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

doi:10.1016/j.cell.2016.03.033

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^*

^*Korrespondierende/r Autor/-in für diese Arbeit

205 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Cell
Jahrgang	165
Ausgabenummer	4
Seiten (von - bis)	882-895
Seitenumfang	14
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2016.03.033
Publikationsstatus	Veröffentlicht - 05.05.2016

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This work was supported by a grant from the DFG (BR 1492/7-1) to J.C.B., and received funding by the DFG within the framework of the TRR134 and within the CMMC and the Excellence Initiative by German Federal and State Governments (CECAD). This work was funded (in part) by the Helmholtz Alliance ICEMED (Imaging and Curing Environmental Metabolic Diseases) through the Initiative and Networking Fund of the Helmholtz Association. Moreover, the research leading to these results has received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement 266408. S.M.S. was funded by the Humboldt-Bayer program of the Alexander Von Humboldt foundation and received a grant from the Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD). A.K. was supported by a DFG fellowship KL2399-3/1. S.T. was funded by a scholarship-program (Gerok-Rotationsstelle, No. 3/2014) of the Medical Faculty of the University of Cologne. G.K. was funded by the National Institute on Aging (NIA) grant 1R01DK104727-01A1. [18F]FDG was provided by B. Neumaier and the radiochemistry department of the Max Planck Institute for Metabolism Research.

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Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

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10.1016/j.cell.2016.03.033

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Jais, A., Solas, M., Backes, H., Chaurasia, B., Kleinridders, A., Theurich, S., Mauer, J., Steculorum, S. M., Hampel, B., Goldau, J., Alber, J., Förster, C. Y., Eming, S. A., Schwaninger, M., Ferrara, N., Karsenty, G., & Brüning, J. C. (2016). Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity. Cell, 165(4), 882-895. https://doi.org/10.1016/j.cell.2016.03.033

@article{b6bf73d5f45e408ab90f201f78a81363,

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 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.",

author = "Alexander Jais and Maite Solas and Heiko Backes and Bhagirath Chaurasia and Andr{\'e} Kleinridders and Sebastian Theurich and Jan Mauer and Steculorum, \{Sophie M.\} and Brigitte Hampel and Julia Goldau and Jens Alber and F{\"o}rster, \{Carola Y.\} and Eming, \{Sabine A.\} and Markus Schwaninger and Napoleone Ferrara and Gerard Karsenty and Br{\"u}ning, \{Jens C.\}",

year = "2016",

month = may,

day = "5",

doi = "10.1016/j.cell.2016.03.033",

language = "English",

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Jais, A, Solas, M, Backes, H, Chaurasia, B, Kleinridders, A, Theurich, S, Mauer, J, Steculorum, SM, Hampel, B, Goldau, J, Alber, J, Förster, CY, Eming, SA, Schwaninger, M, Ferrara, N, Karsenty, G & Brüning, JC 2016, 'Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity', Cell, Jg. 165, Nr. 4, S. 882-895. https://doi.org/10.1016/j.cell.2016.03.033

TY - JOUR

T1 - Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity

AU - Jais, Alexander

AU - Solas, Maite

AU - Backes, Heiko

AU - Chaurasia, Bhagirath

AU - Kleinridders, André

AU - Theurich, Sebastian

AU - Mauer, Jan

AU - Steculorum, Sophie M.

AU - Hampel, Brigitte

AU - Goldau, Julia

AU - Alber, Jens

AU - Förster, Carola Y.

AU - Eming, Sabine A.

AU - Schwaninger, Markus

AU - Ferrara, Napoleone

AU - Karsenty, Gerard

AU - Brüning, Jens C.

PY - 2016/5/5

Y1 - 2016/5/5

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84964595404

U2 - 10.1016/j.cell.2016.03.033

DO - 10.1016/j.cell.2016.03.033

M3 - Journal articles

C2 - 27133169

AN - SCOPUS:84964595404

SN - 0092-8674

VL - 165

SP - 882

EP - 895

JO - Cell

JF - Cell

IS - 4

ER -

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

Abstract

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