Glucagon-like Peptide-1 receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake and motivation to feed

Abstract

Central glucagon-like peptide-1 receptor (GLP-1R) activation reduces food intake and the motivation to work for food, but the neurons and circuits mediating these effects are not fully understood. Although lateral parabrachial nucleus (lPBN) neurons are implicated in the control of food intake and reward, the specific role of GLP-1R-expressing lPBN neurons is unexplored. Here, neuroanatomical tracing, immunohistochemical, and behavioral/pharmacological techniques are used to test the hypothesis that lPBN neurons contribute to the anorexic effect of central GLP-1R activation. Results indicate that GLP-1-producing neurons in the nucleus tractus solitarius project monosynaptically to the lPBN, providing a potential endogenous mechanism by which lPBN GLP-1R signaling may exert effects on food intake control. Pharmacological activation of GLP-1R in the lPBN reduced food intake, and conversely, antagonism of GLP-1R in the lPBN increased food intake. In addition, lPBN GLP-1R activation reduced the motivation to work for food under a progressive ratio schedule of reinforcement. Taken together, these data establish the lPBN as a novel site of action for GLP-1R-mediated control of food intake and reward.

Figures

Figure 1

Colocalizion of caudal NTS GLP-1-producing neurons and lPBN-injected Fluorogold. (a) Representative × 20 magnification image of a coronal NTS section; red immunofluorescence represents Fluorogold-expressing neurons and green immunofluorescence represents GLP-1-expressing neurons. (b) Quantification of neurons in the caudal NTS showed that 23.2±4.2% of ipsilateral NTS GLP-1 neurons and 10.6±3.0% of contralateral NTS GLP-1 neurons project monosynaptically to the lPBN (means±SEM). (c) Representative image of lPBN injection site (white arrow). CB, cerebellum; lPBN, lateral parabrachial nucleus; mPBN, medial parabrachial nucleus; scp, superior cerebellar peduncle; 4 V, fourth ventricle.

Figure 2

GLP-1R agonist (a) or antagonist (b) injected into the aqueduct just rostral from the level of the PBN had no effect on cumulative food intake (means±SEM).

Figure 3

lPBN GLP-1R activation by exendin-4 reduced standard chow and water intake. (a) Cumulative chow intake; (b) noncumulative chow intake; (c) 24 h change in body weight; (d) 24 h water intake; and (e) 24 h kaolin intake (means±SEM, *p<0.05).

Figure 4

lPBN GLP-1R activation by exendin-4 reduced high-fat diet intake, body weight, and water intake. (a) Cumulative high-fat diet intake; (b) noncumulative high-fat diet intake; (c) 24 h change in body weight; (d) 24 h water intake (means±SEM, *p<0.05, **p<0.01).

Figure 5

lPBN GLP-1R antagonism by exendin-(9–39) increased standard chow and high-fat diet intake. (a) Cumulative chow intake; (b) 24 h change in body weight for animals maintained on chow; (c) cumulative HFD intake; (d) 24 h change in body weight for animals maintained on HFD (means±SEM, *p<0.05, **p<0.01).

Figure 6

lPBN GLP-1R activation by exendin-4 reduced operant lever responding under a progressive ratio schedule of reinforcement for a high-fat chocolate-flavored reinforcer. (a) Number of active and inactive lever presses; (b) number of reinforcers earned (means±SEM, **p<0.01).

Figure 7

lPBN GLP-1R activation by exendin-4 had minimal effect on activity parameters: (a) total distance traveled; (b) total time active, with animal still for >1 s to be considered inactive; (c) total time active, with animal still for >2 s to be considered inactive. lPBN GLP-1R blockade by exendin-(9–39) had no effect on activity: (d) total distance traveled; (e) total time active, with animal still for >1 s to be considered inactive; (f) total time active, with animal still for >2 s to be considered inactive (means±SEM, *p<0.05).