Several intertwined mechanisms, including endothelial cell dysfunction from various factors, induction of immuno-inflammatory cascades in endothelial cells and perivascular adipocytes, dysregulation of redox hemostasias and extracellular matrix remodelling, are thought to mediate obesity-related structural and functional alterations in skeletal muscle microcirculation and contribute to insulin dysfunction and glucose dysregulation. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.