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

Gruber, Tim; Pan, Chenchen; Contreras, Raian E.; Wiedemann, Tobias; Morgan, Donald A.; Skowronski, Alicja A.; Lefort, Sandrine; Murat, Cahue De Bernardis; Le Thuc, Ophelia; Legutko, Beata; Ruiz-Ojeda, Francisco J.; Fuente-Fernandez, Maria de la; Garcia-Villalon, Angel Luis; Gonzalez-Hedström, Daniel; Huber, Melanie; Szigeti-Buck, Klara; Müller, Timo D.; Ussar, Siegfried; Pfluger, Paul; Woods, Steve C.; Ertürk, Ali; LeDuc, Charles A.; Rahmouni, Kamal; Granado, Miriam; Horvath, Tamas L.; Tschöp, Matthias H. und Garcia-Caceres, Cristina (2021): Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension. In: Cell Metabolism, Bd. 33, Nr. 6: S. 1155-1170

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 1a-vascular endothelial growth factor (HIF1a-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1a-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 HIF1a-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1550-4131
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198