scholarly journals Regulation of insulin transport across the blood‐brain barrier by CNS insulin receptor signaling

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Elizabeth Rhea ◽  
William A. Banks
Keyword(s):  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Receptor Signaling ◽  
Insulin Transport ◽  
Blood Brain ◽  
Insulin Receptor Signaling

scholarly journals Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood–Brain Barrier Transport

2021 ◽  
Vol 9 (3) ◽  
pp. 56
Author(s):  
Steven Nguyen ◽  
William A. Banks ◽  
Elizabeth M. Rhea
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Receptor Signaling ◽  
Brain Endothelial Cells ◽  
Serum Factors ◽  
Rapamycin Treatment ◽  
Insulin Receptor Signaling

Rapamycin is an exogenous compound that has been shown to improve cognition in Alzheimer’s disease mouse models and can regulate pathways downstream of the insulin receptor signaling pathway. Insulin is also known to improve cognition in rodent models of Alzheimer’s disease. Central nervous system (CNS) insulin must first cross the blood–brain barrier (BBB), a specialized network of brain endothelial cells. This transport process is regulated by physiological factors, such as insulin itself, triglycerides, cytokines, and starvation. Since rapamycin treatment can alter the metabolic state of rodents, increase the circulating triglycerides, and acts as a starvation mimetic, we hypothesized rapamycin could alter the rate of insulin transport across the BBB, providing a potential mechanism for the beneficial effects of rapamycin on cognition. Using young male and female CD-1 mice, we measured the effects of rapamycin on the basal levels of serum factors, insulin receptor signaling, vascular binding, and BBB pharmacokinetics. We found chronic rapamycin treatment was able to affect basal levels of circulating serum factors and endothelial cell insulin receptor signaling. In addition, while acute rapamycin treatment did affect insulin binding at the BBB, overall transport was unaltered. Chronic rapamycin slowed insulin BBB transport non-significantly (p = 0.055). These results suggest that rapamycin may not directly impact the transport of insulin at the BBB but could be acting to alter insulin signaling within brain endothelial cells, which can affect downstream signaling.

scholarly journals The insulin receptor is expressed and functional in cultured blood-brain barrier endothelial cells but does not mediate insulin entry from blood to brain

2018 ◽  
Vol 315 (4) ◽  
pp. E531-E542 ◽  
Author(s):  
Maria Hersom ◽  
Hans C. Helms ◽  
Christoffer Schmalz ◽  
Thomas Å. Pedersen ◽  
Stephen T. Buckley ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Endothelial Cells ◽  
Insulin Transport ◽  
Blood Brain ◽  
The Brain ◽  
Receptor Inhibitor

Insulin and its receptor are known to be present and functional in the brain. Insulin cerebrospinal fluid concentrations have been shown to correlate with plasma levels of insulin in a nonlinear fashion, indicative of a saturable transport pathway from the blood to the brain interstitial fluid. The aim of the present study was to investigate whether insulin was transported across brain endothelial cells in vitro via an insulin receptor-dependent pathway. The study showed that the insulin receptor was expressed at both the mRNA and protein levels in bovine brain endothelial cells. Luminally applied radiolabeled insulin showed insulin receptor-mediated binding to the endothelial cells. This caused a dose-dependent increase in Akt-phosphorylation, which was inhibited by coapplication of an insulin receptor inhibitor, s961, demonstrating activation of insulin receptor signaling pathways. Transport of insulin across the blood-brain barrier in vitro was low and comparable to that of a similarly sized paracellular marker. Furthermore, insulin transport was not inhibited by coapplication of an excess of unlabeled insulin or an insulin receptor inhibitor. The insulin transport and uptake studies were repeated in mouse brain endothelial cells demonstrating similar results. Although it cannot be ruled out that culture-induced changes in the cell model could have impaired a potential insulin transport mechanism, these in vitro data indicate that peripheral insulin must reach the brain parenchyma through alternative pathways rather than crossing the blood-brain barrier via receptor mediated transcytosis.

scholarly journals Insulin transport across the blood-brain barrier can occur independently of the insulin receptor

