These findings suggest that implementing a combined aerobic and resistance exercise program, or a low-frequency HIIT protocol performed at least twice weekly for a minimum of 6–8 weeks, constitutes an effective strategy to reduce systemic inflammation mediated by the NLRP3 inflammasome and IL-1β, particularly in individuals with obesity and type 2 diabetes mellitus. Here, IL1B is linked to obesity due to melanocortin 4 receptor deficiency.