The relationship between obesity, IR and metabolic syndrome is still a matter of discussion and controversy; the two leading hypothesis being the conventional “calorie imbalance (calorie in; calorie out) model” and the more recent “carbohydrate-insulin model.” Whether hyperinsulinemia, a marker of IR, is the cause or effect, is also debated (95). Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.