Mechanisms of leptin-induced endothelial dysfunction

Abstract

Purpose of reviewEndothelial dysfunction is a major risk factor for many cardiovascular diseases, notably hypertension. Obesity increases the risk of endothelial dysfunction in association with increasing production of the adipokine leptin. Preclinical studies have begun to unravel the mechanisms whereby leptin leads to the development of endothelial dysfunction, which are sex-specific. This review will summarize recent findings of mechanisms of leptin-induced endothelial impairment in both male and females and in pregnancy.Recent findingsLeptin receptors are found in high concentrations in the central nervous system (CNS), via which leptin promotes appetite suppression and upregulates sympathetic nervous system activation. However, leptin receptors are expressed in many other tissues, including the vascular endothelial cells and smooth muscle cells. Recent studies in mice with vascular endothelial or smooth muscle-specific knockdown demonstrate that endothelial leptin receptor activation plays a protective role against endothelial dysfunction in male animals, but not necessarily in females. Clinical studies indicate that women may be more sensitive to obesity-associated vascular endothelial dysfunction. Emerging preclinical data indicates that leptin and progesterone increase aldosterone production and endothelial mineralocorticoid receptor activation, respectively. Furthermore, decades of clinical studies indicate that leptin levels increase in the hypertensive pregnancy disorder preeclampsia, which is characterized by systemic endothelial dysfunction. Leptin infusion in mice induces the clinical characteristics of preeclampsia, including endothelial dysfunction.SummaryNovel preclinical data indicate that the mechanisms whereby leptin promotes endothelial dysfunction are sex-specific. Leptin-induced endothelial dysfunction may also play a role in hypertensive pregnancy as well.

The leptin receptor has no role in delta-cell control of beta-cell function in the mouse

“…Together, these data suggest that Lepr is largely or wholely absent from mouse islet endocrine cells. It has been reported previously that LEPR is expressed in mouse T cells (31,32), endothelial cells (33), and smooth muscle cells (33). Our scRNAseq also demonstrates Lepr expression within islet endothelial cells.…”

A cross-sectional analysis of syncytiotrophoblast membrane extracellular vesicles–derived transcriptomic biomarkers in early-onset preeclampsia

“…One review article suggests that intermittent hypoxia, a consequence of sleep-disordered breathing, may impact leptin levels in pregnant women, rather than preeclampsia's pathogenesis ( 22 ). Another study showed that LEP -induced endothelial dysfunction, a possible cause of preeclampsia, might happen even if there are no other health problems related to obesity ( 23 ). The significance of finding elevated LEP mRNA in STB-EVs in the context of PE extends beyond a mere correlation.…”

The leptin receptor has no role in delta-cell control of beta-cell function in the mouse

“…Lepr is expressed in mouse T cells ( 62 , 63 ), endothelial cells ( 64 ), and smooth muscle cells ( 64 ). Here, we show the presence of Lepr in mouse islet endothelial cells using publicly available RNAseq data.…”