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

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

doi:10.1016/j.cell.2016.08.010

Cited by 67 publications

(79 citation statements)

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“…Insulin levels and HOMA-IR did not correlate with BMI in these investigations, suggesting a link between gliosis, pancreatic responses and insulin resistance unrelated to the degree of adiposity92. Recent observations offer evidence in support of a neuroprotective mechanism clearly linked to inflammatory signalling, characterized by similar temporal dynamics and kinetics as the onset and disappearance of HFD-induced gliosis93. Here, perivascular macrophages are recruited to the blood–brain barrier of the cerebral blood vessels when the brain is challenged with a HFD to limit central inflammation.…”

Section: Obesity Perturbs Cns Control Of Peripheral Glucose Metabolismmentioning

confidence: 73%

“…Here, perivascular macrophages are recruited to the blood–brain barrier of the cerebral blood vessels when the brain is challenged with a HFD to limit central inflammation. Via local vascular endothelial growth factor production and increased expression of glucose transporters (GLUT-1), these events are believed to warrant cerebral glucose homeostasis during consumption of energy-dense foods93.…”

Section: Obesity Perturbs Cns Control Of Peripheral Glucose Metabolismmentioning

confidence: 99%

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Neuronal control of peripheral insulin sensitivity and glucose metabolism

2017

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The central nervous system (CNS) has an important role in the regulation of peripheral insulin sensitivity and glucose homeostasis. Research in this dynamically developing field has progressed rapidly due to techniques allowing targeted transgenesis and neurocircuitry mapping, which have defined the primary responsive neurons, associated molecular mechanisms and downstream neurocircuitries and processes involved. Here we review the brain regions, neurons and molecular mechanisms by which the CNS controls peripheral glucose metabolism, particularly via regulation of liver, brown adipose tissue and pancreatic function, and highlight the potential implications of these regulatory pathways in type 2 diabetes and obesity.

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Section: Obesity Perturbs Cns Control Of Peripheral Glucose Metabolismmentioning

confidence: 73%

Section: Obesity Perturbs Cns Control Of Peripheral Glucose Metabolismmentioning

confidence: 99%

Neuronal control of peripheral insulin sensitivity and glucose metabolism

2017

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“…GLUT1 is fundamental to maintaining BBB integrity, capillary networks and blood flow and a reduced expression of GLUT1 is a contributing factor to neurodegeneration and abnormal neuronal function . Reduced GLUT1 expression at the level of the BBB is a feature of Alzheimer's disease and recent studies showed that HFD‐induced a transient decrease in GLUT1 expression, although GLUT1 expression was recovered, despite the maintained HFD, in a myeloid‐cell‐derived vascular endothelial growth factor (VEGF)‐dependent manner . Activation of VEGF and inflammation in response to HFD is proposed as a mechanism that restores glucose availability to the CNS but does not explain the development of brain glucose intolerance described in the present study.…”

Section: Discussionmentioning

confidence: 99%

The impact of ageing, fasting and high‐fat diet on central and peripheral glucose tolerance and glucose‐sensing neural networks in the arcuate nucleus

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Zhao

Viriyapong

et al. 2017

J Neuroendocrinology

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Obesity and ageing are risk factors for diabetes. In the present study, we investigated the effects of ageing, obesity and fasting on central and peripheral glucose tolerance and on glucose-sensing neuronal function in the arcuate nucleus of rats, with a view to providing insight into the central mechanisms regulating glucose homeostasis and how they change or are subject to dysfunction with ageing and obesity. We show that, following a glucose load, central glucose tolerance at the level of the cerebrospinal fluid (CSF) and plasma is significantly reduced in rats maintained on a high-fat diet (HFD). With ageing, up to 2 years, central glucose tolerance was impaired in an age-dependent manner, whereas peripheral glucose tolerance remained unaffected. Ageing-induced peripheral glucose intolerance was improved by a 24-hour fast, whereas central glucose tolerance was not corrected. Pre-wean, immature animals have elevated basal plasma glucose levels and a delayed increase in central glucose levels following peripheral glucose injection compared to mature animals. Electrophysiological recording techniques revealed an energy-status-dependent role for glucose-excited, inhibited and adapting neurones, along with glucose-induced changes in synaptic transmission. We conclude that ageing affects central glucose tolerance, whereas HFD profoundly affects central and peripheral glucose tolerance and, in addition, glucose-sensing neurones adapt function in an energy-status-dependent manner.

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“…Contrarily, the protective role of PVM has also been reported in high‐fat diet (HFD) induced cognitive dysfunction. HFD in mice induced acute reduction of glucose transporter 1 (GLUT1), which was then gradually restored upon prolonged HFD in parallel with compensatory upregulation of vascular endothelial growth factor (VEGF) by CD206 + macrophages at the BBB . Myeloid‐specific deletion of VEGF (VEGFa lox/lox LysM Cre +/‐ ) impaired BBB‐GLUT1 expression, brain glucose uptake, and memory formation in obese mice, as well as exacerbated neuroinflammation and cognitive decline in APP‐PS1 mice.…”

Section: Pvm Alterations In Diseased Brainmentioning

confidence: 99%

Brain perivascular macrophages: Recent advances and implications in health and diseases

2019

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Brain perivascular macrophages (PVMs) belong to a distinct population of brain‐resident myeloid cells located within the perivascular space surrounding arterioles and venules. Their characterization depends on the combination of anatomical localization, phagocytic capacity, and molecular markers. Under physiological status, they provide structural and functional support for maintaining brain homeostasis, including facilitation of blood‐brain barrier integrity and lymphatic drainage, and exertion of immune functions such as phagocytosis and antigen presentation. Increasing evidence also implicates their specific roles in diseased brain, ranging from cerebrovascular diseases, Aβ pathologies, infections, and autoimmunity. Collectively, PVMs are key components of the brain‐resident immune system, actively participate in a broad‐spectrum of processes in normal and diseased status. Details of the processes are largely underexplored. Targeting PVMs would lead to new insights and be a promising strategy for a broad array of human diseases.

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

Cited by 67 publications

References 0 publications

Neuronal control of peripheral insulin sensitivity and glucose metabolism

Neuronal control of peripheral insulin sensitivity and glucose metabolism

The impact of ageing, fasting and high‐fat diet on central and peripheral glucose tolerance and glucose‐sensing neural networks in the arcuate nucleus

Brain perivascular macrophages: Recent advances and implications in health and diseases

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