Association Between Physical Activity and Risk of Non-Alcoholic Fatty Liver Disease: The Mediating Role of Insulin Resistance

Objective: This study aimed to investigate the association between physical activity and the risk of non-alcoholic fatty liver disease (NAFLD), with a specific focus on evaluating the potential mediating role of insulin resistance, quantified using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). Methods: Data for this analysis were derived from the National Health and Nutrition Examination Survey (NHANES), comprising 20,194 adults. To address the complex survey design and missing covariate data, analyses incorporated sampling weights and employed multiple imputation, respectively. Multivariable logistic regression models were employed to assess the association between physical activity levels and NAFLD risk. RCS analysis was conducted to examine potential nonlinear relationships. The mediating effect of HOMA-IR was evaluated using the SPSS PROCESS macro with the bootstrap method. Results: Compared to the low physical activity group, the high physical activity group exhibited a significantly reduced risk of NAFLD (adjusted OR = 0.84, P = 0.002). The RCS analysis suggested a nonlinear association between physical activity and NAFLD risk (P for nonlinearity < 0.05), with the lowest risk observed at moderate activity levels and a slight increase at very high levels. Nevertheless, after adjustment for confounders, the overall association trended toward a monotonic decrease. It is notable that the confidence intervals were wider in the high activity range. Mediation analysis revealed that HOMA-IR played a substantial mediating role in the inverse association between physical activity and NAFLD, accounting for 81.96% of the total effect (P < 0.001). Conclusion: Physical activity exerts an independent protective effect against NAFLD, an effect largely mediated by the amelioration of insulin resistance. Increasing physical activity levels, particularly to achieve and sustain a moderate-to-high intensity, may represent a significant public health strategy for mitigating the population-level risk of NAFLD.