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

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. [Display omitted] •Acute high-fat feeding suppresses GLUT1 expression at the blood-brain barrier (BBB)•Macrophages at the BBB increase VEGF expression upon prolonged HFD feeding•Inducible GLUT1 deletion in brain endothelial cells leads to increased VEGF secretion•Myeloid-cell-specific disruption of VEGF impairs cognitive function in obesity Acute high-fat feeding suppresses brain glucose uptake. To preserve cognitive function after prolonged feeding on a high-fat diet and to forestall neurodegeneration in obesity, there is a compensatory upregulation of glucose transporters at the blood-brain barrier as a result of inflammatory signals from perivascular macrophages.