Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding

Abstract

Central glucagon-like peptide-1 receptor (GLP-1R) signaling reduces food intake by affecting a variety of neural processes, including those mediating satiation, motivation, and reward. While the literature suggests that separable neurons and circuits control these processes, this notion has not been adequately investigated. The intake inhibitory effects of GLP-1R signaling in the hindbrain medial nucleus tractus solitarius (mNTS) have been attributed to interactions with vagally transmitted gastrointestinal satiation signals that are also processed by these neurons. Here, behavioral and pharmacological techniques are used to test the novel hypothesis that the reduction of food intake following mNTS GLP-1R stimulation also results from effects on food-motivated appetitive behaviors. Results show that mNTS GLP-1R activation by microinjection of exendin-4, a long-acting GLP-1R agonist, reduced 1) intake of a palatable high-fat diet, 2) operant responding for sucrose under a progressive ratio schedule of reinforcement and 3) the expression of a conditioned place preference for a palatable food. Together, these data demonstrate that the intake inhibitory effects of mNTS GLP-1R signaling extend beyond satiation and include effects on food reward and motivation that are typically ascribed to midbrain and forebrain neurons.

Keywords: exendin-4; food intake; glucagon-like peptide-1; motivation; nucleus tractus solitarius; reward.

Fig. 1.

Representative image of mNTS injection site (white arrow).

Fig. 2.

mNTS GLP-1R activation by exendin-4 reduced high-fat diet intake (A) and 24-h change in body weight (B) (means ± SE; *P < 0.05, **P < 0.01, ***P < 0.001).

Fig. 3.

mNTS GLP-1R activation by exendin-4 reduced progressive ratio responding for sucrose reinforcers. A: number of active and inactive lever presses. B: number of reinforcers earned (means ± SE; *P < 0.05).

Fig. 4.

mNTS GLP-1R activation by exendin-4 reduced a conditioned place preference (CPP) for a palatable food without disrupting activity parameters. A: percentage shift in CPP for a palatable food. B: difference in time spent in food-associated environment [time spent after training (test) − time spent before training (baseline)] total time active (C), and total distance traveled (D) (means ± SE; *P < 0.05).

Fig. 5.

Exendin-4 did not increase kaolin intake (A) (means ± SE), while mNTS GLP-1R activation by exendin-4 reduced 24-h chow intake (B) and 24-h change in BW (C). **P < 0.01.