Brain Glucagon-Like Peptide-1 Regulates Arterial Blood Flow, Heart Rate, and Insulin Sensitivity
- Cendrine Cabou123,
- Gérard Campistron123,
- Nicolas Marsollier4,
- Corinne Leloup25,
- Celine Cruciani-Guglielmacci4,
- Luc Pénicaud25,
- Daniel J. Drucker6,
- Christophe Magnan4 and
- Rémy Burcelin12
- 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
- Corresponding author: Rémy Burcelin, remy.burcelin{at}inserm.fr
Abstract
OBJECTIVE— To ascertain the importance and mechanisms underlying the role of brain glucagon-like peptide (GLP)-1 in the control of metabolic and cardiovascular function. GLP-1 is a gut hormone secreted in response to oral glucose absorption that 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.
RESEARCH DESIGN AND METHODS— Awake free-moving mice were infused with the GLP-1 receptor agonist exendin-4 (Ex4) 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 3-h brain infusion of Ex4 decreased femoral arterial blood flow and whole-body glucose utilization in the awake free-moving mouse clamped in a hyperinsulinemic-hyperglycemic condition, only demonstrating that this effect was strictly glucose dependent. However, the heart rate remained unchanged. The metabolic and vascular effects of Ex4 were markedly attenuated by central infusion of the GLP-1 receptor (GLP-1R) 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-1R knockout mice. Moreover, hypothalamic nitric oxide synthase 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.
CONCLUSIONS— Our data demonstrate that central GLP-1 signaling is an essential component of circuits integrating cardiovascular and metabolic responses to hyperglycemia.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008.
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- Accepted July 8, 2008.
- Received January 28, 2008.
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