Award details

GPR120: a G protein-coupled receptor with the potential to regulate insulin secretion and inflammation

ReferenceBB/K019864/1
Principal Investigator / Supervisor Professor Graeme Milligan
Co-Investigators /
Co-Supervisors
Professor Mariola Kurowska-Stolarska, Dr Ashley Miller
Institution University of Glasgow
DepartmentCollege of Medical, Veterinary, Life Sci
Funding typeResearch
Value (£) 490,847
StatusCompleted
TypeResearch Grant
Start date 12/08/2013
End date 11/03/2018
Duration55 months

Abstract

GPR120 is a GPCR activated by free fatty acids including the omega-3 polyunsaturated group. It has been suggested to play key roles in physiological processes including release of GLP-1 from enteroendocrine cells, paracrine regulation of pancreatic cell function and inhibition of TLR4-mediated release of pro-inflammatory mediators. Although these implicate GPR120 as a potential therapeutic target in chronic diseases in which inflammation is a driver, such as type II diabetes, efforts to validate GPR120 in this context has been greatly hindered by a lack of specific tools suitable to explore in detail it's function and regulation. We have recently begun to address this deficit by developing the first series of high potency and highly selective GPR120 agonists. A key component of the proposal is to generate a broad panel of reagents to gain further insight into this receptor. Based on detailed characterisation of the identity of sites of phosphorylation in GPR120 in response to both an endogenous free fatty acid and our lead synthetic agonist we will also generate phosphorylation-state dependent and -independent antisera to probe the regulation and activity of GPR120 in both cells and tissues of mouse and man and how this might be modified by a high fat diet for example. Equally, as it has been suggested that the function of GPR120 is mediated by G protein- or phosphorylation-dependent signals in different cells we will produce a mouse line in which a phosphorylation-deficient form of GPR120 replaces wild type. Cells and tissues, including pancreatic islets, derived from this line, as well as from a GPR120 knock-out will be compared to those from wild type animals. Co-cultures of macrophages and white adipocyes from both mouse and man and of related model cell systems will be utilised to explore the contribution of GPR120 in infiltrating macrophages to adipocyte function. These studies will illuminate the true potential of GPR120 as a novel therapeutic target.

Summary

G protein-coupled receptors (GPCRs) are a very large family of cell surface proteins integral to how cells and tissues control their function. Because of this certain GPCRs are the targets for many medicines used to treat disease. In recent times it has also become clear that a number of GPCRs respond to alterations in concentration of nutrients such as fatty acids. Although initially surprising this makes sense as cells need to be able to alter their function as food and nutrient availability changes. One of these GPCRs is designated GPR120. Because of the capacity of GPR120 to respond to a group of fatty acids called omega-3 polyunsaturated fatty acids, which are present in high levels in the types of oily fish that we are encouraged to eat because these fatty acids have many health benefits, there has been great interest in whether synthetic chemicals could be identified that would activate GPR120 and if so might, in the longer term, provide the basis of novel medicines. GPR120 is expressed by a number of tissues in the body, including macrophages, that are important mediators of inflammation, and both pancreatic cells, the source of the hormone insulin, and white fat cells. In recent years it has become clear that 'inflammation' is an important contributor to the development of chronic diseases such as diabetes as well as other diseases of 'aging'. This has further raised interest in the possibility that manipulating the activity of GPR120 might be a useful, novel approach to treat diabetes and related conditions. Although very exciting, to date many of the studies implicating GPR120 as a good target in this area of health and disease have been indirect, because the type of fatty acids that stimulate GPR120 also activate other receptors and have many other effects that are not related to this receptor. Furthermore, because the omega-3 fatty acids are also converted into other mediators by the body it is possible that some of the functions suggested for GPR120 are not actually produced this way. The work we propose in this application is designed to unravel and define fully the functions of GPR120. In the last few months we have developed and characterised the only known group of synthetic chemical ligands that act selectively at GPR120 and at sufficiently low concentrations that we can be sure their effects do require activation of GPR120. We will use these to assess how activation of GPR120 in cells including macrophages, adipocytes and pancreatic cells controls their function, their production of hormones and other mediators and their interactions with other cell types. GPCRs can respond to different ligands in multiple and sometimes in distinct ways (this is termed bias). A common feature is that the receptor is rapidly modified by the addition of phosphate groups to specific amino acids. Such phosphorylation can either limit receptor function or initiate a panoply of new signals. We wish to also explore this for GPR120. We have determined exactly which amino acids in GPR120 become modified and made a version of the receptor in which this cannot happen. We wish to assess the implications of this and to do so we will generate mice in which this altered version of GPR120 replaces the normal form. These animals will then provide cells and tissues to assess which physiological functions of GPR120 require phosphorylation and which do not. In concert with this we will also make antibodies that only identify GPR120 when it is phosphorylated and will use these to determine the extent to which the receptor is activated in different conditions, for example when mice are fed a high fat diet. Interestingly, there is a variant form of GPR120 that is only found in humans and we also define its role. The ultimate objective of our studies is to define if there is a strong case to be made in investing large amounts and time and money in developing synthetic medicines that target GPR120 as a therapeutic strategy.

