Evidence that intestinal glucagon-like peptide-1 plays a physiological role in satiety

Abstract

A physiological role in satiety is proposed for glucagon-like peptide-1 (GLP-1), secreted by the distal intestine in response to ingested nutrients. Here we report that in rats, ip injection of the GLP-1 receptor (GLP-1-R) antagonist exendin 9-39 (Ex9) elicited hyperphagia, but only at times of day when intake is otherwise low. Furthermore, ip administration of Ex9 attenuated satiety induced by either a voluntarily consumed sucrose meal (by 100%) or an intragastric glucose load (by 40%). To determine whether these effects involve blockade of GLP-1-R in brain or at a peripheral site, we injected Ex9 either centrally (into the third ventricle) or peripherally (ip) prior to GLP-1 injected either centrally or peripherally. Anorexia induced by peripheral GLP-1 was fully blocked by peripheral, but not central, pretreatment with Ex9, whereas the opposite was true for anorexic effect of central GLP-1. Thus, ip Ex9 appears to attenuate satiety via peripheral GLP-1-R blockade. Finally, anorexia induced by ip injection of exendin-4 (a GLP-1-R agonist) was due to both reduced meal size and increased duration between meals. We conclude that GLP-1 released from the intestine in response to ingested nutrients is a physiologically active satiety signal.

Figure 1

Ex9 effect on food intake. Food intake was measured in rats at 1 and 2 h after ip injection of either saline vehicle or Ex9 (30 or 100 μg/kg) during the middle of the light phase (A); immediately before the dark phase (B), or 1 h into the dark phase (C). Data are mean ± sem. *, P < 0.05 vs. vehicle.

Figure 2

Effect of GLP-1-R blockade on oral preload-induced satiety. After training rats to receive access to a sucrose solution for 15 min at the same time each day, chow intake was measured after either no preload (NP) or an orally consumed sucrose preload (P). Preloads were followed immediately by ip injection of either saline (SAL) or Ex9 (100 μg/kg), after which standard chow was returned to the cage and intake measured over the subsequent 2 h period. Data are mean ± sem. *, P < 0.05.

Figure 3

Effect of GLP-1-R blockade on IG preload-induced satiety. A, Intake of a palatable liquid diet was measured after IG infusion of either saline (SAL) or glucose, followed immediately by ip injection of either saline or Ex9 (100 μg/kg). B, The percentage of intake suppression induced by the glucose preload shown in A differed after ip saline vs. ip Ex9. Data are mean ± sem. *, P < 0.05.

Figure 4

Effect of central GLP-1-R blockade on central vs. peripheral GLP-1-induced anorexia. Food intake was measured in rats that were pretreated with a 3rd-icv injection of either saline (SAL) or Ex9 (20 μg) and then given either a 3rd-icv injection of saline or GLP-1 (3 μg) (A) or an ip injection of saline or GLP-1 (100 μg/kg) (B). Data are mean ± sem. *, P < 0.05.

Figure 5

Effect of peripheral GLP-1-R blockade on central vs. peripheral GLP-1-induced anorexia. Food intake was measured in rats that received an ip injection of either saline (SAL) or Ex9 (100 μg/kg) before either an ip injection of saline or GLP-1 (100 μg/kg) (A) or 3rd-icv injection of saline or GLP-1 (3 μg) (B). The icv GLP-1 injection was given either 15 or 45 min (Ex9-long) after ip injection. Data are mean ± sem. *, P < 0.05.

Figure 6

Effect of Ex4 on meal pattern. Effect of ip injection of vehicle (Veh) or Ex4 at dark cycle onset on feeding parameters measured during the first 4 h of the dark phase, including food intake (A), average meal size (B), and number of meals (C). D, Effect of Ex4 on meal size varied over time, affecting both the duration (E) and intermeal interval (F) of the first four meals taken. Data are mean ± sem. *, P < 0.05.