Abstract Body: Introduction: Previous work from our group demonstrated that leptin is a major contributor to obesity-associated cardiovascular disease, in females, by acting on the adrenal gland to promote aldosterone production.
Hypothesis: This leptin-mediated aldosterone secretion is dependent on the presence of the long form leptin receptor (LepRb) in adrenal aldosterone synthase (AS) expressing cells.
Methods: We generated AS LepRb deficient mice, ASKO and WT control (ASWT), by crossing LepRb^flox/flox mice with AS-Cre mice to investigate the role of LepRb in AS expressing cells in leptin-mediated cardiovascular alteration in females and also generated db/AS⁺ mice that have LepRb only in AS expressing cells by crossing LepR^TBflox/flox (db/db) with AS-Cre mice to compare their phenotype.
Results: Under baseline conditions, ASKO female mice exhibited no alteration in adrenal AS, plasma aldosterone, systolic blood pressure, and aortic endothelium-dependent relaxation. To mimic obese conditions, we submitted ASWT and ASKO to chronic leptin infusion for a week. Leptin increased adrenal AS expression, aldosterone levels, and blood pressure and impaired endothelial function, which were further elevated in ASKO compared to ASWT, suggesting protective effects of AS LeRb. Both mineralocorticoid receptor (MR) antagonist. eplerenone, or AS antagonist, fadrazole, rescued endothelial function in ASWT and ASKO mice treated with leptin, indicating that leptin-mediated endothelial dysfunction is still aldosterone-dependent in ASKO mice. Restoration of LepRb in AS expressing cells in db/db decreased adrenal AS and plasma aldosterone and improved endothelial function further indicating that AS LepRb blunts leptin-mediated aldosterone production. On a molecular level, leptin treatment elevated aorta NOX1 expression in ASWT, which was further increased in ASKO. Aldosterone treatment increased NOX1 expression in cultured microvascular endothelial cells. Incubation of aortic rings with a selective NOX1 inhibitor restored endothelial function in both ASWT and ASKO treated with leptin, suggesting leptin-mediated aldosterone increased NOX1 expression in the aorta, which causes endothelial dysfunction.
Conclusion: These data indicate that AS LepRb protects from leptin-mediated aldosterone production and vascular dysfunction by mitigating the effects of leptin on aldosterone production and suggests that other isoforms of LepR are involved in stimulating aldosterone production.