that the effect of FTO on BMI and obesity risk is approximately 30% smaller in physically active than in sedentary individuals, at least in adults,115 thereby firmly confirming observations of a growing number of individual studies.43,73,112-114,116,117 This observation emphasizes the importance of physical activity in body weight regulation in adults, showing that even those who are genetically susceptible benefit from being active. It remains unclear what the biological mechanisms are behind the observed interaction between physical activity and FTO and whether this effect attenuation is observed only with physical activity or also with other lifestyle factors. Some studies have suggested that also dietary habits and energy intake97,100,108 and smoking72 might attenuate the effects of FTO on obesity susceptibility. Variants in the first intron of FTO have been shown to be associated with methylation capability, such that some have speculated that this region might be sensitive to epigenetic effects.118-120
