Brain GLP-1 signaling regulates femoral artery blood flow and insulin sensitivity through hypothalamic PKC-?.

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 ?-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-? (but not -?II, -?, or -?) 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-? 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-? 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.

SUBMITTER: Cabou C 

PROVIDER: S-EPMC3161335 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature