In agreement with the role of ER stress in obesity, Williams and colleagues [81] have demonstrated that an inducible, constitutive expression of XBP1 selectively in hypothalamic POMC neurons of mice placed on a HFD can confer resistance to diet-induced obesity, most likely due to enhanced leptin and insulin sensitivity and increased energy expenditure. This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.