GPR120: a G protein-coupled receptor with the potential to regulate insulin secretion and inflammation
Lead Research Organisation:
MRC Toxicology Unit
Department Name: MRC Toxicology Unit
Abstract
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.
Technical Summary
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.
Planned Impact
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.
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.
People |
ORCID iD |
Andrew Tobin (Principal Investigator) |
Publications
Alvarez-Curto E
(2016)
Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling.
in The Journal of biological chemistry
Bolognini D
(2016)
The Pharmacology and Function of Receptors for Short-Chain Fatty Acids.
in Molecular pharmacology
Bolognini D
(2016)
A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias.
in The Journal of biological chemistry
Bradley SJ
(2018)
The use of chemogenetic approaches to study the physiological roles of muscarinic acetylcholine receptors in the central nervous system.
in Neuropharmacology
Bradley SJ
(2018)
Muscarinic acetylcholine receptors in the central nervous system.
in Neuropharmacology
Bradley SJ
(2016)
Design of Next-Generation G Protein-Coupled Receptor Drugs: Linking Novel Pharmacology and In Vivo Animal Models.
in Annual review of pharmacology and toxicology
Brightling CE
(2019)
Fatty airways: a source of good and bad fats?
in The European respiratory journal
Butcher AJ
(2014)
Concomitant action of structural elements and receptor phosphorylation determines arrestin-3 interaction with the free fatty acid receptor FFA4.
in The Journal of biological chemistry
Dorin-Semblat D
(2013)
Experimental tools for the study of protein phosphorylation in Plasmodium.
in Methods in molecular biology (Clifton, N.J.)
Description | We have found that the GPR120 receptor is able to mediate airway smooth muscle relaxation and decrease lung resistance in models of asthma. We have now extended this to include new respiratory models of disease and to show the efficacy of GPR120 ligands in these disease models |
Exploitation Route | By generating antagonists to this receptor it might be possible to treat airway disease such as asthma and COPD |
Sectors | Pharmaceuticals and Medical Biotechnology |
Title | Muscarinic transgenic mice models |
Description | We have made a number of muscarinic receptor mouse models to test the efficacy of muscarinic receptor ligands in disease |
Type Of Material | Model of mechanisms or symptoms - human |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | This has offered novel mouse models to the dementia field |
Title | Novel proteomic approaches |
Description | The facility has allowed for new methods in mass spectrometry based phosphor-proteomics to have been developed |
Type Of Material | Technology assay or reagent |
Year Produced | 2012 |
Provided To Others? | Yes |
Impact | This has allowed for integration of both mammalian (hippocampal) and malaria phosphor-proteomes |
Description | Clinical collaboration on inflammatory lung disease |
Organisation | University of Leicester |
Department | Leicester Medical School |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Support for the targeting of FFA4 in inflammatory lung disease |
Collaborator Contribution | Clinical samples and drug trials |
Impact | Outcome has been to establish FFA4 as a validated target in inflammatory lung disease |
Start Year | 2018 |
Description | Cell block Science - Low moss Bishop Briggs, Glasgow. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Workshop for prisoners |
Year(s) Of Engagement Activity | 2018 |
Description | Cell block Science - Shotts Prison, Glasgow. |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Talk to prisoners |
Year(s) Of Engagement Activity | 2018 |
Description | Cold Spring Harbor, Asia, Membrane Proteins: From Physiology to Pharmacology. Suzhou, China. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation of research data |
Year(s) Of Engagement Activity | 2019 |
Description | Conference invitation: Keystone Meeting: G Protein-Coupled Receptors: Structural Signalling and Drug Discovery. Colorado, USA. Feb 2016. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Keystone Meeting: G Protein-Coupled Receptors: Structural Signalling and Drug Discovery. Colorado, USA. Feb 2016. |
Year(s) Of Engagement Activity | 2016 |
Description | GPCR Interactive Workshop (GLISTEN). Dissecting the in vivo role of GPCRs. Leiden. Holland August 2014. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | GPCR Interactive Workshop (GLISTEN). Dissecting the in vivo role of GPCRs. Leiden. Holland August 2014. |
Year(s) Of Engagement Activity | 2014 |
Description | Hawaiian GPCR workshop. Memory and learning in prion neurodegeneration. Big Island, Hawaii, USA. December 2015. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Hawaiian GPCR workshop. Memory and learning in prion neurodegeneration. Big Island, Hawaii, USA. December 2015. |
Year(s) Of Engagement Activity | 2015 |
Description | Keystone presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Keystone science conference |
Year(s) Of Engagement Activity | 2017 |
Description | Presentation to subcommittee on Life Sciences, Scottish Parliament on the impact of Brexit |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Presented to the subcommittee on Life Sciences |
Year(s) Of Engagement Activity | 2019 |
Description | Protein kinase inhibitor (PKI) meeting. Warsaw, Poland. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation of research data |
Year(s) Of Engagement Activity | 2019 |
Description | Public outreach - big Bang Fair 2015 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Public outreach - big Bang Fair 2015 |
Year(s) Of Engagement Activity | 2015 |
Description | School visit - GCSE year - Beauchamp college |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Spark discussions |
Year(s) Of Engagement Activity | 2014 |
Description | Science School Visit - St johns primary school |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Spark discussions |
Year(s) Of Engagement Activity | 2014 |
Description | Science and Ethics - Beauchamp College |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Spark discussions |
Year(s) Of Engagement Activity | 2014 |
Description | Science and Ethics - Leicester Grammar School |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Science and Ethics - Leicester Grammar School |
Year(s) Of Engagement Activity | 2014 |
Description | |Glasgow science fair 2017 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Stand at the science fair in central Glasgow |
Year(s) Of Engagement Activity | 2017 |
Description | • Pint of Science - Raven pub, Glasgow. June 2018 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | 50 members of the general public at this outreach event |
Year(s) Of Engagement Activity | 2018 |