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

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.

Graphical abstract

Highlights

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  The hypothalamic gliovascular interface is dynamically remodeled during obesity

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  Circulating leptin couples hypercaloric states with hypothalamic microangiopathy

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  Leptin-induced astroglial HIF1α-VEGF drives angiogenesis in the hypothalamus

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  VEGF in astrocytes promotes the development of arterial hypertension during obesity

Abstract

Here, Gruber et al. show that during diet-induced obesity in mice there is a profound remodeling of the gliovascular interface in the hypothalamus, resulting in arterial hypertension. This process is driven by elevated leptin levels and upregulation of a HIF1α-VEGF signaling axis in local astrocytes.