IRS2 and obesity due to melanocortin 4 receptor deficiency: In obesity, although IL-4/STAT6 pathway was preserved, IL-4/Irs2/Akt pathway was selectively impaired due to downregulation of Irs2 induced by hyperinsulinemia via IR signaling, leading to impaired signaling in the IL-4/Irs2/Akt pathway and M2a-subtype MΦ activation by stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex (Fig. 7, right panel).