Leptin Induces Hypertension and Endothelial Dysfunction via Aldosterone-Dependent Mechanisms in Obese Female Mice

Anne-Cécile Huby; Laszlo Otvos Jr; Eric J Belin de Chantemèle

doi:10.1161/HYPERTENSIONAHA.115.06642

Leptin Induces Hypertension and Endothelial Dysfunction via Aldosterone-Dependent Mechanisms in Obese Female Mice

Hypertension. 2016 May;67(5):1020-8. doi: 10.1161/HYPERTENSIONAHA.115.06642. Epub 2016 Mar 7.

Authors

Anne-Cécile Huby¹, Laszlo Otvos Jr¹, Eric J Belin de Chantemèle²

Affiliations

¹ From the Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta (A.-C.H., E.J.B.d.C.); Biology Department, Temple University, Philadelphia, PA (L.O.); and Department of Medical Microbiology, Semmelweis University, Budapest, Hungary (L.O.).
² From the Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta (A.-C.H., E.J.B.d.C.); Biology Department, Temple University, Philadelphia, PA (L.O.); and Department of Medical Microbiology, Semmelweis University, Budapest, Hungary (L.O.). ebelindechanteme@gru.edu.

Abstract

Obesity is a major risk factor for cardiovascular disease in males and females. Whether obesity triggers cardiovascular disease via similar mechanisms in both the sexes is, however, unknown. In males, the adipokine leptin highly contributes to obesity-related cardiovascular disease by increasing sympathetic activity. Females secrete 3× to 4× more leptin than males, but do not exhibit high sympathetic tone with obesity. Nevertheless, females show inappropriately high aldosterone levels that positively correlate with adiposity and blood pressure (BP). We hypothesized that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in females. Leptin control of the cardiovascular function was analyzed in female mice sensitized to leptin via the deletion of protein tyrosine phosphatase 1b (knockout) and in agouti yellow obese hyperleptinemic mice (Ay). Hypersensitivity to leptin (wild-type, 115 ± 2; protein tyrosine phosphatase 1b knockout, 124 ± 2 mm Hg; P<0.05) and obesity elevated BP (a/a, 113 ± 1; Ay, 128 ± 7 mm Hg; P<0.05) and impaired endothelial function. Chronic leptin receptor antagonism restored BP and endothelial function in protein tyrosine phosphatase 1b knockout and Ay mice. Hypersensitivity to leptin and obesity reduced BP response to ganglionic blockade in both strains and plasma catecholamine levels in protein tyrosine phosphatase 1b knockout mice. Hypersensitivity to leptin and obesity significantly increased plasma aldosterone levels and adrenal CYP11B2 expression. Chronic leptin receptor antagonism reduced aldosterone levels. Furthermore, chronic leptin and mineralocorticoid receptor blockade reduced BP and improved endothelial function in both leptin-sensitized and obese hyperleptinemic female mice. Together, these data demonstrate that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in female mice and suggest that obesity leads to cardiovascular disease via sex-specific mechanisms.

Keywords: hypertension; leptin; mineralocorticoid receptor; obesity; sex.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Aldosterone / metabolism*
Analysis of Variance
Animals
Cardiovascular Diseases / physiopathology
Disease Models, Animal
Endothelium, Vascular / metabolism*
Endothelium, Vascular / physiopathology*
Female
Hypertension / etiology
Hypertension / physiopathology*
Leptin / blood*
Male
Mice
Mice, Knockout
Mice, Obese
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism*
Random Allocation
Renin-Angiotensin System / physiology
Sensitivity and Specificity
Sex Factors
Statistics, Nonparametric

Substances

Leptin
Aldosterone
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Ptpn1 protein, mouse

Grants and funding

R01 HL130301/HL/NHLBI NIH HHS/United States