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. 2013 Oct 14;7:181.
doi: 10.3389/fnins.2013.00181.

The Central GLP-1: Implications for Food and Drug Reward

Free PMC article

The Central GLP-1: Implications for Food and Drug Reward

Karolina P Skibicka. Front Neurosci. .
Free PMC article


Glucagon-like-peptide-1 (GLP-1) and its long acting analogs comprise a novel class of type 2 diabetes (T2D) treatment. What makes them unique among other T2D drugs is their concurrent ability to reduce food intake, a great benefit considering the frequent comorbidity of T2D and obesity. The precise neural site of action underlying this beneficial effect is vigorously researched. In accordance with the classical model of food intake control GLP-1 action on feeding has been primarily ascribed to receptor populations in the hypothalamus and the hindbrain. In contrast to this common view, relevant GLP-1 receptor populations are distributed more widely, with a prominent mesolimbic complement emerging. The physiological relevance of the mesolimbic GLP-1 is suggested by the demonstration that similar anorexic effects can be obtained by independent stimulation of the mesolimbic and hypothalamic GLP-1 receptors (GLP-1R). Results reviewed here support the idea that mesolimbic GLP-1R are sufficient to reduce hunger-driven feeding, the hedonic value of food and food-motivation. In parallel, emerging evidence suggests that the range of action of GLP-1 on reward behavior is not limited to food-derived reward but extends to cocaine, amphetamine, and alcohol reward. The new discoveries concerning GLP-1 action on the mesolimbic reward system significantly extend the potential therapeutic range of this drug target.

Keywords: GLP-1; dopamine; ethanol reward; exendin 9–39; food reward; gut peptides; liraglutide; ventral tegmental area.


Figure 1
Figure 1
Effect of GLP-1 on food intake and associated behaviors is neuroanatomicaly distributed. Local application of GLP-1 or GLP-1 analogs (e.g., EX4) into the VTA or the NAc alters food motivation/reward. Moreover, many other GLP-1R expressing CNS sites that directly respond to GLP-1 have clear connections to the mesolimbic dopamine circuitry, key in food reward behaviors (indicated in blue). This neuroanatomical distribution of GLP-1R potentially allows for a multi-center, wide-spread impact of GLP-1on food reward behavior, at several levels of the CNS. Furthermore, it appears that GLP-1 influences feeding in different brain regions by partly overlapping and partly distinct mechanisms. Several GLP-1 terminal sites have been confirmed (in red). Notably two of them are mesolimbic; VTA and NAc. Presumably, however, most GLP-1R expressing sites would receive their GLP-1 supply from the only source of GLP-1 in the brain, the hindbrain NTS GLP-1-producing neurons. This neuroanatomical architecture places the GLP-1 system as a central sensor of an array of key circulating factors and neural inputs from the viscera and tongue that is immediately able to integrate and relay the information to the mesolimbic centers. Prefrontal cortex, PFC; nucleus tractus solitarius, NTS; ventral tegmental area, VTA; paraventricular nucleus of the hypothalamus, PVH; lateral hypothalamus, LH; arcuate nucleus of the hypothalamus, ARC; ventromedial nucleus of the hypothalamus, VMH; dorsomedial nucleus of the hypothalamus, DMH; conditioned taste aversion, CTA.

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