Endogenous hindbrain glucagon-like peptide-1 receptor activation contributes to the control of food intake by mediating gastric satiation signaling

Abstract

Exogenous activation of central nervous system glucagon-like peptide-1 (GLP-1) receptors (GLP-1Rs) reduces food intake. Experiments addressed whether endogenous central GLP-1R activity is involved in the control of normal feeding and examined which gastrointestinal satiation signals contribute to this control. Given that nucleus tractus solitarius (NTS) neurons are the source of central GLP-1, that caudal brainstem circuits mediate the intake suppression triggered by exogenous hindbrain GLP-1R activation, and that these neurons process gastrointestinal vagal signals, the role of endogenous hindbrain GLP-1R activation to intake control was the focus of the analysis. Food intake increased with GLP-1R antagonist [Exendin-(9-39) (Ex-9)] [10 microg, fourth intracerebroventricular (icv)] delivery to overnight food-deprived rats after ingestion of 9 ml Ensure diet. Direct medial NTS injection of a ventricle subthreshold dose (1.0 microg) of Ex-9 increased food intake and established the contribution of this GLP-1R population to the effect observed with ventricular administration. To determine whether satiation signals of gastric vs. intestinal origin drive the GLP-1R-mediated NTS effect on food intake, two experiments were performed in overnight-fasted rats. In one, Ensure was infused intraduodenally (0.4 ml/min for 20 min); in another, the stomach was distended (9 ml SILASTIC brand balloon) for 15 min before fourth icv Ex-9. The intake suppression by duodenal nutrient infusion was not affected by GLP-1R blockade, but the feeding suppression after gastric distension was significantly attenuated by fourth icv Ex-9. We conclude that endogenous NTS GLP-1R activation driven by gastric satiation signals contributes to the control of normal feeding.

Figure 1

Blockade of hindbrain GLP-1R by fourth icv delivery of the GLP-1R selective antagonist Ex-9 significantly increased food intake at a dose of 10 μg at 0.5, 1.0, 1.5, and 24 h after injection in overnight food-deprived rats after ingestion of a 9-ml Ensure preload, whereas a dose of 2 μg Ex-9 was subthreshold for effect. *, P < 0.05 from vehicle.

Figure 2

Selective blockade of NTS GLP-1R by intraparenchymal delivery of Ex-9 at a ventricle subthreshold dose (1.0 μg/100 nl) resulted in a significant increase in food intake compared with intakes after vehicle injections in overnight food-deprived rats. *, P < 0.05 from respective vehicle intakes. Inset photograph of a representative histological section highlights the intraparenchymal caudal NTS (at the level of the AP) injection site by delivery of Pontamine Sky Blue at the same injection volume. CC, Central canal; DMV, dorsal motor nucleus of the vagus; mNTS, medial nucleus of the solitary tract.

Figure 3

Intraduodenal infusion of Ensure (8 ml infused at 0.4 ml/min for 20 min) suppressed food intake compared with intake after 0.9% NaCl infusion in overnight food-deprived rats. Blockade of hindbrain GLP-1R by fourth icv Ex-9 delivery (10 μg) did not affect the suppression of intake resulting from intraduodenal Ensure infusion. *, P < 0.05 from vehicle/0.9% NaCl intakes. NS, Not significant.

Figure 4

Gastric distension (9 ml balloon distension for 15 min before food access) suppressed food intake compared with intake after sham distension in overnight food-deprived rats. Hindbrain-directed blockade of GLP-1R (fourth icv Ex-9; 10 μg) significantly attenuated the suppression of food intake by gastric distension. *, P < 0.05.