TY  - JOUR
AU  - Bakker, Wineke
AU  - Imbernon, Monica
AU  - Salinas, Casper Gravesen
AU  - Moro Chao, Daniela Herrera
AU  - Hassouna, Rim
AU  - Morel, Chloe
AU  - Martin, Claire
AU  - Leger, Caroline
AU  - Denis, Raphael G P
AU  - Castel, Julien
AU  - Peter, Andreas
AU  - Heni, Martin
AU  - Maetzler, Walter
AU  - Nielsen, Heidi Solvang
AU  - Duquenne, Manon
AU  - Schwaninger, Markus
AU  - Lundh, Sofia
AU  - Johan Hogendorf, Wouter Frederic
AU  - Gangarossa, Giuseppe
AU  - Secher, Anna
AU  - Hecksher-Sørensen, Jacob
AU  - Pedersen, Thomas Åskov
AU  - Prevot, Vincent
AU  - Luquet, Serge
TI  - Acute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis.
JO  - Cell reports
VL  - 41
IS  - 8
SN  - 2211-1247
CY  - [New York, NY]
PB  - Elsevier
M1  - DZNE-2022-01738
SP  - 111698
PY  - 2022
AB  - 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.
KW  - Humans
KW  - Blood Glucose: metabolism
KW  - Vascular Endothelial Growth Factor A: metabolism
KW  - Glucagon-Like Peptide 1: metabolism
KW  - Insulin: metabolism
KW  - Homeostasis
KW  - Brain: metabolism
KW  - CP: Metabolism (Other)
KW  - brain access (Other)
KW  - diabetes (Other)
KW  - glucagon-like peptide 1 analogs (Other)
KW  - glycemic control (Other)
KW  - metabolism (Other)
KW  - nutrient partitioning (Other)
KW  - obesity (Other)
KW  - tanycyte (Other)
KW  - Blood Glucose (NLM Chemicals)
KW  - Vascular Endothelial Growth Factor A (NLM Chemicals)
KW  - Glucagon-Like Peptide 1 (NLM Chemicals)
KW  - Insulin (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9715912
C6  - pmid:36417883
DO  - DOI:10.1016/j.celrep.2022.111698
UR  - https://pub.dzne.de/record/165605
ER  -