Absence of adipose tissue in congenital generalized lipodystrophy (CGL) leads to metabolic and cardiovascular disease and reduced leptin levels. We tested the hypothesis that leptin supplementation restores endothelial function and reduces vascular adrenergic response respectively via acting directly on endothelial cells (EC) and desensitizing vascular adrenergic response, in CGL mice. Deletion of Berardinelli-Seip gene (Bscl2) was used to mimic the human pathology in mice. Bscl2-/- mice showed reduced adipose mass [% of fat: wild-type (WT): 8.6 ± 0.3 vs Bscl2-/-: 2.4 ± 0.1, P<0.05], leptin levels [ng/mL: WT: 4.0 ± 0.3 vs Bscl2-/-: 0.3 ± 0.1, *P<0.05], impaired aortic endothelium-dependent relaxation to acetylcholine (Ach): [% relaxation: WT: 71.9 ± 1 vs Bscl2-/-: 49.9 ± 2*, *P<0.05], increased vascular contractility to phenylephrine (Phe), associated with upregulation of α-adrenergic receptors, high mean arterial pressure (MAP) and reduced heart rate (HR): [(mmHg: WT: 100.7 ± 5 vs Bscl2-/-: 109.5 ± 6*), (bpm: WT: 592.7 ± 9 vs Bscl2-/-: 542.9 ± 15*) *P<0.05]. Moreover, Bscl2-/- mice shown increase in Nox1 gene expression and increases in vascular - O 2 and H 2 O 2 levels. Both chronic (in vivo) and acute (organ bath) leptin supplementation or NOX 1 inhibition (GKT771, 10μM) restored endothelial function in addition to reducing endothelial Nox1 expression and ROS production, which suggest a direct role for leptin in endothelial cells. EC leptin receptor deficiency induced an endothelial dysfunction in mice, which was restored by Nox1 inhibition, further supporting a direct role of leptin in endothelial cells. In parallel, leptin supplementation reduced vascular adrenergic tone and aortic α-adrenergic receptors and increased in HR without changing MAP. Our data show that leptin replacement restores endothelial function and reduces vascular adrenergic tone in mouse model of congenital lipodystrophy by acting directly in EC and desensitizing vascular adrenergic response, respectively. This highlight the importance of leptin in the maintenance of vascular homeostasis and presents leptin as a potential therapeutic avenue for the treatment of vascular diseases associated with low leptin levels.