PKR senses and responds to obesity, ER stress, and pathogen-related stress in concert with JNK, leading to metabolic disease under diverse physiological and pathological conditions. In this capacity, PKR not only integrates immune and metabolic response systems but also links endoplasmic reticulum homeostasis and unfolded protein response (UPR), to translational regulation through eIF2α and insulin signaling through IRS-1. Finally, the kinases, IRS-1 and eIF2α may represent a “metabolic inflammasome” complex assembled and regulated by PKR.