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Brain GLP-1 regulates arterial blood flow, heart rate and insulin sensitivity

¹Institut National de la Santé et de la Recherche Médicale (INSERM), U858, Institute of Molecular Medicine Rangueil, Toulouse, France
²Université Toulouse III Paul-Sabatier, IFR31, Toulouse, France
³Faculté des Sciences Pharmaceutiques, Toulouse, France
⁴Université Paris 7, UMR CNRS 7059, Paris, France
⁵UMR UPS-CNRS 5241, Toulouse, France
⁶Banting and Best Diabetes Centre, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

Glucagon-Like Peptide-one (GLP-1) is a gut hormone secreted in response to oral glucose absorption which regulates glucose metabolism and cardiovascular function. GLP-1 is also produced in the brain where its contribution to central regulation of metabolic and cardiovascular homeostasis remains incompletely understood

Objectives: To ascertain the importance and mechanisms underlying the role of brain GLP-1 on the control of metabolic and cardiovascular function

Methods: Awake free moving mice were infused with the GLP-1 receptor agonist Exendin-4 into the lateral ventricle of the brain in the basal state or during hyperinsulinemic eu/hyperglycemic clamps. Arterial femoral blood flow, whole body insulin-stimulated glucose utilization and heart rates were continuously recorded.

Results: A continuous three hour brain infusion of exendin-4 (Ex4) decreased femoral arterial blood flow, and whole body glucose utilization in the awake free moving mouse clamped in hyperinsulinemic hyperglycemic condition only demonstrating that this effect was strictly glucose-dependent. However the heart rate remained unchanged. The metabolic and vascular effect of Ex4 were markedly attenuated by central infusion of the GLP-1 receptor antagonist Exendin-9 (Ex9) and totally abolished in GLP-1 receptor knockout mice. A correlation was observed between the metabolic rate and the vascular flow in control and Ex4 infused mice which disappeared in Ex9 and GLP-1 R knockout mice. Moreover, hypothalamic nitric oxide synthase (NOS) activity and the concentration of reactive oxygen species (ROS) were also reduced in a GLP-1R-dependent manner whereas the glutathione antioxidant capacity was increased. Central GLP-1 activated vagus nerve activity and complementation with ROS donor dose-dependently reversed the effect of brain GLP-1 signaling on peripheral blood flow.

Conclusion: Our data demonstrate that central GLP-1 signaling is an essential component of circuits integrating cardiovascular and metabolic responses to hyperglycemia.

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