IRS1 and obesity due to melanocortin 4 receptor deficiency: In animal models of obesity, the infiltration of CD8+ T cells into adipose tissue precedes the recruitment of macrophages (23); and the resulting increase in local IL-6, TNF-α and other inflammatory mediators act on adipocyte surface receptors and other mechanisms to inhibit insulin signaling via reduced insulin receptor substrate-1 (IRS-1), phosphoinositide 3-kinase p85α, and glucose transporter type 4 (GLUT4) expression (17, 18, 23, 28–32).