Targeting specific brain GLP-1 receptors to treat obesity

Obesity has become one of the key medical and economic challenges because of its impact on health, cardiovascular disease and cancer, and its prevalence in the population. The primary cause of obesity is the consumption of more food than the body requires. The most effective medication for the treatment of obesity in the UK is the drug semaglutide (Ozempic).

Commenting on its recent UK launch, Prime Minister Rishi Sunak described semaglutide as a "game changer" that will be piloted to approximately 50,000 patients with obesity with the objective of "reducing pressure on hospitals, supporting people to live healthier and longer lives and helping deliver on my priority to cut NHS waiting lists". Semaglutide acts on the glucagon-like peptide-1 receptor (GLP-1R) in the brain to reduce food intake.

The medication influences different aspects of food intake, such as decreasing meal size, promoting healthier food choices, delaying food digestion and dampening the "feel-good" effect of foods (called food reward). The common side effects of nausea and vomiting cause some patients to discontinue its use. The brain integrates nutritional information from the gut and contains different regions with distinct functions.

We believe that semaglutide produces its different effects on food ingestion by acting in these different brain regions. However, very little is known about how semaglutide works. The goal of this programme is to fill this important knowledge gap and establish (i) how semaglutide improves obesity, and (ii) how it produces its individual effects.

This programme of research is timely because of the demand to create new forms of GLP-1R drugs that reduce food intake without causing nausea to produce better patient compliance. To do so, more information about how semaglutide works is required. There is huge interest in how GLP-1Rs could be switched on in a slightly different or more targeted way.

Drugs that can do this could work better, have effects that last longer, produce specific therapeutic obesity treatment benefits without the nausea side effect, or treat other conditions such as Dumping syndrome (rapid gastric emptying) or addictive disorders. Here we will use the latest technology to meet this challenge. In this project, our first objective is to individually turn on or off different GLP-1R brain cells to establish their function.

Our second objective is to work out exactly how semaglutide's effect on food ingestion and body weight loss changes if we prevent it from acting at individual groups of GLP-1Rs. Our third objective is to track what happens inside distinct subgroups of living GLP-1R brain cells when semaglutide is used - to discover how semaglutide produces its individual effects on food ingestion.

To achieve these objectives, we have assembled a team from three different UK institutions. We can only now do these types of studies because of the latest technological advances, and we expect our results will provide the blueprint to develop even better obesity medications in the future.

Since the discovery of GLP-1 40-years ago, an array of GLP-1R medicines have been developed with progressively improved formulations, ranging from GLP-1 which is inactivated within minutes to the new long-acting medicine semaglutide that is used once a week. Here we propose essential studies to uncover how semaglutide produces its different effects on food ingestion with the objective of propelling the development of new targeted and better tolerated obesity drugs.