In contrast to the lean phenotype and the resistance to HFD-induced obesity in PIKO mice, inhibition of XBP1 in the hypothalamus results in an obese phenotype in mice [50], and activation of XBP1 in POMC neurons protects mice against HFD-induced obesity [42]. The gene discussed is POMC; the disease is obesity due to melanocortin 4 receptor deficiency.