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. 2015 Mar 20;10(3):e0119034.
doi: 10.1371/journal.pone.0119034. eCollection 2015.

Activation of the GLP-1 Receptors in the Nucleus of the Solitary Tract Reduces Food Reward Behavior and Targets the Mesolimbic System

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Free PMC article

Activation of the GLP-1 Receptors in the Nucleus of the Solitary Tract Reduces Food Reward Behavior and Targets the Mesolimbic System

Jennifer E Richard et al. PLoS One. .
Free PMC article

Abstract

The gut/brain peptide, glucagon like peptide 1 (GLP-1), suppresses food intake by acting on receptors located in key energy balance regulating CNS areas, the hypothalamus or the hindbrain. Moreover, GLP-1 can reduce reward derived from food and motivation to obtain food by acting on its mesolimbic receptors. Together these data suggest a neuroanatomical segregation between homeostatic and reward effects of GLP-1. Here we aim to challenge this view and hypothesize that GLP-1 can regulate food reward behavior by acting directly on the hindbrain, the nucleus of the solitary tract (NTS), GLP-1 receptors (GLP-1R). Using two models of food reward, sucrose progressive ratio operant conditioning and conditioned place preference for food in rats, we show that intra-NTS microinjections of GLP-1 or Exendin-4, a stable analogue of GLP-1, inhibit food reward behavior. When the rats were given a choice between palatable food and chow, intra-NTS Exendin-4 treatment preferentially reduced intake of palatable food but not chow. However, chow intake and body weight were reduced by the NTS GLP-1R activation if chow was offered alone. The NTS GLP-1 activation did not alter general locomotor activity and did not induce nausea, measured by PICA. We further show that GLP-1 fibers are in close apposition to the NTS noradrenergic neurons, which were previously shown to provide a monosynaptic connection between the NTS and the mesolimbic system. Central GLP-1R activation also increased NTS expression of dopamine-β-hydroxylase, a key enzyme in noradrenaline synthesis, indicating a biological link between these two systems. Moreover, NTS GLP-1R activation altered the expression of dopamine-related genes in the ventral tegmental area. These data reveal a food reward-suppressing role of the NTS GLP-1R and indicate that the neurobiological targets underlying food reward control are not limited to the mesolimbic system, instead they are distributed throughout the CNS.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Representative photomicrograph of a coronal section of the rat brain at the level of the NTS illustrating the microinjection site (encircled area) for the behavioral experiments (right panel) and a schematic representation of the NTS from the rat atlas (Paxinos and Watson, 1998) (left panel).
Area postrema (AP), central canal (cc), gracile nucleus (Gr).
Fig 2
Fig 2. NTS GLP-1R activation preferentially affects intake of palatable food but not chow.
Direct NTS GLP-1R stimulation with Ex4 suppressed the intake of palatable food (peanut butter) but not chow when both were offered simultaneously. The effect of Ex4 had a short latency (noted 1h after injection), and lasted throughout the 6h of measurements. The food intake data are represented as grams eaten (A), as calories consumed, since the two foods differ in their caloric density (B), and as the fraction of total intake (by calories) that was represented by the palatable peanut butter intake(C). Data are expressed as mean ±SEM. n = 12 per each treatment group. * p<0.05, ** p<0.01, *** p<0.005.
Fig 3
Fig 3. GLP-1R stimulation by Ex4 in the NTS reduces chow intake and body weight.
Intra-NTS delivery of Ex4 reduced the consumption of chow over the 22h period of data collection (A-B). Body weight (g) was also reduced 22h after injections (C). In a second group of rats intake of kaolin (PICA response) was measured simultaneously with chow intake. While the chow intake was significantly reduced after intra NTS Ex4 administration (D), intake of kaolin was not altered by Ex4 (E). Data are expressed as mean ±SEM. n = 11 per each treatment group (A-C), n = 8 per each treatment group (D-E). * p<0.05, ** p<0.01, ***P < 0.005, **** p<0.0005.
Fig 4
Fig 4. GLP-1R stimulation in the NTS decreased food-motivated behavior.
