The Potential Mediating Role of HDL-Cholesterol Concentrations in the Association between Physical Activity and Depression: A Nationwide Population-Based Study

Background: Depression is a leading cause of global disability. Physical activity (PA) has been found to be associated with lower risk of depression, but the underlying biological mediating factors remain understudied. HDL cholesterol (HDL-C) is an important biomarker with neuroprotective properties, however, its potential mediating role in the relationship between PA and depression has not been explored. Objectives: Our study aimed to investigate the role of HDL cholesterol in the association between PA and depressive symptoms. Methods: A total of 16,535 adults from the NHANES (2009-2016) were analyzed. Depression was assessed with the Patient Health Questionnaire-9, and data on PA and HDL-C were collected for each participant. Multivariate logistic regressions, subgroup analysis, mediation analysis, and sensitivity analysis were performed. Results: After adjusting for covariates, individuals with sufficient PA had 57% lower prevalence of depression [odds ratio (OR): 0.43; 95% confidence interval (CI): 0.35, 0.53] compared with those reporting insufficient PA. Of note, each unit increase in HDL-C associated with 23% lower odds of depression (OR: 0.77; 95% CI: 0.65, 0.90). Mediation analysis suggested a small but statistically significant indirect effect of HDL-C in the association between PA and depressive symptoms (indirect effect: -0.03; 95% CI: -0.04, -0.01), accounting for 3.3% of the total effect. Conclusions: PA showed a protective association with depression through mediation of HDL-C, highlighting a metabolic pathway in the association between PA and mental health. Promoting PA and optimizing HDL-C concentration may help prevent depression at population levels.