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.

Obesity, hypertension and aldosterone: is leptin the link?

“…However, the experiments reported in this article were performed in female rodents; this group subsequently demonstrated that the aldosterone stimulatory effect of leptin underlies obesity-associated hypertension only in female mice, but not in males, in which leptin seems to exert its hypertensive effect instead through activation of the sympathetic nervous system (Huby et al 2016). These data also seem to be consistent with results in humans, in that, for example, women exhibit a greater response to MR antagonists than men (Goodfriend et al 1999).…”

“…O'Seaghdha et al 2012) and/or between BMI and the response to an MR antagonist (Chapman et al 2007, for example). Additional factors that may play a role in the observed heterogeneity of the data resulting from human studies include the proportion of male to female subjects (if as in mice (Huby et al 2016), aldosterone contributes to a greater extent to obesity-associated hypertension in females (Goodfriend et al 1999)), the absolute BMI of the subjects (i.e., normal weight versus overweight versus obese) and the relative adipose tissue distribution (e.g., visceral versus subcutaneous fat), as well as perhaps other parameters that have not yet been determined. Nevertheless, the results presented by Huby and coworkers (Huby et al 2015), demonstrating that adipocyte-derived leptin likely mediates, at least in part, the effect of obesity on blood pressure by modulating aldosterone secretion, indicate that further studies are warranted.…”

Sex‐Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors

“…In response to HFD‐induced obesity, female mice developed impaired resistance vessel endothelial function. This female susceptibility to vascular dysfunction was shown in a prior study in the aorta of mice with elevated leptin, an adipokine that is increased in obesity 27. In human population studies, female sex is associated with increased risk of endothelial dysfunction specifically in microvessels but not in conduit vessels10; therefore, the focus was on resistance vessels in this study.…”

“…In a mouse model of Western diet‐induced obesity, females developed higher plasma aldosterone levels compared with males 25. MR blockade in rodents improved endothelial function in females more than males in the setting of diabetes mellitus or hyperleptinemia—common complications of obesity 26, 27. These studies support a potential role for MR in endothelial dysfunction induced by cardiometabolic risk factors and suggest that the role of MR may be enhanced in females.…”

“…This is consistent with many prior studies demonstrating that vascular NO bioavailability is impaired by obesity and metabolic syndrome; however, much of the data supporting this concept were performed only in males, thereby missing potential sex‐specific mechanisms (reviewed in 7, 40). In addition, many such studies, regardless of sex, measured endothelial responses in the mouse aorta,27, 30 a conduit vessel that is larger and thus easier to study. Resistance vessels differ from conduit vessels, in which NO is the major endothelium‐dependent relaxation factor, and no role has yet been identified for endothelial SK and IK channels 11, 41, 42.…”