Andersen Mette K, Ängquist Lars, Bork-Jensen Jette, Jonsson Anna E, Stinson Sara E, Sandholt Camilla H, Thodberg Malte, Pikkupeura Laura Maarit, Ongstad Emily L, Grarup Niels, Astrup Arne, Pedersen Oluf, Williams Kristine, Barrès Romain, Sørensen Thorkild I A, Linneberg Allan, Grimsby Joseph, Rhodes Christopher J, Hansen Torben
1Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
2Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD.
Diabetes Care. 2023 May 1;46(5):985-992. doi: 10.2337/dc22-2078.
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, to assess whether PA and/or IS modify the association between rs9939609 and cardiometabolic traits, and to elucidate underlying mechanisms.
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.
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.
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.
体力活动（PA）和/或胰岛素敏感性（IS）会改变FTO基因rs9939609与肥胖之间的关联。我们旨在评估这些改变是否相互独立，评估PA和/或IS是否会改变rs9939609与心血管代谢特征之间的关联，并阐明潜在机制。
基因关联分析纳入了多达19585名个体。PA通过自我报告获取，IS根据反向HOMA胰岛素抵抗指数定义。在140名男性的肌肉活检样本和培养的肌肉细胞中进行了功能分析。
FTO基因rs9939609的A等位基因对体重指数（BMI）的增加作用在高PA组中减弱了47%（β[标准误]，-0.32[0.10]kg/m²，P = 0.0013），在高IS组中减弱了51%（-0.31[0.09]kg/m²，P = 0.00028）。有趣的是，这些相互作用基本相互独立（PA，-0.20[0.09]kg/m²，P = 0.023；IS，-0.28[0.09]kg/m²，P = 0.0011）。rs9939609的A等位基因还与全因死亡率升高和某些心血管代谢结局相关（风险比，1.07 - 1.20，P > 0.04），而这些影响往往会因更高的PA和IS而减弱。此外，rs9939609的A等位基因与骨骼肌组织中FTO的高表达相关（0.03[0.01]，P = 0.011），并且在骨骼肌细胞中，我们发现FTO启动子与包含rs9939609的增强子区域之间存在物理相互作用。
更高的PA和IS独立地降低了rs9939609对肥胖的影响。这些影响可能是通过骨骼肌中FTO表达的改变介导的。我们的结果表明，PA和/或其他增加胰岛素敏感性的方法可以抵消FTO相关的肥胖遗传易感性。
