Regulation of the activity of GLP-1 releasing neurones in the nucleus of the solitary tract

Glucagon-like peptide 1 (GLP-1) is secreted from the gut in response to the ingestion of food. It generates the sensation of fullness, or satiety. However, GLP-1 cannot cross from the blood into regions of the brain that regulate appetite, raising the question of how the sensation of satiety is generated by GLP-1. Interestingly, additional cells that secrete GLP-1 exist in the lower brainstem. We hypothesise that it is GLP-1 released from these cells that mediates the observed satiety effects.
Additionally, GLP-1 has been implicated in emesis (nausea and vomiting). Nausea can be caused by various factors, including motion, food poisoning, repugnant smells or chemotherapy. To date no universal anti-emetic drug is known that would alleviate nausea independent of its cause. We speculate that different emesis pathways converge onto the brain GLP-1 cells and that these cells are part of the ‘vomiting center’ in the lower brainstem where the activity pattern leading to vomiting is generated. Thus, the GLP-1 cells might present a target for a novel universal anti-emetic drug.
We will determine how the activity of the GLP-1 secreting neurones is regulated. In doing so we will learn (a) if there are different subpopulations of GLP-1 neurones that are involved in feeding and nausea, respectively, (b) if there is a tight link between peripheral GLP-1 release and its effect in the brain, and (c) what other factors control the release of neuronal GLP-1 which could potentially distort the suppression of appetite, leading to overeating and obesity or conversely to fasting and anorexia.

Glucagon-like-peptide-1 (GLP-1) is released from enteric L-cells in response to a meal. It stimulates insulin release from pancreatic beta-cells and inhibits glucagon secretion from pancreatic alpha-cells and gastric emptying. In addition to these peripheral effects it also inhibits food and water intake. Consequently, GLP-1 is considered to be a satiety hormone. However, central GLP-1 has also been associated with emetic responses, neuroprotection and associative learning. GLP-1 released from L-cells has a short half-life and the general consensus suggests that it cannot cross the blood-brain barrier. Therefore, its CNS action is limited to the few regions of the brain with an incomplete blood brain barrier, such as the area postrema (AP). However, immunocytochemistry has shown that GLP-1 receptors are found in a variety of CNS areas. This raised the question of how GLP-1 could reach those receptors. Interestingly, a subpopulation of neurones of the nucleus tractus solitarius (NTS) produces GLP-1 and have been shown to project to many regions of the brain expressing GLP-1 receptors. This evidence suggests an important role for NTS-derived GLP-1 in satiety. This might not be surprising, considering the established role of the NTS as a relay nucleus for peripheral satiety signals. We propose to explore the factors that determine the electrical activity of GLP-1-releasing NTS neurones. We will use an transgenic in vitro mouse brainstem slice preparation where GLP-1 cells express green fluorescent protein. We will assess the sensitivity of NTS GLP-1 neurones to circulating satiety/hunger factors such as leptin and insulin, their intrinsic metabolic sensitivity, e.g. glucosensing properties, and their response to nausea-inducing substances such as dopamine or neurokinin receptor agonists, employing whole cell patch clamp recordings combined with single cell RT-PCR techniques. This approach will be complemented by in situ hybridisation and immunohistochemical analysis of the distribution and co-localisation of various peptide receptors, neurotransmitter receptors and glucokinase. We hypothesise that GLP-1 neurones of the NTS form distinct or overlapping subpopulations according to their role in feeding versus emesis versus glucosensing. This study will further our understanding of the role of the CNS in the integration of satiety signals and thus the control of appetite. Additionally, it will shed light on the electrical circuits involved in emesis.