INSR and obesity due to melanocortin 4 receptor deficiency: We first reported that SHP-1 negatively regulates glucose metabolism and insulin action through interfering with the insulin receptor-phosphoinositide 3-kinase-AKT (IR-PI3K-AKT) axis, and by inhibiting insulin clearance targeting carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1) thus ultimately contributing to obesity-linked insulin resistance (4, 13, 14).