Herein we report, for the first time, that the three UPR signal transducers, IRE1α, PERK, and ATF6 (Hetz and Papa, 2018), and two effector systems downstream the UPR branches, CHOP and XBP1 splicing, are dysregulated in primary SC and OM preadipocytes in the transition from NG to IR/T2D in severe obesity, in terms of total protein content and/or phosphorylation rate (i.e. activation). This evidence concerns the gene EIF2AK3 and obesity due to melanocortin 4 receptor deficiency.