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Gruber, T. ; Pan, C. ; Contreras, R. ; Wiedemann, T. ; Morgan, D.A.* ; Skowronski, A.A.* ; Lefort, S. ; De Bernardis Murat, C. ; Le Thuc, O. ; Legutko, B. ; Ruiz Ojeda, F.J. ; Fuente-Fernández, M.* ; García-Villalón, A.L.* ; González-Hedström, D.* ; Huber, M. ; Szigeti-Buck, K.* ; Müller, T.D. ; Ussar, S. ; Pfluger, P.T. ; Woods, S.C.* ; Ertürk, A. ; LeDuc, C.A.* ; Rahmouni, K.* ; Granado, M.* ; Horvath, T.L.* ; Tschöp, M.H. ; García-Cáceres, C.

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

Cell Metab. 33, 1155-1170.e10 (2021)
Publ. Version/Full Text DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Hif1α-vegf ; Angiogenesis ; Astrocytes ; Hypertension ; Hypothalamus ; Leptin ; Obesity; Hypoxia-inducible Factor-1-alpha; Brain Glucose-uptake; Blood-pressure; Insulin-resistance; Arcuate Nucleus; Nerve Activity; Collagen-iv; Leptin; Baroreflex; Neurons
ISSN (print) / ISBN 1550-4131
e-ISSN 1932-7420
Journal Cell Metabolism
Quellenangaben Volume: 33, Issue: 6, Pages: 1155-1170.e10 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Institute for Tissue Engineering and Regenerative Medicine (ITERM)
Institute of Diabetes and Cancer (IDC)
Grants European Research Council (AdG grant Hypoflam)
German Research Foundation under Germany's Excellence Strategy
Helmholtz Excellence Network
US National Institutes of Health
Department of Veterans Affairs
University of Iowa Fraternal Order of Eagles Diabetes Research Center
Iowa Neuroscience Institute
Technische UniversitaEurot MuEuronchen - Institute for Advanced Study - German Excellence Initiative
European Union Seventh Framework Programme
European Research Council (STG grant AstroNeuroCrosstalk)
German Research Foundation
Marie SklodowskaCurie grant