A state-of-the-art method for functional imaging of the brainstem and hypothalamus to accelerate treatment development for obesity and reproductive disorders
Lead Researcher:
Supported by the Metabolic & Endocrine Theme
Obesity affects 1 in 4 adults in the UK. It causes heart disease, diabetes, cancer and puts huge financial strains on the NHS (at least 拢6.5 bn per year). Obesity treatments such as lifestyle change (diet and exercise), medications and surgery can help, but vary widely in terms of how much weight is lost and how long the weight loss lasts. There is still a need for effective and long-lasting obesity treatments.
One way to investigate how obesity treatments work is to use special 鈥榝unctional MRI鈥� (fMRI) scans which detect the specific areas of the brain which are activated, for example in response to food. The hypothalamus is a key area which senses hormonal and nutritional signals from various organs such as the gut. The hypothalamus communicates with other brain areas such as the brain stem and reward related areas to control food intake. Previous and existing scanning techniques have pinpointed the areas of the brain that control appetite (the desire to eat) and reward (the enjoyment of eating) and showed that treatments for weight loss can change how these areas work. We have found that different obesity treatment led to different patterns of brain area activation. This could explain why some obesity treatment work better than others, i.e. amount of weight is lost, and how long-lasting the weight loss is. However, we have an incomplete picture of how treatments work as these scans were too crude to look at the small but important appetite-regulating areas such as the hypothalamus and brainstem.
In this study, we will devise a new fMRI technique, using the latest developments in brain-scanning technology, to properly look at these appetite-regulating areas in the hypothalamus and brainstem. This new technique can then be used to understand the effects of weight loss treatments (such as various anti-obesity tablets) on these brain areas and to design more efficient weight-loss medications and interventions such as new eating patterns. Patients living with obesity will benefit as this technique of brain imaging will allow for the development and optimisation of more efficient treatment which may also be individualised and more accessible to them on the NHS. We can also use this technique to design new treatments for infertility, which can be due to problems in the same areas of the brain.
Understanding the impact of amylin receptor genetic mutations on the responses to new weight loss drugs
Lead Researcher:
Supported by the Metabolic & Endocrine Theme
Obesity affects 25% of people in the UK. It causes serious health problems such as type 2 diabetes, heart disease and arthritis. A new class of medications to help people lose weight is currently under development and appears highly promising in clinical trials, producing excellent weight loss and improvement in type 2 diabetes. These new medications target the 鈥渁mylin receptor鈥� (AMYR), which is a protein that responds to hormones in the blood to control hunger. They can therefore help us to lose weight by reducing how much we eat. However, there is wide variation in how well people respond to these medications, with some deriving almost no benefit from them, and others being at high risk of side effects including nausea and vomiting.
One likely explanation for this is genetic variation in the AMYR gene: many people carry at least one mutation that, theoretically, could alter how the medications works. However, very little work has been done to test this idea, and it is not currently known what its effects might be.
In this laboratory-based pilot project, we plan to study the impact of AMYR genetic variability on response to AMYR drugs. We can reproduce AMYR genetic variation in growing cells, allowing us to study the effects of these mutations very precisely. Experiments will mainly involve direct observation of cells using a high-powered microscope to monitor how they respond to AMYR drugs. We have already shown that this method rapidly provides valid information on the effect of genetic variability in similar receptors, such as the target of the type 2 diabetes and obesity drugs Ozempic/Wegovy, matching very well with real-life responses
The results from this project will provide a basis for how we select the most appropriate weight loss treatments for individual patients.