Acute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis

Wineke Bakker*, Monica Imbernon, Casper Gravesen Salinas, Daniela Herrera Moro Chao, Rim Hassouna, Chloe Morel, Claire Martin, Caroline Leger, Raphael G.P. Denis, Julien Castel, Andreas Peter, Martin Heni, Walter Maetzler, Heidi Solvang Nielsen, Manon Duquenne, Markus Schwaninger, Sofia Lundh, Wouter Frederic Johan Hogendorf, Giuseppe Gangarossa, Anna SecherJacob Hecksher-Sørensen, Thomas Åskov Pedersen, Vincent Prevot, Serge Luquet*

*Corresponding author for this work
1 Citation (Scopus)


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, suggesting that blood glucose gates the passage other energy-related signals in the brain. This study implies that the preventing hyperglycemia is important to harnessing the full benefit of GLP-1R agonist entry in the brain and action onto lipid mobilization and body weight loss.

Original languageEnglish
Article number111698
JournalCell Reports
Issue number8
Publication statusPublished - 22.11.2022

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