title: Leptin Induces Hypertension and Endothelial Dysfunction via Aldosterone-Dependent Mechanisms in Obese Female Mice.
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.
authors.affiliation: 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.).
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Huby
authors.affiliation: 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.).
authors.forename: Laszlo
authors.initials: L
authors.lastname: Otvos
authors.affiliation: 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.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Belin de Chantemèle
mesh_terms: D000450:Aldosterone / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D002318:Cardiovascular Diseases / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology*; D005260:Female; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology*; D020738:Leptin / Q000097:blood*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D012084:Renin-Angiotensin System / Q000502:physiology; D012680:Sensitivity and Specificity; D012737:Sex Factors; D018709:Statistics, Nonparametric
chemical_list: D020738:Leptin; D000450:Aldosterone; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
keywords: hypertension; leptin; mineralocorticoid receptor; obesity; sex