Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension Gruber, Tim Pan, Chenchen Contreras, Raian Eduardo Wiedemann, Tobias Morgan, Donald A. Skowronski, Alicja A. lefort, Sandrine Murat, Cahué De Bernadis Le Thuc, Ophelia Legutko, Beata Ruiz Ojeda, Francisco Javier Fuente-Fernández, María de la García-Villalón, Ángel Luis González-Hedstöm, Daniel Huber, Melanie Szigeti-Buck, Klara Müller, Timo D. Ussar, Siegfried Pfluger, Paul Woods, Steve C. Ertück, Ali LeDuc, Charles A. Rahmouni, Kamal Granado, Miriam Horvarth, Tamas L. Tschöp, Matthias H. This work was supported in part by funding to R.E.C. and P.P. from a Marie Skłodowska-Curie grant (ChroMe # 675610) and M.H.T. and C.G.-C. from the European Research Council (AdG grant Hypoflam # 695054 and STG grant AstroNeuroCrosstalk #757393, respectively), and the German Research Foundation under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198) and Helmholtz Excellence Network. T.D.M. received grant support from the German Research Foundation (SFB TRR152/P23 and SFB TRR296). K.R. is supported by the US National Institutes of Health (HL084207), the Department of Veterans Affairs (merit grant BX004249), the University of Iowa Fraternal Order of Eagles Diabetes Research Center, and the Iowa Neuroscience Institute. T.G. and T.L.H. received support from the Technische Universität München – Institute for Advanced Study, funded by the German Excellence Initiative and the European Union Seventh Framework Programme under grant agreement no. 291763. 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. 2026-01-15T10:48:03Z 2026-01-15T10:48:03Z 2021-06-01 journal article Gruber T, Pan C, Contreras RE, Wiedemann T, Morgan DA, Skowronski AA, Lefort S, De Bernardis Murat C, Le Thuc O, Legutko B, Ruiz-Ojeda FJ, Fuente-Fernández M, García-Villalón AL, González-Hedström D, Huber M, Szigeti-Buck K, Müller TD, Ussar S, Pfluger P, Woods SC, Ertürk A, LeDuc CA, Rahmouni K, Granado M, Horvath TL, Tschöp MH, García-Cáceres C. Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension. Cell Metab. 2021 Jun 1;33(6):1155-1170.e10. doi: 10.1016/j.cmet.2021.04.007 https://hdl.handle.net/10481/109740 10.1016/j.cmet.2021.04.007 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier