Premenopausal women have a better endothelial function than men but are more sensitive to obesity induced endothelial dysfunction (ED) and more reactive to mineralocorticoid receptor (MR) blockade. Due to its control of sympathetic activity, leptin has been reported to be the link between metabolic and cardiovascular disease (CVD) in men. Whether a similar correlation exists in females that secrete 4 times more leptin than men is unknown. Using a population based study and mice deficient (KO) in protein tyrosine phosphatase 1B (PTP1B), a leptin sensitizer, we tested the hypothesis that leptin mediated CVD involves sex specific mechanisms. Plasma leptin were 4 times higher in female mice (KOF:1648±271 vs KOM: 347±47 pg/ml; p<0.05) indifferently of the genotype (WTF: 2386±765 vs WTM: 375±37 pg/ml; p<0.05). PTP1B deletion increased leptin sensitivity and raised blood pressure (BP) to a similar extent in males and females (124±4 vs 126±4 respectively; WT 102±5 mmHg) but induced ED in females KO only (p<0.01 vs WT and males). Sympathetic tone was assessed by measuring BP response to ganglionic blockade. Leptin sensitized males only exhibit an increased sympathetic tone, but leptin sensitized females only exhibit high plasma aldosterone levels (aldo; KOF:1234±173 vs WTF: 545±71and KOM: 624±70 pg/ml). Both leptin receptor antagonist and MR blockade restored BP in KO females. In vivo and ex vivo (aortic ring) MR blockade restored endothelial function in females KO suggesting direct aldo effects on the vessels. Neither corticosterone, potassium nor angiotensin II was increased in KO females. However aldosterone synthase expression was impressively increased in females KO only. Aldo levels are low in obese leptin receptor deficient females (333±89 pg/ml), and leptin directly stimulates aldosterone secretion in glomerulosa cells. In parallel we demonstrated that African American adolescent females secrete 4 times more leptin than males, and established a correlation between leptin and aldosterone(r=0.464, p=0.011) in female subjects only. These human and animal data suggest that leptin regulates aldo secretion in females. All together these data suggest that obesity mediated CVD is leptin dependent and involves aldo dependent mechanisms in females.