Leisure-time physical activity on lifelong trajectories of body mass index and obesity risk throughout life: multivariable regression and Mendelian randomization analyses using real-world data from the CORDELIA-Catalunya Study

BackgroundEvidence on how leisure-time physical activity (LTPA) improves lifetime body mass index (BMI) remains fragmented and prone to confounding. MethodsWe pooled 14,993 adults (30-90 y; 52.7% women; cohorts: REGICOR-ACRISC, ILERVAS, ARTPER) with baseline estimated LTPA (moderate-to-vigorous LTPA [MVLTPA] in REGICOR-ACRISC), genotype, and repeated BMI values from electronic health records (1990-2024, 36,157 measures). LTPA was categorized into cohort-specific quartiles; MVLTPA in 0, <100, <200, and [&ge;]200 METs-min/day. In one-sample Mendelian randomization analyses, we categorized participants in quartiles of a cardiorespiratory fitness polygenic risk score derived from a large GWAS in UK Biobank. Group-dependent BMI trajectories were modeled using spline mixed-effects models. Obesity onset (first BMI [&ge;]30 kg/m2) was analyzed with IPW-weighted Kaplan-Meier curves and Cox models. ResultsHigher LTPA was associated with slower BMI increases in ages 30-60 (Q1: +0.120 vs Q4: +0.075 kg/m2{middle dot}year), slower declines in ages 70-90 (Q1: -0.143 vs Q4: -0.123 kg/m2{middle dot}year), and lower obesity risk (Q4 vs Q1: HR 0.83, 95% CI 0.72-0.96). Similar trends were observed for MVLTPA. Higher genetically determined cardiorespiratory fitness showed parallel gradients (ages 30-60, Q1: +0.109 vs Q4: +0.101 kg/m2{middle dot}year; ages 70-90, Q1: -0.130 vs Q4: -0.102 kg/m2{middle dot}year) and lower obesity risk (Q4 vs Q1: HR 0.66, 0.56-0.78). Associations were present for women and men separately, but were stronger in men. ConclusionsHigher LTPA and MVLTPA were associated with more favorable lifelong BMI trajectories, delayed obesity risk, and convergent support from Mendelian randomization analyses, supporting a causal protective role of physical activity (in both sexes but stronger in men).