An intervention study supports this concept as they proposed that changes in HOMA-IR through exercise training were independently correlated with changes in RHI in patients with obesity.34 Along these lines, experimental data in mouse models of obesity demonstrated that reduced glucose uptake within the skeletal muscle is caused by impaired insulin signaling in endothelial cells due to reduced insulin-induced endothelial NO (vasodilator) synthase phosphorylation and insulin receptor substrate 2 expression. The gene discussed is IRS2; the disease is obesity due to melanocortin 4 receptor deficiency.