Acute changes in systemic glycaemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis - CNRS - Centre national de la recherche scientifique
Pré-Publication, Document De Travail Année : 2020

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

Wineke Bakker
  • Fonction : Auteur
Casper Gravesen Salinas
  • Fonction : Auteur
Monica Imbernon
  • Fonction : Auteur
Daniela Herrera Moro Chao
  • Fonction : Auteur
Rim Hassouna
  • Fonction : Auteur
Chloe Morel
  • Fonction : Auteur
Claire Martin
Giuseppe Gangarossa
Raphael Gp Denis
  • Fonction : Auteur
Julien Castel
  • Fonction : Auteur
Andreas Peter
  • Fonction : Auteur
Martin Heni
  • Fonction : Auteur
Walter Maetzler
  • Fonction : Auteur
Heidi Solvang Nielsen
  • Fonction : Auteur
Manon Duquenne
Anna Secher
  • Fonction : Auteur
Jacob Hecksher-Sørensen
  • Fonction : Auteur
Thomas Åskov Pedersen
  • Fonction : Auteur
Vincent Prevot

Résumé

The control of body weight and glucose homeostasis are the bedrock of type 2 diabetes medication. Therapies based on co-administration of glucagon-like peptide-1 (GLP-1) long-acting analogues and insulin are becoming popular in the treatment of T2D. Both insulin and GLP-1 receptors (InsR and GLP1-R, respectively) are expressed in brain regions critically involved in the regulation of energy homeostasis, suggesting a possible cooperative action. However, the mechanisms underlying the synergistic action of insulin and GLP-1R agonists on body weight loss and glucose homeostasis remain largely under-investigated. In this study, we provide evidence that peripheral insulin administration modulates the action of GLP-1R agonists onto fatty acids oxidation. Taking advantage of fluorescently labeled insulin and GLP-1R agonists, we found that glucoprivic condition, either achieved by insulin or by 2-deoxyglucose (2-DG), acts as a permissive signal on the blood-brain barrier (BBB) at circumventricular organs, including the median eminence (ME) and the area postrema (AP), enhancing the passage and action of GLP-1-R agonists. Mechanistically, this phenomenon relied on the release of tanycyctic vascular endothelial growth factor A (VEGF-A) and it was selectively impaired after calorie-rich diet exposure. Finally, we found that in human subjects, low blood glucose also correlates with enhanced blood-to-brain passage of insulin suggesting that changes in glycaemia also affect passage of peptide hormones into the brain in humans.
In conclusion, we describe a yet unappreciated mechanism by which acute variations of glycaemia gate the entry and action of circulating energy-related signals in the brain. This phenomenon has physiological and clinical relevance implying that glycemic control is critical to harnessing the full benefit of GLP-1R agonist co-treatment in body weight loss therapy.
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Dates et versions

hal-03001512 , version 1 (12-11-2020)

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Wineke Bakker, Casper Gravesen Salinas, Monica Imbernon, Daniela Herrera Moro Chao, Rim Hassouna, et al.. Acute changes in systemic glycaemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis. 2020. ⟨hal-03001512⟩
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