Deletion of the TM domain of CREB3L4 results in retention of the protein in the nucleus.11 CREB3L4β, but not CREB3L4α, activates transcription of ER degradation-enhancing α-mannosidase-like protein (Edem), which enhances unfolded protein degradation, presumably by acting on the unfolded protein response element (UPRE).11 The role of CREB3L4 in ER stress is beginning to be understood, while its role in adipocyte differentiation and obesity is unknown. Here, CREB3L4 is linked to obesity due to melanocortin 4 receptor deficiency.