Collectively, these results support that the TRPM2 channel in endothelial cells act as a critical molecular mechanism underlying obesity-associated endothelial insulin resistance [99]; high levels of free fatty acids such as palmitate stimulate ROS generation in endothelial cells to induce TRPM2-mediated Ca2+ signaling and activation of the downstream Ca2+-dependent CaMKII/PERK/ATF4/TRB4 signaling pathway to inhibit insulin-induced eNOS activation and endothelial NO generation and, therefore, endothelium-dependent vasorelaxation (Figure 5). This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.