PuSH - Publication Server of Helmholtz Zentrum München: Reduced notch signaling in hypothalamic endothelial cells mediates obesity-induced alterations in glucose uptake and insulin signaling.

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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)

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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, NotchIC^BMECs 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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