Prebiotic fiber supplementation, aerobic exercise, and the combination of the two interventions completely prevented knee joint damage that is otherwise observed in this rat model of obesity. Prevention of knee damage was associated with a normalization of insulin resistance, leptin levels, dyslipidemia, gut microbiota, and endotoxemia in the high-fat/high-sucrose –fed rats. The gene discussed is LEP; the disease is obesity due to melanocortin 4 receptor deficiency.