GPR103 has multi-tissue effects on health and metabolism

We are experiencing an epidemic in the prevalence of metabolic diseases which are associated mainly with increasing obesity. As the body becomes obese there is an increase in the amount of lipid (fat and cholesterol) and glucose (sugar) circulating in the body, which can lead to diseases such as blocked arteries (increasing the chances of heart attacks or stroke) and diabetes (increasing the chances of kidney failure or blindness). Treating the diseases associated with obesity is close to bankrupting the NHS and, therefore, it is critical that we understand the development of these diseases to save money and promote healthy living. Our metabolism is controlled by different organs in a coordinated fashion. The pancreas produces hormones like insulin to control glucose uptake, while the liver can take up or produce more glucose depending on needs. Likewise, the fat in our bodies is actually stored as another organ: white adipose tissue. White adipose tissue around our abdomens and thighs, not only stores fat, but it too produces hormones. The coordination of these organs (pancreas, liver and adipose tissue), however, is ultimately governed by the brain. Few factors act in a coordinated manner on all of these organs in the body. However, recently, we have found a messenger, called QRFP, has major actions in the brain and other organs to increase food intake, circulating glucose and fat production. We will demonstrate that different types of receptors for QRFP mediate these different actions. We will produce mice which do not have the two types of receptor. Then we will produce a series of other genetically-modified mice in which we can manipulate just the cells in the body that produce QRFP. In this way, we will be able to switch the QRFP cells on and off, simply by giving the mice a drug. We can do this very briefly, or over a longer period to see the development of metabolic disorders. Instead, we can start with a mouse that has no QRFP and then genetically re-introduce QRFP into one organ at a time, to isolate its different effects. Finally, we will be able to use the mice to determine how QRFP-producing cells connect with other cell types. This work will validate QRFP as a key regulator of metabolism. As QRFP has many different effects on different organs, it may be an ideal target to develop drugs against its actions. A drug that can block QRFP would reduce food intake, make the body more sensitive to insulin so that glucose is controlled better, and reduce the amount of fat produced by adipose tissue. Doing this would lead to increasing health and wellbeing.

Few factors act in a coordinated manner on both central and peripheral metabolic pathways to produce anabolic effects in the body. Recent evidence demonstrates that the peptide, QRFP, has major actions in the brain and key metabolic tissues, such as the pancreas and adipose, to increase energy intake, reduce glucose tolerance and cause lipogenesis. We will demonstrate that different populations of QRFP receptors, GPR103A and GPR103B, mediate its varied effects in mice with the two receptors knocked out. We will generate a mouse in which the Qrfp gene promoter drives the expression of cre recombinase and the GFP reporter. This will allow us to record the electrical activity of QRFP neurones following different stimuli. Using the latest adeno-associated virus technology, we will also express selectively in QRFP neurones an anterograde tracer to determine QRFP neuronal projections or "designer" receptors. The latter will allow us to activate or inhibit selective populations of QRFP neurone in vivo by administering a "designer" drug intraperitoneally. Finally, we will generate a loxSTOPlox-Qrfp mouse, which is effectively a peptide null mutant and which is expected to express adverse metabolic phenotypes. By crossing this mouse will other cre-expressing mice, e.g. nestin-Cre or adiponectin-Cre, we can genetically re-introduce QRFP to selective tissues in order to induce different gains in function. This work will validate QRFP as a key regulator of systemic metabolic processes, and potentially as a valuable and novel pharmacological target for the treatment of metabolic disease.

The increase in the incidence of obesity has reached epidemic proportions, such that there will be 2 billion overweight people globally by 2012. Without effective therapeutic interventions the treatment of associated co-morbidities (type 2 diabetes, cardiovascular disease, lipodystrophy) is likely to bankrupt health providers. A conservative commercial estimate of the annual market opportunity for anti-obesity drugs is $60 bn. This project will validate a target and underpin the potential commercial development of drugs to improve metabolism. The applicant has been involved previously in a number of successful discovery programmes with industrial partners, and he has supervised a number of CASE studentships with UK-based pharma. If successful, this grant will be his third BBSRC Industrial Partnership Award. The applicant is academic lead on a cross-Univesity initiative in Integrative Mammalian Biology (IMB), to increase research capacity and training in in vivo sciences, recently highlighted as a key area of concern by the Association of British Pharmaceutical Industries. He has negotiated a number research and training opportunities with both pharma and small- to medium-size commercial enterprises, including through collaboration with the North West Development Agency.
The applicant will continue to consult with a number of bodies regarding obesity research and IMB, which will affect future funding policy. In addition, his own basic research is discussed regularly at meetings of the Child Health Research Network, the Diabetes and Obesity Research Network and the Association for the Study of Obesity. These are forums for basic researchers, psychologists, clinicians, community nurses and other health professionals, as well as patient group representatives. This leads to increased public understanding of the research. He has also discussed his recent research on national and local radio. Furthermore, outreach work is encouraged at all levels. For example, the applicant lectures at local schools and members of his lab have tutored for the Manchester Access and STEM programmes (aimed at helping under-privileged children into further education). They have also completed a Wellcome Trust Researchers in Residence Scheme and a UK GRADshcool. Through the IMB, the applicant is currently planning open public meetings to present the use of animals in research, which will include interactive debate.
This grant provides strong training in both in vivo skills and specialist metabolic techniques, as well as interchange between labs. In the last decade, the applicant has supervised 11 PhD students and 8 post-doctoral associates, all of whom remain in science (some have their own independent research groups and others have moved into the commercial sector). All current collaborations have involved aspects of training and sharing of expertise, and this will be true for the four academic collaborations outlined in the project. The applicant has been invited to join a network of mass spectroscopy imagers, which will be formalised through the European Cooperation in the Field of Scientific and Technical Research. Thus, the applicant will be able to bring his expertise in neuroscience to a large group of imagers in different fields across Europe.
As lead of the IMB initiative, the applicant has started a number of training and research activities. For example, a BBSRC grant to foster collaboration between integrative physiologists and systems biologists through an Initiative in Predictive Biology. His lab also has provided training for an Experimental Officer who is responsible for disseminating good practice within the Centre for IMB. The applicant is currrently programme director for the MRes in Integrative Biology at Manchester (which will benefit from MRes rotations derived from this project) and external examiner on an Integrative Biology MRes course at the University of Liverpool.