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Zhu, Y.* ; Mehlkop, O.* ; Backes, H.* ; Cremer, A.L.* ; Porniece, M.* ; Klemm, P.* ; Steuernagel, L.* ; Chen, W.* ; Johnen, R.* ; Wunderlich, F.T.* ; Jais, A. ; Brüning, J.C.*

Reduced notch signaling in hypothalamic endothelial cells mediates obesity-induced alterations in glucose uptake and insulin signaling.

Cell Rep. 44:115522 (2025)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Short-term transition to high-fat diet (HFD) feeding causes rapid changes in the molecular architecture of the blood-brain barrier (BBB), BBB permeability, and brain glucose uptake. However, the precise mechanisms responsible for these changes remain elusive. Here, we detect a rapid downregulation of Notch signaling after short-term HFD feeding. Conversely, Notch activation restores HFD-fed mouse serum-induced reduction of Glut1 expression and glycolysis in cultured brain microvascular endothelial cells (BMECs). Selective, inducible expression of the Notch intracellular domain (IC) in BMECs prevents HFD-induced reduction of Glut1 expression and hypothalamic glucose uptake. Caveolin (Cav)-1 expression in BMECs is increased upon short-term HFD feeding. However, NotchICBMECs mice display reduced caveola formation and BBB permeability. This ultimately translates into reduced hypothalamic insulin transport, action, and systemic insulin sensitivity. Collectively, we highlight a critical role of Notch signaling in the pleiotropic effects of short-term dietary transitions on BBB functionality.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cp: Metabolism ; Cp: Neuroscience ; Notch Signaling ; Glucose Transport ; Hypothalamus ; Insulin Action ; Obesity ; Vascular Endothelial Cells; Blood-brain-barrier; In-vitro; Caveolin-1; Neurons; Images; Pet
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Zeitschrift Cell Reports
Quellenangaben Band: 44, Heft: 4, Seiten: , Artikelnummer: 115522 Supplement: ,
Verlag Cell Press
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-555600-001
Förderungen federal government of Saxony, Germany
Helmholtz Center Munich
Scholarship Council (CSC) , China
DOI 10.1016/j.celrep.2025.115522
WOS ID 001472556500001
PubMed ID 40186867
Erfassungsdatum 2025-05-11
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