Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation.

The FDA-approved glucagon-like-peptide-1 receptor (GLP-1R) agonists exendin-4 and liraglutide reduce food intake and body weight. Nausea is the most common adverse side effect reported with these GLP-1R agonists. Whether food intake suppression by exendin-4 and liraglutide occurs independently of nausea is unknown. Further, the neurophysiological mechanisms mediating the nausea associated with peripheral GLP-1R agonist use are poorly understood. Using two established rodent models of nausea [conditioned taste avoidance (CTA) and pica (ingestion of non-nutritive substances)], results show that all peripheral doses of exendin-4 that suppress food intake also produce CTA, whereas one dose of liraglutide suppresses intake without producing CTA. Chronic (12 days) daily peripheral administration of exendin-4 produces a progressive increase in pica coupled with stable, sustained food intake and body weight suppression, whereas the pica response and food intake reduction by daily liraglutide are more transient. Results demonstrate that the nausea response accompanying peripheral exendin-4 occurs via a vagal-independent pathway involving GLP-1R activation in the brain as the exendin-4-induced pica response is attenuated with CNS co-administration of the GLP-1R antagonist exendin-(9-39), but not by vagotomy. Direct administration of exendin-4 to the medial subnucleus of the nucleus tractus solitarius (mNTS), but not to the central nucleus of the amygdala, reduced food intake and produced a pica response, establishing the mNTS as a potential GLP-1R-expressing site mediating nausea responses associated with GLP-1R agonists.

Background The stomach-derived hormone ghrelin drives higher-order feeding processes related to food reward and food seeking via CNS signaling at its receptor (GHSR1A). The specific nuclei mediating these effects are only partially understood. Here, we use a rat model to examine whether ghrelin signaling in the ventral subregion of the hippocampus (VHPC), a brain substrate of recent interest in energy balance control, affects learned and motivational aspects of feeding behavior. Methods The effects of VHPC ghrelin administration were examined on feeding-relevant behavioral paradigms, including meal pattern analysis, operant lever pressing for sucrose, and conditioned stimulus-induced feeding. The intracellular signaling and downstream neuronal pathways stimulated by VHPC GHSR1A activation were assessed using immunoblot analysis and behavioral pharmacology. Results Ghrelin delivery to the VHPC, but not the dorsal hippocampus, increased food intake primarily by increasing meal frequency. Intra-VHPC ghrelin delivery also increased willingness to work for sucrose and increased spontaneous meal initiation in nondeprived rats following the presentation of a conditioned stimulus that previously signaled meal access when the rats were food restricted. The food intake enhancing effects of VHPC ghrelin were blocked by co-administration of a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002). Immunoblot analyses provided complementary support for ghrelin activated PI3K-Akt signaling in the VHPC and revealed that this activation is blunted with high fat diet consumption. Other immunoblot results show that VHPC GHSR1A signaling activates downstream dopaminergic activity in the nucleus accumbens. Conclusions These findings illuminate novel neuronal and behavioral mechanisms mediating ghrelin's modulation of cognitive aspects of feeding control.

Phasic dopamine signaling participates in associative learning by reinforcing associations between outcomes (unconditioned stimulus; US) and their predictors (conditioned stimulus; CS). However, prior work has always engendered these associations with innately rewarding stimuli. Thus, whether dopamine neurons can acquire prediction signals in the absence of appetitive experience and update them when the value of the outcome changes remains unknown. Here, we used sodium depletion to reversibly manipulate the appetitive value of a hypertonic sodium solution while measuring phasic dopamine signaling in rat nucleus accumbens. Dopamine responses to the NaCl US following sodium depletion updated independent of prior experience. In contrast, prediction signals were only acquired through extensive experience with a US that had positive affective value. Once learned, dopamine prediction signals were flexibly expressed in a state-dependent manner. Our results reveal striking differences with respect to how physiological state shapes dopamine signals evoked by outcomes and their predictors.nucleus accumbens | dopamine | voltammetry | learning | motivation R econciling differences between anticipated and experienced outcomes is fundamental for how an organism learns about the world. A key component of temporal difference (TD) learning models is the reward prediction error (RPE) term (1, 2), which is thought to be represented by phasic activity of midbrain dopamine neurons (3-5). Indeed, conditioned stimulus (CS)-related dopamine activity correlates with multiple behavioral indices of learning (6-8), and phasic dopamine signaling is sufficient to drive CSunconditioned stimulus (US) learning (9).In much of the supportive empirical work, food-or fluidrestricted animals first experience and then learn to anticipate an innately appetitive US (e.g., sucrose, juice, water). Thus, the US always has an inherent caloric, nutritive, or positive affective value to the organism. Consequently, it is uncertain whether dopamine neurons can acquire CS-US associations without first experiencing the US as a reward. Resolving this question is critical, because the striatal underpinnings of goal-directed behavior may encompass both RPE and experience-independent, model-based strategies (10, 11). One way to delineate dopamine's role in these different learning strategies would be to promote associations between a CS and a neutral or normally avoided US whose affective value could be manipulated and then determine the experience dependency of dopamine CS responses.Sodium appetite is an ideal platform on which to address this question. Sodium depletion induces a powerful sodium hunger and radically but reversibly alters the rewarding value of hypertonic NaCl solutions (12, 13). The appetite is highly selective for sodium and manifests independent of prior experience with either sodium solutions or sodium deficiency (14, 15). Therefore, sodium appetite facilitates the delivery of a US (hypertonic NaCl) that is rewarding only in a specific physiolog...

The increase in obesity prevalence highlights the need for a more comprehensive understanding of the neural systems controlling food intake; one that extends beyond food intake driven by metabolic need and considers that driven by higher-order cognitive factors. The hippocampus, a brain structure involved in learning and memory function, has recently been linked with food intake control. Here we examine whether administration of the adiposity hormone leptin to the dorsal and ventral sub-regions of the hippocampus influences food intake and memory for food. Leptin (0.1 mg) delivered bilaterally to the ventral hippocampus suppressed food intake and body weight measured 24 h after administration; a higher dose (0.4 mg) was needed to suppress intake following dorsal hippocampal delivery. Leptin administration to the ventral but not dorsal hippocampus blocked the expression of a conditioned place preference for food and increased the latency to run for food in an operant runway paradigm. Additionally, ventral but not dorsal hippocampal leptin delivery suppressed memory consolidation for the spatial location of food, whereas hippocampal leptin delivery had no effect on memory consolidation in a non-spatial appetitive response paradigm. Collectively these findings indicate that ventral hippocampal leptin signaling contributes to the inhibition of food-related memories elicited by contextual stimuli. To conclude, the results support a role for hippocampal leptin signaling in the control of food intake and food-related memory processing.