Abstract
Glucagon-like peptide 1 (GLP-1) in addition to regulating glucose-dependent insulin and glucagon secretion exerts anorexic and neuroprotective effects. While brain-derived GLP-1 may participate in these central actions, evidence suggests that peripherally derived GLP-1 plays an important role and GLP-1 analogs are known to cross the blood brain barrier. To define the role of brain microvascular endothelial cells in GLP-1 entry into the brain, we infused labeled GLP-1 or exendin-4 into rats intravenously and examined their appearance and protein kinase A activities in various brain regions. We also studied the role of endothelial cell GLP-1 receptor and its signaling in endothelial cell uptake and transport of GLP-1. Systemically infused labeled GLP-1 or exendin-4 appeared rapidly in various brain regions and this was associated with increased protein kinase A activity in these brain regions. Pretreatment with GLP-1 receptor antagonist reduced labeled GLP-1 or exendin-4 enrichment in the brain. Sub-diaphragmatic vagus nerve resection did not alter GLP-1-mediated increases in protein kinase A activity in the brain. Rat brain microvascular endothelial cells rapidly took up labeled GLP-1 and this was blunted by either GLP-1 receptor antagonism or protein kinase A inhibition but enhanced through adenylyl cyclase activation. Using an artificially assembled blood brain barrier consisting of endothelial and astrocyte layers, we found that labeled GLP-1 time-dependently crossed the barrier and the presence of GLP-1 receptor antagonist blunted this transit. We conclude that GLP-1 crosses the blood brain barrier through active trans-endothelial transport which requires GLP-1 receptor binding and activation.
Highlights
Glucagon-like peptide (GLP-1) regulates glucose-dependent insulin and glucagon secretion
Infusion of exendin-(9-39), a Glucagon-like peptide 1 (GLP-1) receptor antagonist, markedly decreased the amount of GLP-1-FAM fluorescence and almost completely abolished exendin-4-FAM fluorescence in various brain regions. Consistent with these findings, we found that GLP-1 receptors are abundantly expressed in all brain regions studied (Figure 1D)
We have previously shown that GLP-1 has a profound vasodilatory action in skeletal muscle microvasculature and this action is associated with increased muscle delivery of insulin and oxygen, via a protein kinase A (PKA)-mediated pathway (Chai et al, 2012, 2014; Dong et al, 2013)
Summary
Glucagon-like peptide (GLP-1) regulates glucose-dependent insulin and glucagon secretion. Many of GLP-1’s effects are mediated via actions on various parts of the brain. Manipulation of brain GLP-1 action clearly alters glucose metabolism and insulin sensitivity but brain GLP-1 receptors are not needed for normal glucose control (Cabou et al, 2011; Sandoval and Sisley, 2015). GLP-1 receptors are expressed in various regions of human, primate, and rodent brains including cerebellum, cortex, hippocampus, and hypothalamus (Alvarez et al, 2005; Hamilton and Hölscher, 2009; Cork et al, 2015; Heppner et al, 2015). Brain derived GLP-1, produced in pre-proglucagon neurons located in the nucleus of the solitary tract and projecting to numerous brain regions, has been shown to control a range of feeding responses and energy balance (Trapp and Richards, 2013). Peripherally administered GLP-1 analogs, such as liraglutide and Val(8)GLP-1, can reduce amyloid plaque formation, prevent memory impairment and synapse loss in hippocampus, and rescue synaptic plasticity in a mouse model of Alzheimer disease (McClean et al, 2011; Gengler et al, 2012) and protect against Aβ1-40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats (Wang et al, 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
