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

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

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.

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.