{"doi":"10.3389/fphys.2020.00555","title":"Brain Endothelial Cells Regulate Glucagon-Like Peptide 1 Entry Into the Brain via a Receptor-Mediated Process","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.","journal":"Frontiers in Physiology","year":2020,"id":63191,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":46,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":334281,"name":"Liying Gong","orcid":"0000-0002-9569-8450","position":1,"is_corresponding":false},{"id":334282,"name":"Jia Liu","orcid":"0000-0001-9522-6624","position":2,"is_corresponding":false},{"id":334283,"name":"Jing Wu","orcid":"0000-0002-4512-9436","position":3,"is_corresponding":false},{"id":230170,"name":"Eugene J. Barrett","orcid":"0000-0003-0689-4044","position":4,"is_corresponding":false},{"id":335666,"name":"Kevin W. Aylor","orcid":null,"position":5,"is_corresponding":false},{"id":334284,"name":"Zhenqi Liu","orcid":"0000-0001-5077-0941","position":6,"is_corresponding":false},{"id":334280,"name":"Zhuo Fu","orcid":"0000-0001-6462-7695","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-18T21:11:00.632961Z","pmid":"32547420","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}