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

Abstract

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.

• Authors: Tim Gruber, Chenchen Pan, Raian E Contreras, Tobias Wiedemann, Donald A Morgan, Alicja A Skowronski, Sandrine Lefort, Cahuê De Bernardis Murat, Ophelia Le Thuc, Beata Legutko, Francisco J Ruiz-Ojeda, María de la Fuente-Fernández, Angel Luis García-Villalón, Daniel González-Hedström, Melanie Huber, Klara Szigeti-Buck, Timo D Müller, Siegfried Ussar, Paul Pfluger, Steve C Woods, Ali Ertürk, Charles A LeDuc, Kamal Rahmouni, Miriam Granado, Tamas L Horvath, Matthias H Tschöp, Cristina García-Cáceres
• Journal: Cell metabolism (Cell Metab) Vol. 33 Issue 6 Pg. 1155-1170.e10 (06 01 2021) ISSN: 1932-7420 [Electronic] United States
• PMID: 33951475 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Leptin

Topics

• Animals
• Astrocytes (metabolism, pathology)
• Female
• Hypertension (metabolism)
• Hypothalamus (metabolism, pathology)
• Leptin (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Obesity (metabolism)