title: Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity.
abstract: 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 VEGF(Δmyel) mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not in lean mice. Moreover, obese VEGF(Δmyel) 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.
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jais
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany.
authors.forename: Maite
authors.initials: M
authors.lastname: Solas
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Backes
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany.
authors.forename: Bhagirath
authors.initials: B
authors.lastname: Chaurasia
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; German Institute of Human Nutrition Potsdam-Rehbruecke, Central Regulation of Metabolism, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany; National Center for Diabetes Research (DZD), Ingolstädter Land Strasse 1, 85764 Neuherberg, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Kleinridders
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Theurich
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Mauer
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany.
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Steculorum
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hampel
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Goldau
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Alber
authors.affiliation: Department of Anaesthesia and Critical Care, University of Würzburg, Oberdürrbacher Strasse 6, 97080 Würzburg, Germany.
authors.forename: Carola Y
authors.initials: CY
authors.lastname: Förster
authors.affiliation: Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany; Department of Dermatology, University of Cologne, 50937 Cologne, Germany.
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Eming
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
authors.affiliation: Moores Cancer Center, University of California, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.affiliation: Department of Genetics and Development, Columbia University, 701 West 168th Street, New York, NY 10032, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.affiliation: Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Joseph Stelzmann Strasse 26, 50931 Cologne, Germany; National Center for Diabetes Research (DZD), Ingolstädter Land Strasse 1, 85764 Neuherberg, Germany. Electronic address: bruening@sf.mpg.de.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D003071:Cognition; D059305:Diet, High-Fat; D042783:Endothelial Cells / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D051272:Glucose Transporter Type 1; C495678:Slc2a1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D005947:Glucose