INS and obesity due to melanocortin 4 receptor deficiency: In obesity, PVAT-secreted high-concentrations of adipokines (e.g., TNF-α and IL-6) access the vascular lumen and suppress the PI3-K pathway of insulin signaling, which unlocks the vasoconstrictor effects of endothelin 1, leading to a reduction in insulin-mediated muscle nutritive blood flow, contributing to insulin resistance (23).