With these unique intrinsic molecular functions of PKR, it was perhaps not surprising that in obesity, PKR was found to be activated in metabolic tissues, and, upon activation, PKR induces JNK activation and eIF2α phosphorylation, followed by the inhibitory serine phosphorylation of insulin receptor substrate-1 (IRS-1), a critical insulin signaling component, by directly acting on IRS-1 or by indirectly activating JNK respectively (20). Here, EIF2AK2 is linked to obesity due to melanocortin 4 receptor deficiency.