NF-κB is activated in obesity—a state of chronic overnutrition40—by persistent endoplasmic reticulum (ER) stress: activation of the protein kinase RNA-like ER kinase (PERK)–eukaryotic translation initiation factor (eIF)2α pathway suppresses IκB translation41, while activated inositol-requiring protein (IRE)1α interacts with TNF receptor-associated factor 2 to activate IKK42 as well as JNK43, leading to NF-κB activation. The gene discussed is NFKB1; the disease is obesity due to melanocortin 4 receptor deficiency.