Here, we report that in mice with obesity-induced diabetes, chronic restoration of aortic SIRT1 levels (i) increased night time activity and energy expenditure of the mice, (ii) reduced weight gain, (iii) improved glucose metabolism, (iv) significantly improved endothelial dysfunction, (v) reduced increased PWV, an index of vascular compliance due to reversed vascular remodelling, (vi) restoring eNOS activity by increasing phosphorylation at its active site Ser1177, (vii) down-regulated NOX1 and NOX4, and (viii) eventually attenuated oxidative stress in the vessel wall. The gene discussed is NOX4; the disease is obesity due to melanocortin 4 receptor deficiency.