LEP and obesity due to melanocortin 4 receptor deficiency: The significance of the melanocortin system is not only due to the direct action of leptin in the hypothalamus but also the fact that the loss of melanocortin 4 receptor (MC4R) function, a key MCR expressed in the hypothalamus, is the most common genetic cause of obesity in humans and occurs in 3-5% people with extreme obesity (38, 39).