Colocalization of glucagon-like peptide-1 (GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an inhibitory signal for food and water intake

J Neurochem. 1996 Nov;67(5):1982-91. doi: 10.1046/j.1471-4159.1996.67051982.x.


This study was designed to determine the possible role of brain glucagon-like peptide-1 (GLP-1) receptors in feeding behavior. In situ hybridization showed colocalization of the mRNAs for GLP-1 receptors, glucokinase, and GLUT-2 in the third ventricle wall and adjacent arcuate nucleus, median eminence, and supraoptic nucleus. These brain areas are considered to contain glucose-sensitive neurons mediating feeding behavior. Because GLP-1 receptors, GLUT-2, and glucokinase are proteins involved in the multistep process of glucose sensing in pancreatic beta cells, the colocalization of specific GLP-1 receptors and glucose sensing-related proteins in hypothalamic neurons supports a role of this peptide in the hypothalamic regulation of macronutrient and water intake. This hypothesis was confirmed by analyzing the effects of both systemic and central administration of GLP-1 receptor ligands. Acute or subchronic intraperitoneal administration of GLP-1 (7-36) amide did not modify food and water intake, although a dose-dependent loss of body weight 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 food intake characterized by an increase in the amount of food intake after 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. These effects seemed to be specific because i.c.v. administration of GLP-1 (1-37), a peptide with lower biological activity than GLP-1 (7-36) amide, did not change feeding behavior in food-deprived animals. Exendin-4, when given by i.c.v. administration in a broad range of doses (0.2, 1, 5, 25, 100, and 500 ng), proved to be a potent agonist of GLP-1 (7-36) amide. It decreased, in a dose-dependent manner, both food and water intake, starting at the dose of 25 ng per injection. Pretreatment with an i.c.v. dose of 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. These findings suggest that GLP-1 (7-36) amide may modulate both food and drink intake in the rat through a central mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Ventricles / drug effects
  • Cerebral Ventricles / physiology*
  • Drinking Behavior / drug effects
  • Drinking Behavior / physiology*
  • Feeding Behavior / drug effects
  • Feeding Behavior / physiology*
  • Glucagon
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor
  • Glucagon-Like Peptides
  • Glucokinase / biosynthesis*
  • Glucose Transporter Type 2
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Hypothalamus / physiology*
  • In Situ Hybridization
  • Injections, Intraventricular
  • Male
  • Monosaccharide Transport Proteins / biosynthesis*
  • Neurotransmitter Agents / pharmacology*
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / pharmacology*
  • Peptides / administration & dosage
  • Peptides / pharmacology*
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Wistar
  • Receptors, Glucagon / agonists
  • Receptors, Glucagon / biosynthesis*
  • Signal Transduction
  • Transcription, Genetic*


  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Glucose Transporter Type 2
  • Monosaccharide Transport Proteins
  • Neurotransmitter Agents
  • Peptide Fragments
  • Peptides
  • RNA, Messenger
  • Receptors, Glucagon
  • glucagon-like peptide 1 (7-36)amide
  • Glucagon-Like Peptides
  • glucagon-like peptide 1 (1-37)
  • Glucagon-Like Peptide 1
  • Glucagon
  • Glucokinase