The effects of metformin on endothelial function are largely mediated through AMPK and PPARδ with a subsequent alleviation of ER stress and oxidative stress as well as increased eNOS activity and NO production, highlighting the central role of PPARδ downstream of AMPK activation to combat against diabetes- and obesity-related vasculopathy, inflammation and hypertension [91,92,93]. The gene discussed is PRKAA2; the disease is obesity due to melanocortin 4 receptor deficiency.