Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension

Abstract

Summary Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis. By using a series of cell- and region-specific loss- and gain-of-function models, we show that this pathophysiological process depends on hypothalamic astroglial hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1α-VEGF pathway disruption in astrocytes are protected not only from obesity-induced hypothalamic angiopathy but also from sympathetic hyperactivity or arterial hypertension. These results suggest that hyperleptinemia promotes obesity-induced hypertension via a HIF1α-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure.

High-Fat Diet Impairs Mouse Median Eminence: A Study by Transmission and Scanning Electron Microscopy Coupled with Raman Spectroscopy

“…On the other side, although histochemical staining confirmed the localization of collagen around the fenestrated capillaries of the ME, it did not show an evident higher level of staining in HFD compared to CTRL, which was possibly due to the low sensitivity of the technique. However, hypothalamic hypervascularization and micro-angioarchitecture anomalies consisting of increased extracellular matrix protein deposition, collagen IV, basal membrane size and vascular impairments were recently documented [ 51 ] and are consistent with other report [ 31 ]. Interestingly, diet-induced hyperleptinemia was recently demonstrated to lead to alteration in the HIF1-α/VEGF signaling in hypothalamic astrocytes, which is in turn responsible for the obesity-induced hypertension [ 51 ].…”

“…However, hypothalamic hypervascularization and micro-angioarchitecture anomalies consisting of increased extracellular matrix protein deposition, collagen IV, basal membrane size and vascular impairments were recently documented [ 51 ] and are consistent with other report [ 31 ]. Interestingly, diet-induced hyperleptinemia was recently demonstrated to lead to alteration in the HIF1-α/VEGF signaling in hypothalamic astrocytes, which is in turn responsible for the obesity-induced hypertension [ 51 ]. Thus, it is possible that the detected Arc-ME increase in collagen is a consequence of the obesity-induced hypothalamic microangiopathy, which is a phenomenon with critical pathophysiologic implications.…”

Leptin Receptor Blockade Attenuates Hypertension, but Does Not Affect Ventilatory Response to Hypoxia in a Model of Polygenic Obesity

“…In contrast, the sites of hypertensive effects of leptin have not been determined. Earlier studies have suggested that the central regulation of blood pressure by leptin is localized to the dorsomedial hypothalamus (Simonds et al, 2014;Gruber et al, 2021). Here, we showed that the systemic blockade of leptin receptors in NZO mice reduced blood pressure, but did not affect ventilation and metabolism, since food intake remained unchanged.…”

Moderate Caloric Restriction Partially Improved Oxidative Stress Markers in Obese Humans

“…Moreover, leptin is involved in blood pressure regulation [36], and obese patients usually have hypertension. Decreased leptin concentration could be engaged in the SBP reduction observed in this study (Table 4).…”