The role of biased agonism in the treatment of obesity

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Almost one billion people are obese, including one third of the UK population. People who are obese are at high risk of developing diabetes, heart disease, joint problems and cancer. Obesity is an area of high priority for the MRC and for the NHS. Many people find it difficult to lose weight naturally. The only truly effective treatment is weight loss surgery, such as the "gastric bypass" operation, but this can lead to complications and is not popular with all patients. As a result, there is enormous interest in producing medicines to help people lose weight. A group of medicines known as "glucagon-like peptide-1 receptor (GLP-1R) agonists" has recently been approved for weight loss. These mimic the effect of a natural hormone (GLP-1) by activating its target, or "receptor", in the brain to reduce hunger. Other hunger-reducing hormones, including "amylin", are also under investigation as potential weight loss treatments. However, none of these are as effective as gastric bypass surgery because the maximum dose is limited by nausea and/or vomiting. I have recently generated new, improved GLP-1R agonists that behave differently to existing versions on the market as they activate GLP-1R in an unusual way, referred to as "biased agonism". Biased GLP-1R agonists appear very promising as they produce more weight loss but less nausea. Interestingly, they also work particularly well in combination with amylin-based treatments (amylin analogues), causing larger reductions in hunger even at low doses.The overall aim of my research is to understand why biased GLP-1R agonists work so well for weight loss, both on their own and when combined with with amylin analogues. Fully understanding their mechanism of action will help develop this approach into a better treatment for obesity. I will address three main research questions: 1. Which neurons in the brain respond to biased GLP-1R agonists and amylin analogues - are they the same or different? This will be done by measuring the effect of different GLP-1 and amylin analogues on feeding behaviour and changes to brain tissue in mice. 2. How do neurons respond to biased GLP-1R agonists and amylin analogues - what is happening inside the neurons themselves that allows them to reduce hunger? To answer this, I will generate a genetically modified mouse in which the receptor itself has a fluorescent molecule attached, meaning individual receptors and how they behave can be directly observed using a microscope.3. How do biased GLP-1R agonists and amylin analogues physically interact with their receptors, and how is this affected by natural genetic variations in receptor structure found in different people? To do this I will develop a new technique called "deep mutational scanning", which allows thousands of receptor variations to be tested in in a single experiment, which is much faster than the normal method based on testing each variation individually.This work will be done at Imperial College London but involve collaborations with other researchers in the UK and internationally. The results will be an important step to developing a new weight loss treatment, and will also show how genetic differences can influence how well the drugs work, meaning that in the future we may be able to individualise treatments based on genetic testing.The overall design of the experiments should also be applicable to other hormone targets, meaning it could be used to develop other obesity treatments in the future.