The effect of intra-NTS injection of Ex4 on progressive ratio operant responding for sucrose was tested. Ex4 potently decreased the number of sucrose rewards earned (A) and the number of active lever presses (B) in an operant lever-pressing paradigm. Importantly this suppression in food-motivated behavior was not associated with a reduction in locomotor activity (C). n = 11 per each treatment group. ** p<0.01, ***P < 0.0005.
Fig 5
Fig 5. GLP-1 injected into the NTS decreased food-motivated behavior.
GLP-1 decreased the number of sucrose rewards earned (A) and the number of active lever presses (B) in an operant lever-pressing paradigm, and this suppression in food-motivated behavior was not associated with a reduction in locomotor activity (C). n = 11 per each treatment group. * p<0.05.
Fig 6
Fig 6. GLP-1R stimulation in the NTS decreased food reward behavior.
The effect of intra-NTS injection of Ex4 on the ability of palatable food to condition a place preference was tested. Preference for the chamber paired to palatable food was abolished by Ex4 treatment. The preference [% conditioned place preference (CPP)] was calculated using the following formula: ((test − pre-test)/(total time − pre-test)) × 100. n = 11 (vehicle group) and n = 8 (Ex4 group). ****p < 0.0005. Data represent mean ±SEM.
Fig 7
Fig 7. NTS expression of two enzymes key in noradrenaline synthesis after central GLP-1R stimulation.
Central activation of GLP-1R with Ex4 increases the expression of dBH but not TH or CCK. Data are expressed as mean ±SEM. n = 9 (pair-fed control group), n = 11 (ad libitum fed control group) and n = 10 (Ex4 group). *p<0.05. Tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (dBH).
Fig 8
Fig 8. Many YFP-immunoreactive axons (green) closely apposed the TH-positive neurons (red) of the NTS.
Fluorescent YFP– preproglucagon neurons (green) and DAPI (nuclear stain, blue) in coronal sections through the NTS of YFP–PPG mice. Micrographs showing the caudal NTS (A-B), the NTS at the level of the area postrema (C-D) and the NTS at the level of the 4th ventricle (E-F). Cell bodies of YFP-immunoreactive preproglucagon neurons (green) were detected at the level of the area postrema and just caudally to the area postrema (A-D). Many green YFP-immunoreactive axons closely appose blue DAPI-labeled cell bodies in the NTS. White arrows indicate NTS TH-positive neuronal cell bodies closely apposed by the GLP-1 fibers. Insets in panels B,D and F show the interaction at a single neuron level. Area postrema (AP), central canal (cc), dorsal motor nucleus of the vagus (DMV), gracile nucleus (Gr), 4th ventricle (4thV). B,D and F show higher magnification of areas in A,C and D, respectively.
Fig 9
Fig 9. Activation of GLP-1R in the NTS alters gene expression in the mesolimbic reward system.
GLP-1R activation by Ex4 in the NTS increased the mRNA expression of the gene that encodes tyrosine hydroxylase (TH), and dopamine 2 receptor (Drd2) without significantly changing the mRNA expression of other dopamine receptors in the VTA (A). The expression of several other genes previously associated with changes in reward behavior: FosB, Creb1 and Gad1 remained unchanged after intra-NTS Ex4 treatment (B). Intra-NTS Ex4 treatment did not alter the expression of dopamine receptors, dopamine transporter (DAT), FosB, Gad1 or Creb1 in the nucleus accumbens (Fig C-D). Data are expressed as mean ±SEM. n = 6 (vehicle group) and n = 5 (Ex4 group). ** p<0.01, *** p<0.005. Dopamine receptor 1 (Drd1a), dopamine receptor 3 (Drd3), dopamine receptor 5 (Drd5), glutamate decarboxylase 1 (Gad1), cAMP responsive element binding protein 1 (Creb1), FBJ osteosarcoma viral oncogene B (FosB).

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References

    1. Saper CB, Chou TC, Elmquist JK (2002) The need to feed: homeostatic and hedonic control of eating. Neuron 36: 199–211. - PubMed
    1. Grill HJ, Skibicka KP, Hayes MR (2007) Imaging obesity: fMRI, food reward, and feeding. Cell Metab 6: 423–425. - PubMed
    1. Berthoud HR (2011) Metabolic and hedonic drives in the neural control of appetite: who is the boss? Curr Opin Neurobiol 21: 888–896. 10.1016/j.conb.2011.09.004 - DOI - PMC - PubMed
    1. Zheng H, Lenard NR, Shin AC, Berthoud HR (2009) Appetite control and energy balance regulation in the modern world: reward-driven brain overrides repletion signals. Int J Obes (Lond) 33 Suppl 2: S8–13. - PMC - PubMed
    1. Vucetic Z, Reyes TM (2010) Central dopaminergic circuitry controlling food intake and reward: implications for the regulation of obesity. Wiley Interdiscip Rev Syst Biol Med 2: 577–593. 10.1002/wsbm.77 - DOI - PubMed

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