Since our pioneer study (Tanti et al., 1994), it is now admitted that during obesity, activation of inflammatory, and stress kinases such as JNK and IKK is responsible for an uncontrolled phosphorylation of IRS on inhibitory serine sites resulting in a decrease in IRS tyrosine phosphorylation and a desensitization of insulin signaling (Boura-Halfon and Zick, 2009; Tanti and Jager, 2009). The gene discussed is MAPK8; the disease is obesity due to melanocortin 4 receptor deficiency.