Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity

Alexander Jais, Maite Solas, Heiko Backes, Bhagirath Chaurasia, André Kleinridders, Sebastian Theurich, Jan Mauer, Sophie M. Steculorum, Brigitte Hampel, Julia Goldau, Jens Alber, Carola Y. Förster, Sabine A. Eming, Markus Schwaninger, Napoleone Ferrara, Gerard Karsenty, Jens C. Brüning*

*Corresponding author for this work
23 Citations (Scopus)


High-fat diet (HFD) feeding induces rapid reprogramming of systemic metabolism. Here, we demonstrate that HFD feeding of mice downregulates glucose transporter (GLUT)-1 expression in blood-brain barrier (BBB) vascular endothelial cells (BECs) and reduces brain glucose uptake. Upon prolonged HFD feeding, GLUT1 expression is restored, which is paralleled by increased expression of vascular endothelial growth factor (VEGF) in macrophages at the BBB. In turn, inducible reduction of GLUT1 expression specifically in BECs reduces brain glucose uptake and increases VEGF serum concentrations in lean mice. Conversely, myeloid-cell-specific deletion of VEGF in VEGFΔmyel mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not in lean mice. Moreover, obese VEGFΔmyel mice exhibit exaggerated progression of cognitive decline and neuroinflammation on an Alzheimer's disease background. These experiments reveal that transient, HFD-elicited reduction of brain glucose uptake initiates a compensatory increase of VEGF production and assign obesity-associated macrophage activation a homeostatic role to restore cerebral glucose metabolism, preserve cognitive function, and limit neurodegeneration in obesity.

Original languageEnglish
Issue number4
Pages (from-to)882-895
Number of pages14
Publication statusPublished - 05.05.2016

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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