Leptin‐induced hypertension is independent of the sympathetic nervous system in obese female agouti mice (680.12)

Abstract

The recent epidemic of obesity induced a three‐fold increase in the prevalence of cardiovascular disease (CVD) in premenopausal women. However, the mechanisms contributing to obesity‐related CVD in females of reproductive age remain completely unknown. We used obese agouti mice (Ag), lacking the anorexigenic effect of leptin, to test the hypothesis that leptin, the factor linking metabolic and CVD in men, triggers hypertension and vascular dysfunction in obese females. Conscious blood pressure (BP, telemetry) recording revealed that obesity elevated BP in both males (Lean: 99±5 vs. Ag: 125±2 mmHg) and females (Lean: 104±1 vs. Ag: 121±1 mmHg). Chronic leptin receptor inhibition reduced BP (AgMale: 117±2 and AgFemale: 112±5 mmHg) in both sexes supporting a role for leptin in the elevated BP. We assessed sympathetic tone by measuring BP response to ganglionic blockade and reported a bigger drop in BP in obese male mice only (LeanMale: ‐29±3 vs. AgMale: ‐44±4% vs. LeanFemale: ‐28±6 vs. AgFemale: ‐25±5%) supporting a higher sympathetic contribution to BP control in male mice only. In addition, male only displayed an increased vascular adrenergic tone. Females showed a reduction. Obesity induced adrenal hyperplasia, raised aldosterone levels (Lean Male: 415±73 vs. AgMale: 76±46 vs. LeanFemale: 545±71 vs. AgFemale: 1152±204) and induced an exaggerated increased in CYP11B2 expression in obese female mice only. Collectively these data suggest that obesity‐induced hypertension is leptin mediated, independent of sympatho‐activation and likely triggered by elevated aldosterone levels in obese female mice. These data highlight the need for sex‐based therapy.