The critical role of the hypothalamic circuits in causing obesity is proven by the fact that all the rare forms of severe obesity arising from single-gene mutations are related to alterations in genes involved in the normal functioning of the circuits, like leptin, leptin receptor, pro-opiomelanocortin (POMC), prohormone subtilisin/kexin 1 convertase (PCSK1) and melanocortin receptor (MC4-R) [2]. The gene discussed is PCSK1; the disease is obesity due to melanocortin 4 receptor deficiency.