Purpose: Endocannabinoids (eCB) and interleukin 6 (IL-6) levels change during physical activity, thus suggesting their involvement in the modulation of exercise-related processes like inflammation and energy homeostasis. To investigate whether lifestyle might affect the activity of the eCB-degrading enzyme fatty acid amide hydrolase (FAAH), active and sedentary subjects were enrolled.
Methods: Plasma IL-6 levels and lymphocyte FAAH activity of eight physically active male subjects (mean ± SEM; age = 39.3 ± 2.9 yr, body mass index = 21.1 ± 0.4 kg·m), usually practicing aerobic exercise (8.1 ± 1.2 h·wk), and eight sedentary subjects (38.8 ± 3.7 yr, body mass index = 23.1 ± 0.8 kg·m) were measured. Also, in vitro effect of IL-6 was tested on FAAH expression and activity and on FAAH promoter activity in lymphocytes from sedentary subjects.
Results: Under resting conditions (at least 12 h from the last exercise), the active group showed plasma IL-6 levels (2.74 ± 0.73 pg·mL) and lymphocyte FAAH activity (215.7 ± 38.5 pmol·min·mg protein) significantly higher than those measured in the sedentary group (0.20 ± 0.02 pg·mL, and 42.0 ± 4.2 pmol·min·mg protein). Increased IL-6 levels paralleled increased FAAH activity, and consistently, the in vitro treatment of lymphocytes from sedentary individuals with 10 ng·mL IL-6 for 48 h significantly increased FAAH expression and activity. Transient transfection experiments showed that IL-6 induced the expression of a reporter gene under the control of a cAMP response element-like region in the human FAAH promoter. A mutation in the same element abolished IL-6 up-regulation, demonstrating that this cytokine regulates FAAH activity at the transcriptional level.
Conclusion: IL-6 leads to activation of the FAAH promoter, thus enhancing FAAH activity that modulates the eCB tone in physically active people.