The increased circulating free fatty acids in obesity probably triggers the early phase of microvascular dysfunction via downregulation of the of the endothelial AMPK-PI3K-Akt-eNOS pathway [59], while other factors such as alterations in adipokines (e.g., leptins, adiponectin, monocyte chemotactic protein-1, and retinol binding protein 4) and inflammatory cytokines (e.g., interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNFα)) released from both visceral and perivascular adipose tissue, help to drive the progression of the dysfunction (Figure 1) [60,61,62]. This evidence concerns the gene NOS3 and obesity due to melanocortin 4 receptor deficiency.