The Glucagon-Like Peptide 1 (GLP-1) Analogue, Exendin-4, Decreases the Rewarding Value of Food: A New Role for Mesolimbic GLP-1 Receptors

Apr 12, 2012The Journal of neuroscience : the official journal of the Society for Neuroscience

Exendin-4 reduces the pleasure of food by acting on reward system GLP-1 receptors

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Abstract

GLP-1 receptor activation significantly reduces food reward motivation in rats through the mesolimbic reward system.

A GLP-1 agonist, Exendin-4 (EX4), was shown to reduce food-reward behavior in rats.
Conditioned place preference tests indicated that EX4 diminished the preference for environments associated with food rewards.
EX4 also decreased motivation for sucrose in a progressive ratio operant-conditioning task when given peripherally.
The effects of EX4 on food reward are mediated through central GLP-1 receptors in the mesolimbic system.
Key mesolimbic structures involved include the ventral tegmental area and nucleus accumbens.
The suppression of food reward by EX4 occurs without causing malaise or locomotor impairment.

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The glucagon-like peptide 1 (GLP-1) system is a recently established target for type 2 diabetes treatment. In addition to regulating glucose homeostasis, GLP-1 also reduces food intake. Previous studies demonstrate that the anorexigenic effects of GLP-1 can be mediated through hypothalamic and brainstem circuits which regulate homeostatic feeding. Here, we demonstrate an entirely novel neurobiological mechanism for GLP-1-induced anorexia in rats, involving direct effects of a GLP-1 agonist, Exendin-4 (EX4) on food reward that are exerted at the level of the mesolimbic reward system. We assessed the impact of peripheral, central, and intramesolimbic EX4 on two models of food reward: conditioned place preference (CPP) and progressive ratio operant-conditioning. Food-reward behavior was reduced in the CPP test by EX4, as rats no longer preferred an environment previously paired to chocolate pellets. EX4 also decreased motivated behavior for sucrose in a progressive ratio operant-conditioning paradigm when administered peripherally. We show that this effect is mediated centrally, via GLP-1 receptors (GLP-1Rs). GLP-1Rs are expressed in several key nodes of the mesolimbic reward system; however, their function remains unexplored. Thus we sought to determine the neurobiological substrates underlying the food-reward effect. We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures-ventral tegmental area and nucleus accumbens-without inducing concurrent malaise or locomotor impairment. The current findings, that activation of central GLP-1Rs strikingly suppresses food reward/motivation by interacting with the mesolimbic system, indicate an entirely novel mechanism by which the GLP-1R stimulation affects feeding-oriented behavior.

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The Glucagon-Like Peptide 1 (GLP-1) Analogue, Exendin-4, Decreases the Rewarding Value of Food: A New Role for Mesolimbic GLP-1 Receptors

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