Journal article
Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension
Cell metabolism, Vol.33(6), pp.1155-1170.e10
05/2021
DOI: 10.1016/j.cmet.2021.04.007
PMID: 33951475
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.
Keywords: HIF1α-VEGF; angiogenesis; astrocytes; hypertension; hypothalamus; leptin; obesity.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Details
- Title: Subtitle
- Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension
- Creators
- Tim GruberChenchen PanRaian E ContrerasTobias WiedemannDonald A MorganAlicja A SkowronskiSandrine LefortCahuê De Bernardis MuratOphelia Le ThucBeata LegutkoFrancisco J Ruiz-OjedaMaría de la Fuente-FernándezAngel Luis García-VillalónDaniel González-HedströmMelanie HuberKlara Szigeti-BuckTimo D MüllerSiegfried UssarPaul PflugerSteve C WoodsAli ErtürkCharles A LeDucKamal RahmouniMiriam GranadoTamas L HorvathMatthias H TschöpCristina García-Cáceres
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.33(6), pp.1155-1170.e10
- DOI
- 10.1016/j.cmet.2021.04.007
- PMID
- 33951475
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Grant note
- DOI: 10.13039/501100015072, name: TUM Institute for Advanced Study; DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/501100001659, name: German Research Foundation; DOI: 10.13039/100010665, name: EU Framework Programme for Research and Innovation Marie Skłodowska-Curie Actions; DOI: 10.13039/100010663, name: European Research Council; DOI: 10.13039/100000738, name: Department of Veterans Affairs
- Language
- English
- Date published
- 05/2021
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984072072902771
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