Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 305, Issue 11, Pages E1367-E1374Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00413.2013
Keywords
2-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid; obesity; glucagon-like peptide-1; glutamate; dopamine; reward; diabetes
Categories
Funding
- University of Pennsylvania Research Foundation
- Diabetes Research Center [DK-19525]
- [DA-031747]
- [DA-22339]
- [DA-18678]
- [DK-097954]
- [DK-096139]
- [DK-085435]
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Glucagon-like peptide-1 receptor (GLP-1R) activation in the ventral tegmental area (VTA) is physiologically relevant for the control of palatable food intake. Here, we tested whether the food intake-suppressive effects of VTA GLP-1R activation are mediated by glutamatergic signaling within the VTA. Intra-VTA injections of the GLP-1R agonist exendin-4 (Ex-4) reduced palatable high-fat food intake in rats primarily by reducing meal size; these effects were mediated in part via glutamatergic AMPA/kainate but not NMDA receptor signaling. Additional behavioral data indicated that GLP-1R expressed specifically within the VTA can partially mediate the intake- and body weight-suppressive effects of systemically administered Ex-4, offering the intriguing possibility that this receptor population may be clinically relevant for food intake control. Intra-VTA Ex-4 rapidly increased tyrosine hydroxylase levels within the VTA, suggesting that GLP-1R activation modulates VTA dopaminergic signaling. Further evidence for this hypothesis was provided by electrophysiological data showing that Ex-4 increased the frequency of AMPA-mediated currents and reduced the paired/pulse ratio in VTA dopamine neurons. Together, these data provide novel mechanisms by which GLP-1R agonists in the mesolimbic reward system control for palatable food intake.
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