Neural circuits of glucagon-like peptide-1 (GLP-1) action in health and disease

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Obesity, diabetes and co-morbidities, such as hypertension, are a serious health burden for the patient and a strain on public resources. Promising drugs that might be beneficial for the treatment of these conditions are glucagon-like peptide-1 (GLP-1) analogues. GLP-1 is a hormone that is secreted from the gut after a meal. Its principal role is to improve the digestion of sugars, and to generate the sensation of fullness, or satiety. Besides their anti-diabetic actions, GLP-1 analogues have been shown to cause nausea, mild hypertension and tachycardia, possibly indicating action in the brain. In fact, microinjection of GLP-1 into the brain reduces food intake and lowers blood glucose. The aim of our project is to improve our knowledge of the relative importance of the brain and gut GLP-1 signalling in the control of blood sugar and food intake, and to clarify whether GLP-1 analogues, which are already in clinical use, activate the brain GLP-1 system. To understand GLP-1 action in brain it is imperative to know the detailed expression pattern of the GLP-1 receptor (GLP-1R) in brain. In addition, manipulation of GLP-1R in the brain, by controlling the activity of GLP-1R expressing cells, would enable clarification of the role of these receptors in vivo. We will use a novel transgenic mouse (glp-1r-cre) that expresses both a red fluorescent label (RFP) and cre-recombinase in GLP-1R expressing neurons, and thus allows in vitro identification of these cells as well as their genetic targeting with 'flex-switch' virus constructs in vivo. We will use a gene therapy approach where new genes are delivered by a virus to GLP-1R cells in specific areas of the brain. These genes will produce proteins allowing cell-specific suppression of the activity of GLP-1R cells with unprecedented temporal and spatial resolution. By measuring the effects of inhibiting the activity of specific GLP-1R-expressing cells groups on blood glucose control, food intake and behaviour, we will be able to tease out the exact physiological function played by GLP-1R-expressing central neurons. Using this mouse line we propose to define and validate the precise distribution of GLP-1R expressing cells in mouse brain. We will then determine the functional significance of these cells in different brain regions and characterise the GLP-1R expressing neuron populations in vitro by electrophysiological and optical Ca2+ recordings. Finally, we will assess the action of GLP-1 analogues in brain and whether it changes under high fat diet. This project will clarify the physiological importance of brain GLP-1Rs and provide vital information regarding activation of central GLP-1Rs by stable GLP-1 analogues. This is especially important for understanding potential unwanted effects that may be observed during GLP-1 therapy. These data will provide further insight into the clinical benefit of GLP-1-based treatments, possibly not only for patients with diabetes, but more generally in metabolic disease. Furthermore, it will provide information on the cause of undesired side effects such as nausea, as well as clarifying whether there is a role for neuronal GLP-1Rs in cardiovascular disease and in olfactory signal processing. Since GLP-1 analogues are already on the market for the treatment of type 2 diabetes, we expect that the knowledge from this project will feed into drug development and formulation, and thus an influence on therapy could be hoped for in the near future.