Abstract
Objective: FKBP5 is a critical gene involved in regulating the hypothalamic-pituitary-adrenal (HPA) axis and stress response. Aberrant DNA methylation at FKBP5 cytosine-phosphate-guanine (CpG) sites, such as cg22363520 and cg00862770, has been implicated in mental health disorders and metabolic diseases, including Type 2 diabetes. Exercise is a modulator of DNA methylation and metabolic health. This study investigates the interaction between exercise, diabetes, and FKBP5 methylation at cg22363520 and cg00862770 and explores their implications for mental health and disease development. Materials and Methods: FKBP5 methylation levels at cg22363520 and cg00862770 were analyzed in a cohort stratified by diabetes and exercise. Multiple linear regression models assessed the main effects and interactions of exercise and diabetes on FKBP5 methylation, with further stratified analyses for site-specific effects. Results: Exercise and diabetes showed significant and site-specific effects on FKBP5 methylation at cg22363520 and cg00862770. At cg22363520, exercise significantly reduced methylation levels in nondiabetic participants (β = -0.00195, p = 0.0157), while no significant effect was observed in diabetic individuals. Conversely, at cg00862770, exercise significantly decreased methylation levels in diabetic participants (β = -0.00611, p = 0.0081), with no significant effect in the nondiabetic group. Diabetes itself was associated with increased FKBP5 methylation at both sites, particularly in individuals without regular exercise. Additionally, significant interaction effects between exercise and diabetes were identified for both cg22363520 (p = 0.0336) and cg00862770 (p = 0.0021), highlighting the interplay between metabolic status and physical activity in regulating FKBP5 methylation. Conclusion: This study demonstrates that the effects of exercise on FKBP5 methylation are site-specific and influenced by diabetes status. Exercise reduces methylation at cg22363520 in nondiabetics and at cg00862770 in diabetics, indicating its role in modulating epigenetic regulation of stress and metabolic pathways. These findings underscore the interplay between exercise, diabetes, and FKBP5 methylation, with potential implications for improving mental health and metabolic outcomes.