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

Summary

Short-term HFD rapidly suppresses Notch signaling in hypothalamic endothelial cells, reducing GLUT1 and brain glucose uptake. Notch activation rescues GLUT1 expression and glucose uptake in vivo and in cultured BMECs, suggesting endothelial Notch as a neurovascular target in obesity.

Key Findings

• Short-term high-fat diet rapidly downregulates Notch signaling in brain microvascular endothelial cells.
• Notch activation restores GLUT1 expression and glycolysis in cultured BMECs exposed to HFD-fed mouse serum.
• Endothelial Notch intracellular domain expression prevents HFD-induced reduction of GLUT1 and hypothalamic glucose uptake in vivo.
• Caveolin-1 expression in BMECs increases with short-term HFD feeding.

Clinical Implications

While preclinical, targeting endothelial Notch-GLUT1 pathways could inspire therapies to improve central glucose sensing and insulin signaling in obesity and type 2 diabetes.

Limitations

• Abstract truncation limits detailed understanding of downstream pathways (e.g., Cav-1 role with Notch activation).
• Short-term HFD model; translational relevance to chronic obesity requires further validation.

Future Directions

Define how endothelial Notch interfaces with caveolar trafficking and insulin signaling at the BBB, and test pharmacologic modulation in chronic metabolic disease models.