INSR and obesity due to melanocortin 4 receptor deficiency: Nevertheless, these limitations, the profound endothelial dysfunction in S961-treated mice in both the TA and AA related to a direct effect of IRA (insulin receptor blockade and hyperglycemia) as well as indirectly by eliciting altered signaling in PVAT [14] uncovered that altered insulin signaling in diabetes induces not only pronounced endothelial dysfunction as evidenced by numerous previous studies, but simultaneously induces PVAT dysfunction, even in the absence of fat overload and obesity.