Analysis of the brain GLP-1 circuitry at cellular level to characterise its roles in the control of food intake

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Obesity, diabetes, and associated diseases such as hypertension, are a serious health burden for patients and a strain on healthcare services. A class of drugs that are increasingly being used clinically to treat obesity (and diabetes) are glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs). GLP-1 is a hormone that is produced by our gut and released into the blood after a meal. Its main role is to help keeping sugars low in the blood, but it also generates the feeling of fullness, i.e. satiation. GLP-1RAs reproduce the effect of the hormone GLP-1 and that is how they suppress eating.Interestingly, GLP-1 is also produced in the brain, and acts there to suppress eating. It has been widely assumed that GLP-1RAs also mimic the action of GLP-1 released by the brain and that this contributes to their anti-obesity effect. However, our laboratory has now shown that this is not the case, but that activation of the nerve cells in the brain that produce GLP-1, the PPG neurons, suppress eating independently from and in addition to clinically-used GLP-1RAs. Whilst this is a highly exciting finding PPG neurons fulfil a variety of roles in our brain; they reduce food intake, but they also raise heart rate, reduce alcohol consumption, change body temperature and play a role in our response to stress. We hypothesise that different subgroups of these cells govern these different functions. Thus, the major aim of this research is to identify those different subgroups of PPG neurons that fulfil the different functions, and then selectively activate only those that suppress food intake for obesity treatment, and possibly even inhibit another group of these neurons that raises heart rate. Understanding in detail how these PPG neuron groups fulfil their functions and revealing their individual properties will then facilitate the design a novel treatment strategy that could work in patients.