GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake

Abstract

Central glucagon-like-peptide-1 (GLP-1) receptor activation reduces food intake; however, brain nuclei and mechanism(s) mediating this effect remain poorly understood. Although central nervous system GLP-1 is produced almost exclusively in the nucleus of the solitary tract in the hindbrain, GLP-1 receptors (GLP-1R) are expressed throughout the brain, including nuclei in the mesolimbic reward system (MRS), e.g. the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Here, we examine the MRS as a potential site of action for GLP-1-mediated control of food intake and body weight. Double immunohistochemistry for Fluorogold (monosynaptic retrograde tracer) and GLP-1 neuron immunoreactivity indicated that GLP-1-producing nucleus tractus solitarius neurons project directly to the VTA, the NAc core, and the NAc shell. Pharmacological data showed that GLP-1R activation in the VTA, NAc core, and NAc shell decreased food intake, especially of highly-palatable foods, and body weight. Moreover, blockade of endogenous GLP-1R signaling in the VTA and NAc core resulted in a significant increase in food intake, establishing a physiological relevance for GLP-1 signaling in the MRS. Current data highlight these nuclei within the MRS as novel sites for GLP-1R-mediated control of food intake and body weight.

Fig. 1.

Colocalization of caudal NTS PPG neurons with VTA- and NAc-injected Fluorogold; green immunofluorescence represents neurons positive for PPG, red immunofluorescence represents neurons positive for Fluorogold. A, Representative low magnification (×10) image of coronal section at the level of the caudal NTS; cc, central canal. B, Semiquantification of neurons in the caudal dorsal vagal complex showed that 32.4 ± 2.3%, 41.5 ± 7.0%, and 46.8 ± 6.5% of immunofluorescing PPG neurons in the NTS project to the VTA, NAc core, and NAc shell, respectively. C, Semiquantification of neurons in the caudal dorsal vagal complex showed that 30.3 ± 7.8%, 46.0 ± 2.5%, and 31.5 ± 6.5% of caudal NTS neurons that express immunofluorescence for Fluorogold injected into the VTA, NAc core, and NAc shell, respectively, also show immunofluorescence for PPG. Representative high magnification (×20) images for colocalization of Fluorogold-expressing neurons (red) and PPG-expressing neurons (green), along with individual images for Fluorogold and PPG neurons, are shown for animals in which Fluorogold was injected in the VTA (D), the NAc core (E), and the NAc shell (F).

Fig. 2.

Intra-VTA injection of a GLP-1R agonist reduces intake of highly-palatable foods. Food intake and body weight measurements of rats after injection of aCSF, 0.025 μg exendin-4, or 0.05 μg exendin-4 in the VTA. A, Cumulative sucrose intake, after overnight food deprivation, at 10, 20, 30, 40, 50, and 60 min after injection. B, Modified chow intake after overnight food deprivation and 1 h of sucrose exposure at 1 h, 4 h, and 24 h after chow was returned. C, Change in body weight 24 h postinjection after overnight food deprivation and then sucrose and chow exposure. HF diet intake (D) and chow intake (E) at 1, 3, 6, and 24 h after injection when non-food-deprived rats were given choice between HF diet and chow, in addition to 24 h change in body weight (F). *, P < 0.05 from aCSF (vehicle) condition; #, P ≤ 0.057 from aCSF (vehicle) condition.

Fig. 3.

Intra-NAc core injection of a GLP-1R agonist reduces intake of highly-palatable foods. Food and body weight measurements in ad libitum fed rats after injection of aCSF, 0.025 μg exendin-4, or 0.05 μg exendin-4 aimed at the NAc core. A, Assessment of cumulative sucrose intake at 10, 20, 30, 40, 50, and 60 min after injection of exendin-4 aimed at the NAc core. HF diet intake (B) and chow intake (C) at 1, 3, 6, and 24 h after NAc core-aimed injection when given choice between HF diet and chow, in addition to 24 h change in body weight (D). *, P < 0.05 from aCSF (vehicle) condition; #, P ≤ 0.059 from aCSF (vehicle) condition.

Fig. 4.

Intra-NAc shell injection of a GLP-1R agonist reduces intake of highly-palatable foods. Food and body weight measurements in ad libitum fed rats after injection of aCSF, 0.025 μg exendin-4, or 0.05 μg exendin-4 aimed at the NAc shell. A, Assessment of cumulative sucrose intake at 10, 20, 30, 40, 50, and 60 min after injection of exendin-4 aimed at the NAc shell. HF diet intake (B) and chow intake (C) at 1, 3, 6, and 24 h after NAc shell-aimed injection when given choice between HF diet and chow, in addition to 24 h change in body weight (D). *, P < 0.05 from aCSF (vehicle) condition.

Fig. 5.

Intra-VTA and NAc core injection of a GLP-1R antagonist increases intake of HF diet. HF diet and body weight measurements in ad libitum fed rats after injection of aCSF or 10 μg exendin-9 aimed at the VTA, NAc core, and NAc shell. HF diet intake (A, B, and C) at 1 h, 3 h, 6 h, and 24 h, and 24-h change in body weight (D, E, and F) after VTA-, NAc core-, or NAc shell-aimed injection, respectively. *, P < 0.05 from aCSF (vehicle) condition. BW, Body weight.

Fig. 6.

Intra-VTA, -NAc core, and -NAc shell injection of a GLP-1R agonist does not induce a pica response or decrease chow intake. Chow, kaolin, and body weight measurements in ad libitum fed rats after injection of aCSF or 0.05 μg exendin-4 aimed at the VTA, NAc core, and NAc shell. Chow intake (24 h) after injections aimed at the VTA (A), NAc core (B), and NAc shell (C); 24 h kaolin intake after injections aimed at the VTA (D), NAc core (E), NAc shell (F); 24 h change in body weight for rats injected in the VTA (G), NAc core (H), and NAc shell (I). BW, Body weight.