A cell-autonomous mechanism that involves the negative regulation of IRS1 function by serine phosphorylation was implicated in the regulation of insulin resistance induced by JNK1 and possibly by IKKβ during obesity (Hirosumi et al., 2002; Sabio et al., 2010b). The gene discussed is IKBKB; the disease is obesity due to melanocortin 4 receptor deficiency.