Arcuate GLP-1 receptors regulate glucose homeostasis but not food intake

Abstract

Objective: Glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis through regulation of islet hormone secretion, as well as hepatic and gastric function. Because GLP-1 is also synthesized in the brain, where it regulates food intake, we hypothesized that the CNS GLP-1 system regulates glucose tolerance as well.

Methods and Results: We found that central, but not peripheral, administration of low doses of a GLP-1 receptor (GLP-1r) antagonist caused relative hyperglycemia during a glucose tolerance test suggesting that activation of CNS GLP-1r regulates key processes involved in the maintenance of glucose homeostasis. Central administration of GLP-1 augmented glucose-stimulated insulin secretion, and direct administration of GLP-1 into the arcuate, but not the paraventricular nucleus of the hypothalamus reduced hepatic glucose production. Consistent with a role for GLP-1r in the arcuate, GLP-1r mRNA was found to be expressed in 68.1% of arcuate neurons that expressed POMC mRNA but was not significantly co-expressed with NPY.

Conclusions: These data suggest that the arcuate GLP-1r are a key component of the GLP-1 system to improve glucose homeostasis by both regulating insulin secretion and glucose production.