Leptin‐induced Hypertension is Aldosterone Dependent in Obese Females

Abstract

The obesity epidemic affects more women than men worldwide and is a major risk factor for cardiovascular disease (CVD). Obesity is associated with inappropriately high levels of aldosterone, that correlates to the level of adiposity and blood pressure (BP) in women but not in men. Mechanisms controlling aldosterone secretion in obesity and by which obesity sensitizes premenopausal women to CVD remain unknown. The adipocyte-derived hormone leptin is a main contributor to obesity-related CVD in men. As women secrete 4 times more leptin than men, we hypothesized that excessive levels of leptin trigger CVD via aldosterone in obese females. We combined the analysis of the cardiovascular phenotype of mice presenting hypersensitivity to leptin (PTP1B KO) or high leptin levels (Obese Agouti Ag), to the study of the interaction between percentage of body fat, leptin and aldosterone levels in adult Caucasians. Increasing leptin sensitivity with PTP1B deletion or leptin levels in Obese Ag mice induced a similar increase in BP, in both males (WT: 97±1; KO: 119±2; Ag:126±3 mmHg) and female mice (WT: 110±2; KO: 121±2; Ag:144±7 mmHg). It also increased sympathetic activity in males (WT: -29; KO: -40; Ag:-44% drop in BP) but not in females (WT: -22; KO: -25; Ag:-28% drop in BP) that presented increased aldosterone levels. Chronic treatment with the mineralocorticoid receptor antagonist spironolactone reduced BP in female mice only (WT: 110±2; KO: 114±3; Ag: 127±2mmHg). In parallel, we reported a positive correlation between adiposity and aldosterone, and between leptin and aldosterone in adult women only. These data suggest that leptin is a new regulator of aldosterone secretion and demonstrated that obesity-mediated hypertension involves sex-specific mechanisms and is aldosterone-dependent in females.