IRE1 dysfunction contributes to the development of numerous diseases, including cancer (such as multiple myeloma [Mimura et al., 2012]), metabolic disorders (such as obesity and diabetes [Fonseca et al., 2009; Hotamisligil, 2010]) and neurodegenerative diseases (such as amyotrophic lateral sclerosis and Hungtinton’s disease [Hetz et al., 2009; Matus et al., 2009; Vidal et al., 2012]). Here, ERN1 is linked to obesity due to melanocortin 4 receptor deficiency.