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

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.

The Aversive Agent Lithium Chloride Suppresses Phasic Dopamine Release Through Central GLP-1 Receptors

“…Here, we demonstrate that central GLP-1 receptors are necessary for the LiClsuppressive effects on phasic dopamine signaling (Experiment 4). Although NTS GLP-1R activation has been shown to suppress aspects of food reward and alter indices of dopamine function (Richard et al, 2015), our results suggest that NTS and other caudal brainstem GLP-1 receptors are not involved in LiCl-induced dopamine suppression. Restricting Ex-9 to the hindbrain (fourth ventricle) failed to block the dopamine-suppressive effects of LiCl (Experiment 5).…”

GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1

“…However, most of these studies observed the short-term effect on food intake, such as over 24 h or 1 week [4,21,22]. In a study with 28 days of exendin-4 treatment in mice with dietinduced obesity, the initial transient reduction in food intake disappeared over time [23].…”

PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation

“…Activation of NTS GLP-1R through microinjection of the GLP-1R agonist Ex4 eliminated the preference for peanut butter over chow. NTS Ex4 increased dopamine-␤-hydroxylase expression in the NTS, as well as tyrosine-hydroxylase and dopamine receptor 2 expression in the VTA, suggesting that GLP-1 acts on NTS catecholaminergic neurons to elicit this effect (77). Interestingly, these catecholaminergic A2 cells in the NTS are also activated by food intake, and in contrast to PPG neurons, which are only activated by satiating meals, A2 neurons are also activated by smaller amounts of food intake (50), suggesting that this activation is independent of GLP-1 released from PPG neurons.…”