The chronic inflammation typical of obesity can alter GR functioning, preventing the negative feedback generated by cortisol on the HPA axis, and proinflammatory cytokines activate elements of the cellular transduction cascades that prevent GR translocation to the nucleus or interfere with the interaction of GRs with response elements that promote gene activation [53], resulting in insensitivity to GC and loss of anti-inflammatory feedback [52]. The gene discussed is NR3C1; the disease is obesity due to melanocortin 4 receptor deficiency.