Loss of SIRT3 in endothelium elevates mitochondrial superoxide, blunts Akt/eNOS signaling, reduces NO bioavailability, and drives endothelial dysfunction; these effects are shown in humans with obesity and in rodent hypertension models, and endothelial-specific SIRT3 knockout causes diastolic dysfunction via impaired glycolysis and angiogenesis [124,125,126]. Here, SIRT3 is linked to obesity due to melanocortin 4 receptor deficiency.