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 w ater consumption in rats after intracerebroventricular (icv) administr ation. To assess the potential for desensitization of these effects, w e investigated the effects of chronic icy administration of GLP-1 on f ood 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 Kin m5F insulin oma cells to GLP-1 at concentrations up to 10 nM. Administration of GL P-1 to SD rats (30 mu g icv twice a day for 6 days) resulted in signif icant reductions in 24-hour food consumption each day (25 +/- 1%). Con tinuous icy infusion of GLP-1 for 7 and 14 days significantly inhibite d cumulative food consumption and reduced body weight in SD rats. In t he genetically obese Zucker rat, chronic dosing with GLP-1 (30 mu g ic y) once a day for 6 days caused significant reductions in food consump tion each day and a reduction in body weight. These results indicate t hat the GLP-1 pathways in the central nervous system controlling food consumption do not desensitize after chronic exposure to GLP-1 and sug gest that agonists of the central GLP-1 receptor may be effective agen ts for the treatment of obesity.