Glucagon-Like Peptide-1 (GLP-1) is an incretin released from enteroendocrine L-cells postprandially and has glucoregulatory and satiety effects. Mounting evidence implicates GLP-1 receptors within the brain in these effects, but the short halflife of GLP-1 in the circulation makes it questionable whether peripheral GLP-1 reaches brain receptors. Within the brain, preproglucagon (PPG) neurons, found mainly in the nucleus tractus solitarius, produce GLP-1. Little is known about what governs the activity of these neurons, primarily because of difficulties identifying these cells in vitro. We have addressed this issue with transgenic mice expressing yellow fluorescent protein (YFP) under PPG promoter control. We showed that PPG neurons are spontaneously active and their electrical activity is enhanced by peripheral satiety factors such as leptin and cholecystokinin (CCK), but not GLP-1 or peptide YY. PPG neurons do not actually express the GLP-1 receptor. They receive glutamatergic input from the solitary tract, reflecting vagal afferent activity. A proportion of PPG cells respond to changes in ambient glucose levels with altered electrical activity. Our immunohistochemical studies showed that PPG neurons project widely to central autonomic regions, including various brainstem nuclei. Recent in vivo studies have highlighted the importance of hindbrain receptors for GLP-1's anorexic effects, and our results might indicate that GLP-1 released from PPG cells, rather than peripheral GLP-1 entering the brain, interacts with these receptors. We hypothesise that PPG neurons are central to integrating peripheral satiety signals and brain energy status into a feeding response. Further studies should target these neurons in vivo to test this hypothesis.

Supported by the Medical Research Council, UK