Journal Article

DZNE-2022-01738

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Acute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis.

Bakker, W. ; Imbernon, M. ; Salinas, C. G. ; Moro Chao, D. H. ; Hassouna, R. ; Morel, C. ; Martin, C. ; Leger, C. ; Denis, R. G. P. ; Castel, J. ; Peter, A. ; Heni, M. ; Maetzler, W.DZNE* ; Nielsen, H. S. ; Duquenne, M. ; Schwaninger, M. ; Lundh, S. ; Johan Hogendorf, W. F. ; Gangarossa, G. ; Secher, A. ; Hecksher-Sørensen, J. ; Pedersen, T. Å. ; Prevot, V. ; Luquet, S.

2022
Elsevier [New York, NY]

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Please use a persistent id in citations: doi:10.1016/j.celrep.2022.111698

Abstract: 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.

Keyword(s): Humans (MeSH) ; Blood Glucose: metabolism (MeSH) ; Vascular Endothelial Growth Factor A: metabolism (MeSH) ; Glucagon-Like Peptide 1: metabolism (MeSH) ; Insulin: metabolism (MeSH) ; Homeostasis (MeSH) ; Brain: metabolism (MeSH) ; CP: Metabolism ; brain access ; diabetes ; glucagon-like peptide 1 analogs ; glycemic control ; metabolism ; nutrient partitioning ; obesity ; tanycyte ; Blood Glucose ; Vascular Endothelial Growth Factor A ; Glucagon-Like Peptide 1 ; Insulin

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Contributing Institute(s):

1. Functional Neurogeriatrics (AG Maetzler)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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