The role of GPRC6A agonists in satiety

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Alamshah A (2016) L-arginine promotes gut hormone release and reduces food intake in rodents. in Diabetes, obesity & metabolism

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Kinsey-Jones JS (2011) Current models and strategies in the development of antiobesity drugs. in Annals of the New York Academy of Sciences

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Kinsey-Jones JS (2015) GPRC6a is not required for the effects of a high-protein diet on body weight in mice. in Obesity (Silver Spring, Md.)

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McGavigan AK (2012) Gut hormones: the future of obesity treatment? in British journal of clinical pharmacology

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McGavigan AK (2015) L-cysteine suppresses ghrelin and reduces appetite in rodents and humans. in International journal of obesity (2005)

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Norton M (2017) Targeting gastrointestinal nutrient sensing mechanisms to treat obesity. in Current opinion in pharmacology

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Spreckley E (2015) The L-Cell in Nutritional Sensing and the Regulation of Appetite. in Frontiers in nutrition

 
Description To demonstrate that:

1) Proteinogenic amino acids can modulate food intake and body weight.

2) L-cysteine, a GPRC6a agonist, suppresses food intake via delayed gastric emptying, suppression of ghrelin and effects on central anorectic circuits (McGavigan et al 2014).The anorectic effects of L-cysteine have commercial potential, leading to Imperial Innovations, Imperial College's independent technology commercialisation company, to support a patent for the use of cysteine as a food ingredient to suppress appetite.

3) L-arginine, a GPRC6a agonist, suppresses food intake and stimulates the release of the anorectic gut hormones PYY and GLP-1.

4) GPRC6a is not necessary for the effects of a high or low protein diet on energy homeostasis , suggesting that other mechanisms mediate the effects of GPRC6a agonists on food intake, and that such mechanisms are better putative targets for anti-obesity agents.
Exploitation Route L-cysteine, L-arginine, and the mechanisms which mediate their effects on appetite, may be exploited to treat obesity, either as pharmaceutical agents, or as components of functional foods. We are also investigating the effects of other amino acids on energy homeostasis, with our data suggesting that aromatic amino acids may be useful.
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description The findings from the work funded by this award have only recently been published or are still waiting to be published. Although they have been picked up by news agencies (http://www.bioportfolio.com/news/article/2098837/l-cysteine-suppresses-ghrelin-and-reduces-appetite-in-rodents-and-humans.html and http://www.dailymail.co.uk/health/article-3914960/Forget-Atkins-diet-Atkins-pill-help-lose-weight-fast.html), as yet they have not been used in wider society.
First Year Of Impact 2014
Sector Pharmaceuticals and Medical Biotechnology
 
Description Developing novel technologies to target amino acids to specific gut regions to increase satiety
Amount £84,097 (GBP)
Funding ID 101127 
Organisation Technology Strategy Board (TSB) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2012 
End 03/2015
 
Description Collaboration with Institute of Metabolic Science, University of Cambridge 
Organisation University of Cambridge
Department Institute of Metabolic Science (IMS)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Collaboration to investigate links between the amino acid sensing GPRC6a and FTO systems in the regulation of energy homeostasis.
Start Year 2012
 
Description Collaboration with TasteTech Ltd. 
Organisation TasteTech
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution Technology Strategy Board 'Nutrition for Life' award for project 'Developing novel technologies to target amino acids to specific gut regions to increase satiety'. We are providing expertise on food intake and gut hormone release.
Collaborator Contribution Taste Tech are providing expertise on encapsulation and encapsulated amino acids for study at Imperial.
Impact Unpublished data so far.
Start Year 2012
 
Title Patent on GPRC6a agonist in appetite suppression 
Description UK Priority patent app no. 1203589.5, titled 'Cysteine Appetite Suppression' 
IP Reference P020216 
Protection Patent granted
Year Protection Granted 2012
Licensed No
Impact Continued research into utility of cysteine to reduce appetite and body weight in humans
 
Description Brighton Science festival talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The talk stimulated questions and discussion in the audience.

Increased sympathy for obesity as a disease.
Year(s) Of Engagement Activity 2012
 
Description Cheltenham science festival talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The talk was well received, and I took part in a discussion session with members of the audience afterwards, which seemed to stimulate interest in the issue of obesity and how to tackle it.

I was subsequently asked to speak at the Brighton Science festival.
Year(s) Of Engagement Activity 2011
URL http://www.endocrinology.org/public/events/2011/hungry/index.html
 
Description Daily Mail article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Online comments on article.

The comments section of the online article suggested engagement of the public with the issues involved.
Year(s) Of Engagement Activity 2011
URL http://www.dailymail.co.uk/health/article-2005983/Why-biscuit-Doctors-reveal-science-hunger-pangs--t...
 
Description Dana centre talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I spoke as part of a session called 'Fat of the land' on the role of nutritional sensing and gut hormones in appetite and obesity. The session seemed well received, stimulated much discussion in the crowd, and, from a show of hands, seemed to increase sympathy for the obese in the audience.

Increased sympathy for the obese.
Year(s) Of Engagement Activity 2011
URL http://www.danacentre.org.uk/events/2011/01/18/610
 
Description STEM talk to school children 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Sixth form pupils from the Greater London area attended STEM subjects talks at Imperial College. I spoke on my work on obesity and nutritional sensing, including amino acid sensing. The pupils were engaged and asked lots of questions at the end, and certain points on treating obesity etc turned into discussions.

Several pupils mentioned that the talk had changed their views on obesity as a disease, and that they now thought it an appropriate target for medical intervention.
Year(s) Of Engagement Activity 2014