Peripheral Glucagon-like peptide 2 administration inhibits food intake in mice: Analysis of the mechanism of action.

OBJECTIVE: Previously we showed that, in mice, peripheral administration of glucagon-like peptide 2 (GLP-2) or [Gly2]GLP-2, the degradation-resistant analogue of GLP-2, reduces food intake in the short term. The purposes of the present study were to compare the influence of [Gly2]GLP-2 with the anorectic effect induced by glucagon-like peptide 1 (GLP-1) and to analyze the mechanism of action responsible for GLP-2-induced effects. METHODS: Food intake was measured in mice, fasted for 16-18 h, at the first hour following peptide or vehicle intraperitoneally (i.p.) administration. The effects of GLP-2 (3-33), GLP-2 receptor (GLP-2R) antagonist, and exendin (9-39), GLP-1R antagonist were also evaluated. To analyze the mechanism of action the effects of [Gly2]GLP-2 on gastric emptying were determined, and its influence on the food intake was examined in mice with sensory deafferentation induced by capsaicin pretreatment. RESULTS: Administration of [Gly2]GLP-2 (0.60 µg/g b.w.) caused a significant reduction in the food intake when compared with vehicle treated mice, which was blocked by the GLP-2 receptor antagonist, GLP-2 (3-33), or by the GLP-1 receptor antagonist, exendin (9-39). Both antagonists per se did not alter food intake. Also GLP-1 (0.30 µg/g b.w.) significantly inhibited food intake and the dose that inhibited the food intake by 50%, was lower than that determined for [Gly2]GLP-2. The effect was antagonized by the GLP-1 receptor antagonist, but not by the GLP-2 receptor antagonist. Coadministration of [Gly2]GLP-2 and GLP-1 did not cause any additive inhibition on the food intake. The rate of gastric emptying was significant decreased in [Gly2]GLP-2 treated animals compared with vehicle treated mice. Sensory deafferentation by capsaicin blocked the effects of [Gly2]GLP-2 peripheral injection, while it did not alter food intake in vehicle treated mice. CONCLUSIONS: Our results suggest that [Gly2]GLP-2 is less potent than GLP-1 in inducing inhibition of the food intake in mice. GLP-1 and GLP-2 appear to act through a common pathway. GLP-2 exerts its effect through peripheral neural mechanisms and requires the functional activity of GLP-1R signaling.