title: Brain GLP-1 signaling regulates femoral artery blood flow and insulin sensitivity through hypothalamic PKC-δ.
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.
  
  
  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.
authors.affiliation: INSERM U1048, Institute of Metabolic and Cardiovascular Diseases, Rangueil, Université Paul-Sabatier, Toulouse, France.
authors.forename: Cendrine
authors.initials: C
authors.lastname: Cabou
authors.forename: Christelle
authors.initials: C
authors.lastname: Vachoux
authors.forename: Gérard
authors.initials: G
authors.lastname: Campistron
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Rémy
authors.initials: R
authors.lastname: Burcelin
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000077270:Exenatide; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000819:agonists / Q000235:genetics; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014688:Venoms / Q000494:pharmacology
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D051745:Protein Kinase C-delta