NF-κB, an important mediator of metabolic inflammation, is enriched in hypothalamic neurons but normally remains inactive.21 Over-nutrition alone, even before the onset of obesity, activates hypothalamic NF-κB partly through increased endoplasmic reticulum stress.21 Furthermore, activation of hypothalamic NF-κB interrupts central insulin and leptin signalling and actions, whereas local suppression in the mediobasal hypothalamus, or more specifically in hypothalamic Agouti-related peptide neurons, significantly protects against obesity and glucose intolerance.21 The gene discussed is INS; the disease is obesity due to melanocortin 4 receptor deficiency.