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

被引：178

作者：

Jais, Alexander ^{[1
,2
,3
,4
]}

Solas, Maite ^{[1
,2
,3
,4
]}

Backes, Heiko ^{[1
]}

Chaurasia, Bhagirath ^{[1
]}

Kleinridders, Andre ^{[1
,5
,6
]}

Theurich, Sebastian ^{[1
,2
,3
,4
]}

Mauer, Jan ^{[1
,2
,3
,4
]}

Steculorum, Sophie M. ^{[1
,2
,3
,4
]}

Hampel, Brigitte ^{[1
,2
,3
,4
]}

Goldau, Julia ^{[1
,2
,3
,4
]}

Alber, Jens ^{[1
,2
,3
,4
]}

Foerster, Carola Y. ^{[7
]}

Eming, Sabine A. ^{[3
,4
,8
]}

Schwaninger, Markus ^{[9
]}

Ferrara, Napoleone ^{[10
]}

Karsenty, Gerard ^{[11
]}

Bruening, Jens C. ^{[1
,2
,3
,4
,6
]}

机构：

[1] Max Planck Inst Metab Res, Dept Neuronal Control Metab, Gleueler Str 50, D-50931 Cologne, Germany

[2] Univ Hosp Cologne, Ctr Endocrinol Diabet & Prevent Med CEDP, D-50924 Cologne, Germany

[3] Univ Cologne, Excellence Cluster Cellular Stress Responses Agin, Joseph Stelzmann Str 26, D-50931 Cologne, Germany

[4] Univ Cologne, Ctr Mol Med Cologne CMMC, Joseph Stelzmann Str 26, D-50931 Cologne, Germany

[5] German Inst Human Nutr Potsdam Rehbrucke, Cent Regulat Metab, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany

[6] Natl Ctr Diabet Res DZD, Ingolstadter Land Str 1, D-85764 Neuherberg, Germany

[7] Univ Wurzburg, Dept Anaesthesia & Crit Care, Oberdurrbacher Str 6, D-97080 Wurzburg, Germany

[8] Univ Cologne, Dept Dermatol, D-50937 Cologne, Germany

[9] Med Univ Lubeck, Inst Expt & Clin Pharmacol & Toxicol, Ratzeburger Allee 160, D-23562 Lubeck, Germany

[10] Univ Calif San Diego, Moores Canc Ctr, 3855 Hlth Sci Dr, La Jolla, CA 92093 USA

[11] Columbia Univ, Dept Genet & Dev, 701 W 168th St, New York, NY 10032 USA

来源：

CELL | 2016年 / 165卷 / 04期

关键词：

INDUCED INSULIN-RESISTANCE; ENDOTHELIAL GROWTH-FACTOR; ENERGY HOMEOSTASIS; ALZHEIMERS-DISEASE; IMMUNE-SYSTEM; IN-VIVO; MACROPHAGES; TRANSPORTER; BARRIER; CNS;

D O I：

10.1016/j.cell.2016.03.033

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Dmyel mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not in lean mice. Moreover, obese VEGF Dmyel 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.

引用

页码：882 / 895

页数：14

共 53 条

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