While chronic inhibition of Arc POMC or PVH MC4R neurons led to massive obesity, animal models with chronic activation of either group, or with specific overexpression of POMC and its derived peptides α-MSH and β-endorphin in Arc POMC neurons, or specific overexpressing MC4Rs in PVH MC4R neurons, failed to cause a significant reduction in body weight or obesity development. Here, MC4R is linked to obesity due to melanocortin 4 receptor deficiency.