2018 ◽  
Vol 596 (19) ◽  
pp. 4753-4765 ◽  
Author(s):  
Elizabeth M. Rhea ◽  
Christian Rask-Madsen ◽  
William A. Banks
Keyword(s):  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Insulin Transport ◽  
Blood Brain

scholarly journals Adenosine Receptor Signaling Modulates Permeability of the Blood-Brain Barrier

2011 ◽  
Vol 31 (37) ◽  
pp. 13272-13280 ◽  
Author(s):  
A. J. Carman ◽  
J. H. Mills ◽  
A. Krenz ◽  
D.-G. Kim ◽  
M. S. Bynoe
Keyword(s):  
Blood Brain Barrier ◽  
Adenosine Receptor ◽  
Brain Barrier ◽  
Receptor Signaling ◽  
Blood Brain

Selective Alteration in Blood-Brain Barrier and Insulin Transport in Iron-Deficient Rats

1988 ◽  
Vol 50 (5) ◽  
pp. 1434-1437 ◽  
Author(s):  
Dorit Ben-Shachar ◽  
S. Yehuda ◽  
J. P. M. Finberg ◽  
I. Spanier ◽  
M. B. H. Youdim
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Insulin Transport ◽  
Blood Brain ◽  
Iron Deficient

scholarly journals Nitric Oxide Isoenzymes Regulate Lipopolysaccharide-Enhanced Insulin Transport across the Blood-Brain Barrier

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1514-1523 ◽  
Author(s):  
William A. Banks ◽  
Shinya Dohgu ◽  
Jessica L. Lynch ◽  
Melissa A. Fleegal-DeMotta ◽  
Michelle A. Erickson ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Brain Barrier ◽  
Mrna Levels ◽  
Insulin Transport ◽  
Blood Brain ◽  
Inducible Nos

Insulin transported across the blood-brain barrier (BBB) has many effects within the central nervous system. Insulin transport is not static but altered by obesity and inflammation. Lipopolysaccharide (LPS), derived from the cell walls of Gram-negative bacteria, enhances insulin transport across the BBB but also releases nitric oxide (NO), which opposes LPS-enhanced insulin transport. Here we determined the role of NO synthase (NOS) in mediating the effects of LPS on insulin BBB transport. The activity of all three NOS isoenzymes was stimulated in vivo by LPS. Endothelial NOS and inducible NOS together mediated the LPS-enhanced transport of insulin, whereas neuronal NOS (nNOS) opposed LPS-enhanced insulin transport. This dual pattern of NOS action was found in most brain regions with the exception of the striatum, which did not respond to LPS, and the parietal cortex, hippocampus, and pons medulla, which did not respond to nNOS inhibition. In vitro studies of a brain endothelial cell (BEC) monolayer BBB model showed that LPS did not directly affect insulin transport, whereas NO inhibited insulin transport. This suggests that the stimulatory effect of LPS and NOS on insulin transport is mediated through cells of the neurovascular unit other than BECs. Protein and mRNA levels of the isoenzymes indicated that the effects of LPS are mainly posttranslational. In conclusion, LPS affects insulin transport across the BBB by modulating NOS isoenzyme activity. NO released by endothelial NOS and inducible NOS acts indirectly to stimulate insulin transport, whereas NO released by nNOS acts directly on BECs to inhibit insulin transport.

Diet and TNF-α differentially regulate the insulin receptor and its transporter at the blood–brain barrier

Appetite ◽  
2009 ◽  
Vol 52 (3) ◽  
pp. 817
Author(s):  
L. Asarian ◽  
S.M. Robinson ◽  
N. Geary ◽  
W. Langhans ◽  
W.A. Banks
Keyword(s):  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Tnf Α

scholarly journals Triglycerides cross the blood–brain barrier and induce central leptin and insulin receptor resistance

2017 ◽  
Vol 42 (3) ◽  
pp. 391-397 ◽  
Author(s):  
W A Banks ◽  
S A Farr ◽  
T S Salameh ◽  
M L Niehoff ◽  
E M Rhea ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain
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