Impact Summary

The studies proposed in the current application plan to make fundamental progress in our understanding of the challenging topic of the physiological consequences of activation of the G protein-coupled receptor GPR120. Who will benefit from this research and how will they benefit? This receptor is attracting considerable interest as a potential novel therapeutic target at the interface between inflammation and chronic metabolic disease. However, despite a series of provocative and highly interesting published studies GPR120 remains poorly validated as a therapeutic target. As such, the most direct beneficiaries of this research within the private commercial sector will be those working in the pharmaceutical industry. Our research will assist this sector in a number of ways. Firstly, for poorly validated GPCRs that have not previously been the targets of sustained effort within the pharmaceutical industry there are often a paucity of suitably selective pharmacological tools to define receptor function. This is true of GPR120 and the ligands we have already described and will continue to develop can be synthesised within the commercial sector and used as reference ligands to support their own work. Secondly, our research will provide important guidance and answers to key questions that remain uncertain from the currently published work. These outcomes may encourage or (just as importantly) dissuade companies from investing heavily in programmes to target this receptor. Thirdly, although the concept of ligand and receptor bias in function is well established conceptually within the academic research community and when using in vitro cell-based assays, this has yet to be adopted whole heartedly by the commercial sector. In part this reflects that although GPCRs can signal via a variety of mechanisms the significance of this for physiology is unknown and, therefore, it is unclear to the commercial sector if biased ligands offer unique commercial opportunities in different therapeutic areas. Our studies employing the phosphorylation-deficient form of GPR120 are likely to help define this. Finally, although the applicants have strong and long term links with the pharmaceutical sector, the proposed collaboration will allow us to perform studies with a breadth of scope and concept that neither could achieve separately. This will result in even stronger links to the pharmaceutical industry that will impact to the benefit of both sides as we move to address questions linked directly to the major intellectual and practical challenges facing the industry to translate basic science into commercial products. Translation of basic research to the production of approved medicines is a long and challenging process, typically taking between 10-12 years. However, greater confidence in the selected target, based on the type of studies proposed herein, may improve company performance. In the longer term, if successful this would potentially improve quality of life for many individuals as chronic diseases associated with aging and poor nutritional selection are increasing burdens on economies. Inflammation is implicated in the development of many such diseases including metabolic disorders and vascular/heart disease. Targetting GPR120 may offer a novel approach. The studies will also impact on training of staff who may move subsequently into the commercial health research sector. The breadth of approaches and skills that the post-doctoral fellows will be exposed to will range from medicinal chemistry design to transgenic amimal studies and equip them with excellent skills sets for their future careers.
Committee Research Committee D (Molecules, cells and industrial biotechnology)
Research TopicsX – not assigned to a current Research Topic
Research PriorityX – Research Priority information not available
Research Initiative X - not in an Initiative
Funding SchemeX – not Funded via a specific Funding Scheme
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