• Jiacheng Wang, Yi Zheng, Yanfeng Jiang, Chen Suo, Tiejun Zhang, Xingdong Chen, and Kelin Xu.
• School of Public Health, and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China.
• Prev Med. 2024 Dec 19; 191: 108211108211.

ObjectivePhysical activity has protective effects on cardiometabolic diseases (CMDs), but the role of metabolism related to physical activity in this process is unclear.MethodsIn the prospective cohort study from UK Biobank between 2006 and 2022, participants free of CMDs at baseline were included (n = 73,990). We identified physical activity-related metabolites and constructed metabolic signature using linear regression and elastic net regression. Association between physical activity, metabolic signature, and CMDs (type 2 diabetes [T2D], coronary heart disease [CHD], and stroke) were explored using Cox and mediation analyses. Interactions between the metabolic signature and genetic susceptibility (categorized into "low" and "high" based on the median of polygenic risk scores) were assessed by additive hazard models and relative excess risk due to interaction (RERI). Multi-state models evaluated the association between metabolic signature and disease progression.ResultsWe found 58 metabolites were related to physical activity, of which 17 were used to construct metabolic signature. The metabolic signature was associated with reduced risk of T2D (HR = 0.13[0.10-0.16]), CHD (HR = 0.40[0.34-0.47]), and stroke (HR = 0.67[0.53-0.86]), and mediated 40.56 % of the association between physical activity and T2D. The metabolic signature exhibited additive interactions with genetic risk for T2D (RERI = 1.57[1.09-2.05]) and CHD (RERI = 0.27[0.05-0.49]). Finally, the metabolic signature was associated with a reduced risk of transition from CMD to CMM (HR = 0.58[0.42-0.81]).ConclusionPhysical activity-related metabolic signature is linked to reduced risks of CMDs and CMM. We once again emphasize the importance of physical activity for CMDs prevention from a metabolic perspective, especially for individuals at high genetic risk.Copyright © 2024 Elsevier Inc. All rights reserved.

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