Foundational experimental studies, in both humans and mice, demonstrated that adipose expression of TNF-α drives obesity-associated insulin resistance; resistin and RBP4 link adipocyte inflammation to systemic metabolic and vascular injury; and reduced adiponectin and omentin expression attenuates AMP-activated protein kinase and endothelial nitric oxide synthase (eNOS) signaling [25,26,27,28,29,30,31]. This evidence concerns the gene RETN and obesity due to melanocortin 4 receptor deficiency.