The role of GPRC6A agonists in satiety

Recent research has highlighted the importance of nutrient sensing in the regulation of food intake and body weight. Meals and diets high in protein have a well characterised satiating effect. However, the mechanisms by which high levels of protein inhibit food intake are largely unknown. Proteins are digested to form amino acids in the gut. We have found that specific amino acids which bind to an amino acids-sensing receptor called GPRC6A reduce food intake when injected into the blood stream of rats and mice. These amino acids appear to act on the brain, which may in response reduce the release of an appetite-increasing hormone called ghrelin from the stomach. We now aim to determine the specific mechanisms behind the effects of these amino acids on food intake and determine whether they form part of the system that regulates food intake and body weight on a day to day basis. Determining the role of GPRC6A in food intake may facilitate the design of foods or drugs designed to comabt obesity.

Recent research has highlighted the importance of nutrient sensing in the regulation of food intake and metabolism. However, the mechanisms by which a high protein diet regulates food intake are largely unknown. We have found that specific amino acids which agonise the G-protein coupled receptor family C group 6 member A (GPRC6A) reduce food intake when peripherally administered, and that this effect may be mediated via the gastric hormone ghrelin. We now aim to determine the molecular mechanisms behind these effects and whether they represent physiological systems controlling food intake and body weight. Aim To investigate the mechanisms by which GPRC6A agonists reduce food intake Objectives 1) To determine the site at which GPRC6A agonists act to cause their anorectic effects. 2) To investigate the mechanisms mediating the effects of GPRC6A agonists on food intake. 3) To determine the physiological role of GPRC6A agonists in the regulation of satiety. Together this programme of work will determine the mechanisms by which the GPRC6A receptor regulates food intake and suppresses ghrelin levels, and investigate the physiological role of GPRC6A in the regulation of energy homeostasis. The role of GPRC6A in food intake has not previously been investigated.

The proposed studies will determine the pharmacological effects of GPRC6A agonists on, and the physiological role of GPRC6A in, the regulation of food intake. The findings will provide valuable information to scientists studying the control of food intake. They may also identify the GPRC6A system, or related systems, as possible targets for the treatment of obesity. Who will benefit from this research? Data from this project will benefit academics who study the control of food intake, and also those investigating the treatment of obesity in the pharmaceutical industry. Understanding the mechanisms by which GPRC6A agonists regulate food intake will aid the understanding of its role in economically important animals and obese humans. How will they benefit from this research? Demonstrating a pharmacological effect of GPRC6A agonists on, and a physiological role for GPRC6A in, food intake, will provide vital information to those studying the systems that regulate food intake and energy homeostasis. It may demonstrate that GPRC6A is a viable target for drugs or foods to modify feeding behaviour and treat obesity. What will be done to ensure that they have the opportunity to benefit from this research? The results of this project will be published in peer-reviewed scientific journals, made available in the public domain, and submitted to international meetings to reach a wider audience. It is anticipated all of the data arising during the course of this grant will be included in peer reviewed publications and thus placed in the public domain within a year of the completion of the grant. The Department of Investigative Medicine has a strong commitment to public engagement with science. Food intake, and obesity have important implications for society, and the discoveries made in this field have relevance to the general public. The Department has a track record of drawing public attention to its scientific findings through both printed and broadcast media. We intend to use the links forged with media and health contacts from previous studies to publicise new findings on energy homeostasis to both the general public and interest groups who may eventually benefit from the results of the studies. In addition, the Department is involved in a popular Imperial College Outreach scheme which organises science education events for pre-university students, their teachers and their parents or guardians, introducing them to the science of Endocrinology and discussing the Department's latest discoveries. The Department also collaborates with the Dana Centre to promote public awareness of science. Exploitation and Application This project may give rise to commercially exploitable results if the GPRC6A does prove to be a viable target for pharmacological agents targeting obesity. If IPR arises from these studies it will be exploited in consultation with Innovations, Imperial College's technology transfer company. The Department of Investigative Medicine has a track record of commercial exploitation of research results having established a spinout company, Thiakis, to exploit previous discoveries in the field of gut hormones in the regulation of food intake. Thiakis was recently sold to Wyeth in a deal worth £100 million. Capability Dr Murphy is the lead applicant on this grant, and will therefore manage the communications and engagement and exploitation and application components of the project. He has recently completed a BBSRC science media training course. Impact activities associated with this proposal would be undertaken in collaboration with staff from Imperial's Communications Division, who are specialised in communicating research through a variety of channels, including media relations, events management and digital media applications. Resource for the activity There are no major resource implications from the impact activities described above. Please see impact plan for further details.