1. Brain GLP-1 Signaling Regulates Femoral Artery Blood Flow and Insulin Sensitivity Through Hypothalamic PKC-{delta}
- Author
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Christelle Vachoux, Daniel J. Drucker, Rémy Burcelin, Cendrine Cabou, Gérard Campistron, Simon, Marie Francoise, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie, Faculté de Pharmacie de Toulouse, Department of Medicine, and University of Toronto-Samuel Lunenfeld Research Institute-Mount Sinai Hospital [Toronto, Canada] (MSH)
- Subjects
Male ,medicine.medical_specialty ,endocrine system ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,medicine.medical_treatment ,Hypothalamus ,Femoral artery ,Biology ,Glucagon-Like Peptide-1 Receptor ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Glucagon-Like Peptide 1 ,Internal medicine ,medicine.artery ,Receptors, Glucagon ,Internal Medicine ,medicine ,Animals ,Hypoglycemic Agents ,Insulin ,Receptor ,Protein kinase C ,030304 developmental biology ,Mice, Knockout ,2. Zero hunger ,0303 health sciences ,Venoms ,digestive, oral, and skin physiology ,Brain ,Glucagon-like peptide-1 ,Femoral Artery ,Protein Kinase C-delta ,Metabolism ,Endocrinology ,Regional Blood Flow ,Exenatide ,Signal transduction ,Peptides ,030217 neurology & neurosurgery ,Signal Transduction ,Hormone - Abstract
OBJECTIVE Glucagon-like peptide 1 (GLP-1) is a gut-brain hormone that regulates food intake, energy metabolism, and cardiovascular functions. In the brain, through a currently unknown molecular mechanism, it simultaneously reduces femoral artery blood flow and muscle glucose uptake. By analogy to pancreatic β-cells where GLP-1 activates protein kinase C (PKC) to stimulate insulin secretion, we postulated that PKC enzymes would be molecular targets of brain GLP-1 signaling that regulate metabolic and vascular function. RESEARCH DESIGN AND METHODS We used both genetic and pharmacological approaches to investigate the role of PKC isoforms in brain GLP-1 signaling in the conscious, free-moving mouse simultaneous with metabolic and vascular measurements. RESULTS In normal wild-type (WT) mouse brain, the GLP-1 receptor (GLP-1R) agonist exendin-4 selectively promotes translocation of PKC-δ (but not -βII, -α, or -ε) to the plasma membrane. This translocation is blocked in Glp1r−/− mice and in WT mice infused in the brain with exendin-9, an antagonist of the GLP-1R. This mechanism coordinates both blood flow in the femoral artery and whole-body insulin sensitivity. Consequently, in hyperglycemic, high-fat diet–fed diabetic mice, hypothalamic PKC-δ activity was increased and its pharmacological inhibition improved both insulin-sensitive metabolic and vascular phenotypes. CONCLUSIONS Our studies show that brain GLP-1 signaling activates hypothalamic glucose-dependent PKC-δ to regulate femoral artery blood flow and insulin sensitivity. This mechanism is attenuated during the development of experimental hyperglycemia and may contribute to the pathophysiology of type 2 diabetes.
- Published
- 2011
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