Abstract P303: Contribution Of Adrenal Leptin Receptor To The Control Of Aldosterone Synthase Expression And Endothelial Function In Female Mice

Abstract

While premenopausal women are severally affected by the current obesity epidemic, the mechanisms whereby obesity promotes vascular dysfunction in this population remain ill-defined. We previously demonstrated that the adipokine leptin acts on the adrenal gland to promote aldosterone production and that leptin-mediated aldosterone production impairs endothelial function in female mice only. Herein, we investigated whether these mechanisms are dependent on the presence of leptin receptors (lepR) in adrenal glands. We generated lean female mice exhibiting a selective deficiency in LepR in adrenals (AdKO), and obese mice expressing LepR in adrenal glands (db/ad + ) only. Under baseline conditions, AdKO exhibited no alteration in adrenal CYP11B2, renal renin level, aortic endothelial function (measured by acetylcholine-mediated relaxation), arterial stiffness (pulse wave velocity test, PWV), or metabolic parameters including heart and visceral adipose tissue (VAT) weights, fluid amount, glycemia, and HbA1c. Chronic leptin infusion for a week induced trends towards increases in adrenal CYP11B2 (ΔΔCt 1.10±0.12 vs 2.01±0.51, P=0.077), aldosterone (557±95 vs 918±526 pg/ml, P=0.859), and renin levels in WT. AdKO conferred no protection against any of these changes. Leptin infusion impaired endothelial function in WT (Emax 73.3±3.9 vs 52.8±3.1%, P=0.019), which was exacerbated in AdKO (52.8±3.1 vs 34.3±4.1%, P=0.052). However, leptin infusion did not change PWV in WT (3.93±0.22 vs 4.17±0.32 m/s, P=0.999), but induced a trend towards a decrease in AdKO (4.17±0.32 vs 3.11±0.44 m/s, P=0.228). Restoration of adrenal LepR in db/db mice did not alter CYP11B2 nor aldosterone levels but increased renin (ΔΔCt 1.04±0.11 vs 1.48±0.12, P=0.029), heart weight, VAT weight (5.14±0.29 vs 6.52±0.62 g/g, P=0.052), and HbA1c (5.7±0.2 vs 6.9±0.4 %, P=0.035). Although PWV was worsened in db/ad + (5.40±0.27 vs 6.39±0.49 m/s, P=0.035), db/ad + presented improved relaxation compared to db/db (58.5±5.6 vs 73.0±2.2%, P=0.067), inconsistent with our hypothesis. Collectively these data indicate that adrenal LepR might not directly control adrenal CYP11B2 levels expression but latently contributes to changes in endothelial function and arterial stiffness.