Effect of chronic central administration of glucagon-like peptide-1 (7-36) amide on food consumption and body weight in normal and obese rats.
Glucagon-like peptide (7-36) amide (GLP-1) acutely inhibits food and water consumption in rats after intracerebroventricular (icv) administration. To assess the potential for desensitization of these effects, we investigated the effects of chronic icv administration of GLP-1 on food consumption and body weight in Sprague-Dawley (SD) rats and Zucker (fa/fa) obese rats. In vitro functional densensitization of the GLP-1 receptor was not observed after overnight exposure of Rin m5F insulinoma cells to GLP-1 at concentrations up to 10 nM. Administration of GLP-1 to SD rats (30 microg icv twice a day for 6 days) resulted in significant reductions in 24-hour food consumption each day (25 +/- 1%). Continuous icv infusion of GLP-1 for 7 and 14 days significantly inhibited cumulative food consumption and reduced body weight in SD rats. In the genetically obese Zucker rat, chronic dosing with GLP-1 (30 microg icv) once a day for 6 days caused significant reductions in food consumption each day and a reduction in body weight. These results indicate that the GLP-1 pathways in the central nervous system controlling food consumption do not desensitize after chronic exposure to GLP-1 and suggest that agonists of the central GLP-1 receptor may be effective agents for the treatment of obesity.
Davis
H R
HR
Department of CNS and Cardiovascular Research, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Mullins
D E
DE
Pines
J M
JM
Hoos
L M
LM
France
C F
CF
Compton
D S
DS
Graziano
M P
MP
Sybertz
E J
EJ
Strader
C D
CD
Van Heek
M
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D004435:Eating / Q000187:drug effects*; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides; D007276:Injections, Intraventricular; D007340:Insulinoma / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D009765:Obesity / Q000503:physiopathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D018027:Receptors, Glucagon / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C055453:glucagon-like peptide 1 (7-36)amide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon