FGF21 and obesity due to melanocortin 4 receptor deficiency: To the best of our knowledge, this is the first study implementing a one-year life-style intervention program of diet and exercise, which has investigated the relation between Irisin, FGF-21, BMI, and cardiometabolic risk factors in such a large number of children and adolescents with overweight and obesity, and for such a long period of monitoring and follow-up.