In addition, the IL-4/IRS2 pathway is essential for M2 activation in the steady state of VAT, whereas in obesity, hyperinsulinemia inhibits the IL-4/IRS2 pathway by reducing IRS2 expression on macrophages, which finally leads to the impairment of M2 activation (27). Here, IL4 is linked to obesity due to melanocortin 4 receptor deficiency.