Here, our main focus was related to the description of recent studies regarding hypothalamic energy balance control and obesity, particularly triggered by HFD, because it has been widely documented that overnutrition, especially lipid overload, induces a state of hypothalamic dysfunction in which low-grade inflammation (or “metaflammation”) through TLR4 receptor and NFK-B pathways, ER stress, and lipotoxicity are tightly associated with insulin/leptin resistance in a vicious cycle. The gene discussed is INS; the disease is obesity due to melanocortin 4 receptor deficiency.