biostudies-literatureBakker WNovo NordiskEuropean Research CouncilAgence Nationale de la RechercheNational Institute of Diabetes and Digestive and Kidney DiseasesHorizon 2020 Framework ProgrammeUniversité de ParisCentre National de la Recherche ScientifiqueFondation pour la Recherche MédicaleBoston Foundation for ArchitectureH2020 Marie Skłodowska-Curie Actions111698https://www.ebi.ac.uk/biostudies/studies/S-EPMC9715912biostudies-literatureUnknown41(8)Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggestingCell reportsAcute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis.PMC9715912ANR-15-CE14-0030-01DK076169810331UMR 8251748134DK115255ANR-17-CE37-0007-02Lundh SDuquenne MSalinas CGPedersen TAMorel CMaetzler WImbernon MLuquet SCastel JSecher AMartin CGangarossa GBakker WLeger CDenis RGPHecksher-Sorensen JMoro Chao DHHassouna RPeter AJohan Hogendorf WFSchwaninger MNielsen HSHeni MPrevot VfalseAcute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis.Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggesting2022-01-01T00:00:00Z2022 Nov2025-04-22T01:54:43.948Z2025-04-05T20:07:35.157ZS-EPMC97159123641788310.1016/j.celrep.2022.111698