Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake

Abstract

Central glucagon-like peptide 1 receptor (GLP-1R) stimulation suppresses food intake, and hindbrain GLP-1 neurons project to numerous feeding-relevant brain regions. One such region is the nucleus accumbens (NAc), which plays a role in reward and motivated behavior. Using immunohistochemical and retrograde tracing techniques in rats, we identified a robust projection from GLP-1 neurons in the nucleus of the solitary tract to the NAc. We hypothesized that activation of NAc GLP-1Rs suppresses feeding. When injected into the NAc core of rats at doses subthreshold for effect when administered to the lateral ventricle, GLP-1 significantly reduced food intake relative to vehicle at 1, 2, and 24 h posttreatment. The same doses had no effect when injected into the NAc shell. NAc core treatment with ventricle-subthreshold doses of the GLP-1R antagonist exendin (9-39) caused significant hyperphagia at 2 h posttreatment, suggesting that endogenous stimulation of NAc core GLP-1Rs plays a role in limiting food intake. It has been suggested that GLP-1 can cause nausea, but we found that NAc core administration of GLP-1 did not cause a conditioned taste aversion to saccharin, suggesting that the anorexic effect of NAc core GLP-1 is not caused by malaise. Finally, we observed that NAc core injection of GLP-1 significantly increased c-Fos expression in the NAc core. We conclude that that GLP-1Rs in the NAc play a physiologic role in food intake control, and suggest that the GLP-1 projection to NAc core may link satiation signal processing in the hindbrain with forebrain processing of food reward.

Figure 1.

Representative images of fluorescent immunostaining and retrograde tracing of the projection from NTS neurons to NAc. A, NAc image showing the location and minimal spread of RetroBead injection (ac, anterior commissure). B, C, A low-magnification image of the caudal NTS (B) and a corresponding diagram (C) based on Paxinos and Watson (2007) are provided for orientation (Cu, cuneate nucleus; Gr, gracile nucleus; st, solitary tract; 10N, dorsal motor nucleus of the vagus; c, central canal). Higher-magnification images are taken from the area inside the white box in B. B, D, F, G, I, GLP-1 neurons (green cytoplasmic fluorescence) are visible in the NTS. B, E, F, H, I, Magenta cytoplasmic fluorescence identifies neurons that are retrogradely labeled by RetroBeads (B, E, F) or Fluorogold (H, I). B, F, I, Colocalization of GLP-1 and tracer is shown by merging images of GLP-1 and tracer. Arrows indicate several double-labeled cells.

Figure 2.

A, B, Dose–response function for the food intake effects of LV-injected GLP-1 (A) and Ex9 (B). *p < 0.05 relative to saline.

Figure 3.

A, Diagram of representative NAc core and shell injection placements based on the atlas of Paxinos and Watson (2007). Additional rats' injections were identified in similar locations at points between the anterior–posterior levels shown here. B, NAc core, but not shell, injection of GLP-1 reduced food intake. C, Ex9 injected into the NAc core increased feeding. D, Percentage of saccharin out of total saccharin plus water consumed in a 24 h test of CTA. Rats that previously experienced saccharin paired with intra-NAc core saline or GLP-1 strongly preferred to drink saccharin over water, but rats that received a saccharin-LiCl pairing showed aversion to saccharin. *p < 0.05 relative to saline.

Figure 4.

A–D, Representative images of c-Fos immunoreactivity (dark nuclear staining) in the NAc of a rat that received intra-NAc core saline (A, core region; B, shell region) and a rat that received intra-NAc core GLP-1 (C, core region; D, shell region). ac, Anterior commissure.