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

Tim Gruber1, Chenchen Pan2, Raian E Contreras3, Tobias Wiedemann4, Donald A Morgan5, Alicja A Skowronski6, Sandrine Lefort7, Cahuê De Bernardis Murat7, Ophelia Le Thuc7, Beata Legutko7, Francisco J Ruiz-Ojeda8, María de la Fuente-Fernández9, Angel Luis García-Villalón9, Daniel González-Hedström9, Melanie Huber7, Klara Szigeti-Buck10, Timo D Müller11, Siegfried Ussar12, Paul Pfluger3, Steve C Woods13, Ali Ertürk2, Charles A LeDuc6, Kamal Rahmouni5, Miriam Granado9, Tamas L Horvath14, Matthias H Tschöp15, Cristina García-Cáceres16

  1. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Advanced Studies, Technische Universität, 85748 Garching, Germany.
  2. Institute for Tissue Engineering and Regenerative Medicine (ITERM), Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilian University of Munich (LMU), 81377 Munich, Germany.
  3. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit Neurobiology of Diabetes, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Neurobiology of Diabetes, TUM School of Medicine, Technical University Munich, 80333 Munich, Germany.
  4. Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
  5. Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, USA.
  6. Division of Molecular Genetics, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY, USA.
  7. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
  8. German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; RG Adipocytes & Metabolism, Institute for Diabetes & Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany.
  9. Physiology Department, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
  10. Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
  11. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany.
  12. German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; RG Adipocytes & Metabolism, Institute for Diabetes & Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany; Department of Medicine, Technische Universität, Munich, Germany.
  13. Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.
  14. Institute for Advanced Studies, Technische Universität, 85748 Garching, Germany; Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
  15. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität, Munich, Germany. Electronic address: matthias.tschoep@helmholtz-muenchen.de.
  16. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Medizinische Klinik and Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address: garcia-caceres@helmholtz-muenchen.de.

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.

Presented By Tim Gruber | ORCID iD

Metabolism, NeuroscienceNicholas Liao2021-07 (Jul)