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

Jul 19, 2014Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

Hippocampus GLP-1 receptors affect eating behavior and motivation for food through widespread signaling

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Abstract

Increased GLP-1 receptor activity in the ventral hippocampal formation is associated with a significant reduction in food intake and body weight in rats.

Activation of GLP-1 receptors in the ventral hippocampal formation led to decreased food intake from both standard and Western diets.
Blockade of GLP-1 receptors in this region resulted in increased food consumption.
The reduction in food intake primarily occurred through smaller meal sizes and was not linked to nausea.
GLP-1 receptor activation also lowered the effort required for food acquisition in an operant task.
Immunohistochemical analysis indicated a lack of GLP-1 axon terminals in the ventral hippocampal formation, suggesting a different signaling mechanism.
Active GLP-1 was found in both cerebrospinal fluid and the ventral hippocampal formation, potentially sourced from neurons in the nucleus tractus solitarius.

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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.

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

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