These studies of IRS‐1 phosphorylation in mice suggest that the obesity of the metabolic syndrome might result in insulin resistance via obesity‐related chronic inflammation and activation of the JNK1 pathway and the IKK‐NFkB cascade causing serine phosphorylation of IRS‐1 at Ser307 and Ser636. The gene discussed is IRS1; the disease is obesity due to melanocortin 4 receptor deficiency.