Physical activity and insulin sensitivity independently attenuate the effect of FTO rs9939609 on obesity

<p>  </p> <p><strong>Objective</strong></p> <p>The association between <em>FTO</em> rs9939609 and obesity is modified by physical activity (PA) and/or insulin sensitivity (IS). We aimed to assess whether these modifications are independent, if PA and/or IS modify the association between rs9939609 and cardiometabolic traits, and to elucidate underlying mechanisms.</p> <p><strong>Research Design and Methods</strong></p> <p>Genetic association analyses comprised up to 19,585 individuals. PA was self-reported and IS was defined based on inverted HOMA-IR. Functional analyses were performed in muscle biopsies from 140 men, and in cultured muscle cells.</p> <p><strong>Results</strong></p> <p>The BMI-increasing effect of the <em>FTO</em> rs9939609 A-allele was attenuated by 47% with high PA (β (standard error (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 <em>FTO </em>in skeletal muscle tissue (0.03 (0.01), p=0.011), and in skeletal muscle cells, we identified a physical interaction between the <em>FTO</em> promoter and an enhancer region encompassing rs9939609. </p> <p><strong>Conclusions </strong></p> <p>Greater PA and IS independently reduced the effect of rs9939609 on obesity. These effects might be mediated through altered expression of <em>FTO</em> in skeletal muscle. Our results indicated that PA and/or other means of increasing insulin sensitivity could counteract <em>FTO</em>–related genetic predisposition to obesity.</p>