COLOCALIZATION OF GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTORS, GLUCOSE-TRANSPORTER GLUT-2, AND GLUCOKINASE MESSENGER-RNAS IN RAT HYPOTHALAMICCELLS - EVIDENCE FOR A ROLE OF GLP-1 RECEPTOR AGONISTS AS AN INHIBITORY SIGNAL FOR FOOD AND WATER-INTAKE

This study was designed to determine the possible role of brain glucag on-like peptide-1 (GLP-1) receptors in feeding behavior. In situ hybri dization showed colocalization of the mRNAs for GLP-1 receptors, gluco kinase, and GLUT-2 in the third ventricle waif and adjacent arcuate nu cleus, median eminence, and supraoptic nucleus. These brain areas are considered to contain glucose-sensitive neurons mediating feeding beha vior. Because GLP-1 receptors, GLUT-2, and glucokinase are proteins in volved in the multistep process of glucose sensing in pancreatic beta cells, the colocalization of specific GLP-1 receptors and glucose sens ing-related proteins in hypothalamic neurons supports a role of this p eptide in the hypothalamic regulation of macronutrient and water intak e. This hypothesis was confirmed by analyzing the effects of both syst emic and central administration of GLP-1 receptor ligands. Acute or su bchronic intraperitoneal administration of GLP-1 (7-36) amide did not modify food and water intake, although a dose-dependent loss of body w eight gain was observed 24 h after acute administration of the higher dose of the peptide. By contrast, the intracerebroventricular (i.c.v.) administration of GLP-1 (7-36) amide produced a biphasic effect on fo od intake characterized by an increase in the amount of food intake af ter acute i.c.v. delivery of 100 ng of the peptide. There was a marked reduction of food ingestion with the 1,000 and 2,000 ng doses of the peptide, which also produced a significant decrease of water intake. T hese effects seemed to be specific because i.c.v. administration of GL P-1 (1-37), a peptide with lower biological activity than GLP-1 (7-36) amide, did not change feeding behavior in food-deprived animals. Exen din-4, when given by i.c.v. administration in a broad range of doses ( 0.2, 1, 5, 25, 100, acid 500 ng), proved to be a potent agonist of GLP -1 (7-36) amide. It decreased, in a dose-dependent manner, both food a nd water intake, starting at the dose of 25 ng per injection. Pretreat ment with an i.c.v. dose a GLP-1 receptor antagonist [exendin (9-39); 2,500 ng] reversed the inhibitory effects of GLP-1 (7-36) amide (1,000 ng dose) and exendin-4 (25 ng dose) on food and water ingestion. Thes e findings suggest that GLP-1 (7-36) amide may modulate both food and drink intake in the rat through a central mechanism.