Physical Activity and Insulin Sensitivity Independently Attenuate the Effect of FTO rs9939609 on Obesity

OBJECTIVE The association between FTO rs9939609 and obesity is modified by physical activity (PA) and/or insulin sensitivity (IS). We aimed to assess whether these modifications are independent, whether PA and/or IS modify the association between rs9939609 and cardiometabolic traits, and to elucidate underlying mechanisms. RESEARCH DESIGN AND METHODS Genetic association analyses comprised up to 19,585 individuals. PA was self-reported, and IS was defined based on inverted HOMA insulin resistance index. Functional analyses were performed in muscle biopsies from 140 men, and in cultured muscle cells. RESULTS The BMI-increasing effect of the FTO rs9939609 A allele was attenuated by 47% with high PA (β [SE], −0.32 [0.10] kg/m2, P = 0.0013), and by 51% with high IS (−0.31 [0.09] kg/m2, P = 0.00028). Interestingly, these interactions were essentially independent (PA, −0.20 [0.09] kg/m2, P = 0.023; IS, −0.28 [0.09] kg/m2, P = 0.0011). The rs9939609 A allele was also associated with higher all-cause mortality and certain cardiometabolic outcomes (hazard ratio, 1.07–1.20, P > 0.04), and these effects tended to be weakened by greater PA and IS. Moreover, the rs9939609 A allele was associated with higher expression of FTO in skeletal muscle tissue (0.03 [0.01], P = 0.011), and in skeletal muscle cells, we identified a physical interaction between the FTO promoter and an enhancer region encompassing rs9939609. CONCLUSIONS Greater PA and IS independently reduced the effect of rs9939609 on obesity. These effects might be mediated through altered expression of FTO in skeletal muscle. Our results indicated that PA and/or other means of increasing insulin sensitivity could counteract FTO-related genetic predisposition to obesity.