AbstractBackgroundWe previously reported an association of high fat mass levels from age 9 to 15 years with lower forced expiratory flow in 1 s (FEV₁)/forced vital capacity (FVC) ratio (i.e., increased risk of airflow limitation) at 15 years. Here, we aimed to assess whether insulin resistance and C‐reactive protein (CRP) at 15 years partially mediate this association.MethodsWe included 2263 children from the UK Avon Longitudinal Study of Parents and Children population‐based cohort (ALSPAC). Four fat mass index (FMI) trajectories (“low,” “medium‐low,” “medium‐high,” “high”) from 9 to 15 years were previously identified using Group‐Based Trajectory Modeling. Data on CRP, glucose, insulin, and post‐bronchodilator FEV₁/FVC were available at 15 years. We defined insulin resistance by the homeostasis model assessment‐estimated insulin resistance index (HOMA‐IR). We used adjusted linear regression models and a causal mediation analysis to assess the mediating role of HOMA‐IR and CRP.ResultsCompared to children in the “low” FMI trajectory, children in the “medium‐high” and “high” FMI trajectories had lower FEV₁/FVC at 15 years. The percentage of the total effect explained by HOMA‐IR was 19.8% [−114.1 to 170.0] and 20.4% [1.6 to 69.0] for the “medium‐high” and “high” trajectories, respectively. In contrast, there was little evidence for a mediating role of CRP.ConclusionThe association between mid‐childhood fat mass and FEV₁/FVC ratio at 15 years may be partially mediated by insulin resistance.