Hippocampal GLP-1 Receptors Influence Food Intake, Meal Size, and Effort-Based Responding for Food through Volume Transmission

Abstract

Glucagon-like peptide-1 (GLP-1) is produced in the small intestines and in nucleus tractus solitarius (NTS) neurons. Activation of central GLP-1 receptors (GLP-1Rs) reduces feeding and body weight. The neural circuits mediating these effects are only partially understood. Here we investigate the inhibition of food intake and motivated responding for food in rats following GLP-1R activation in the ventral hippocampal formation (HPFv), a region only recently highlighted in food intake control. Increased HPFv GLP-1R activity following exendin-4 administration potently reduced food intake (both chow and Western diet) and body weight, whereas HPFv GLP-1R blockade increased food intake. These hypophagic effects were based on reduced meal size, and likely do not involve nausea as HPFv exendin-4 did not induce a conditioned flavor avoidance. HPFv GLP-1R activation also reduced effort-based responding for food under an operant progressive ratio reinforcement schedule, but did not affect food conditioned place preference expression. To investigate possible routes of HPFv GLP-1 signaling, immunohistochemical analysis revealed the absence of GLP-1 axon terminals in the HPFv, suggesting volume transmission as a mechanism of action. Consistent with this, the presence of active GLP-1 was detected in both the cerebrospinal fluid (CSF) and the HPFv. The source of CSF GLP-1 may be NTS GLP-1-producing neurons, as, (1) ∼30% of NTS GLP-1 neurons colocalized with the retrograde tracer fluorogold (FG) following lateral ventricle FG injection, and (2) GLP-1-immunoreactive axon terminals were observed adjacent to the ventricular ependymal layer. Collectively these findings illuminate novel neuronal and behavioral mechanisms mediating food intake reduction by GLP-1.

The anterior medial temporal lobes: Their role in food intake and body weight regulation

“…For instance, while the ventral hippocampus has bi-directional connections to the amygdala, the dorsal hippocampus does not have any [33]. Moreover, as mentioned before, GLP-I receptors in the ventral hippocampus, but not in the dorsal hippocampus, influence food intake and willingness to work to obtain food [65,81]. However, the respective roles of the ventral and dorsal hippocampus in meal onset are not currently known [117].…”

“…For instance, Hsu et al [66] have shown that ghrelin signaling in the hippocampus can stimulate conditioned appetite. Additionally, glucagon-like peptide-I (GLP-I) receptors in the ventral hippocampus also influence food intake and willingness to work to obtain food (i.e., "wanting"; [65,81]). Furthermore, there is solid evidence showing that hippocampal neurons form a memory of a meal and inhibit meal onset after a meal has been consumed [53,115,117].…”

Leptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus

“…naling across the blood-cerebrospinal fluid-brain and bloodbrain barrier (22); however, for hormones such as leptin, the importance of volume transmission still needs to be established. Our current data provide no evidence either for or against this mechanism, and additional experiments are needed in order include or exclude the probability of this mechanism.…”

The outward spiral: a vicious cycle model of obesity and cognitive dysfunction

“…Interference with this conversion in the dorsal hippocampus increases weight gain in rodents [29]. In the ventral hippocampus, activation of receptors for the anorectic peptides leptin and GLP-1 decreases food intake and appetitive behavior based on food rewards [30, 31], whereas direct administration of the orexigenic hormone ghrelin (which presumably antagonizes satiety signaling) increases meal frequency and the ability of environmental food-related cues to stimulate eating [32]. These results suggest that interference with the hippocampal processing of either anorectic or orexigenic promotes positive energy balance.…”