Award details

Delineating the roles of GPR55 in cellular metabolism and energy homeostasis

Reference	BB/S00033X/1
Principal Investigator / Supervisor	Professor Hari Hundal
Co-Investigators / Co-Supervisors	Dr Christopher Lipina
Institution	University of Dundee
Department	School of Life Sciences
Funding type	Research
Value (£)	411,233
Status	Completed
Type	Research Grant
Start date	01/01/2019
End date	31/08/2022
Duration	44 months

Abstract

Proper control of metabolic signalling in skeletal muscle, liver and adipose tissue, which are major sites for fuel utilisation/storage, is crucial for maintaining glucose and lipid homeostasis. Consequently, disorders such as insulin resistance and type 2 diabetes may arise due to metabolic impairments in these tissues, by mechanisms that remain poorly defined. Recently we discovered that G-protein coupled receptor GPR55 functions to modulate several metabolic processes, and that mice deficient for this receptor exhibit impaired insulin sensitivity and heightened inflammation. Allied to this, GPR55-null mice also display reduced abundance of proteins regulating mitochondrial lipid oxidation within key metabolic tissues including the heart, coinciding with the development of cardiac dysfunction. Strikingly, we find GPR55 activation enhances insulin sensitivity and upregulates activity/expression of proteins involved in promoting mitochondrial biogenesis and respiration in muscle, hepatocytes and adipocytes. Intriguingly, impaired muscle insulin action in GPR55-null mice concurs with reduced protein abundance of IRS-1, a critical insulin signalling intermediate. In contrast, liver and adipose tissue deficient for GPR55 show no change in IRS-1 content but, instead, exhibit elevated expression of PTEN, a key repressor of insulin action. In addition, GPR55-deficient mice show increased adiposity and lipogenic drive, a phenotype mimicked in cultured fat cells treated with a GPR55 antagonist. We hypothesise that GPR55 stimulation would help alleviate diet-induced obesity, insulin resistance, impaired fuel utilisation/storage and cardiac dysfunction by altering expression and/or function of key insulin signalling components, as well as suppressing lipogenic drive and/or improving mitochondrial function. This project will delineate, mechanistically and functionally, how GPR55 regulates these metabolic processes in skeletal muscle, liver, adipose tissue, and the heart.

Summary

The G-protein coupled receptor (GPCR) superfamily play crucial roles in cell communication. As such, they mediate the effects of circulating hormones and other biologically active molecules across the blood-facing membranes of cells to regulate diverse cell/tissue processes including, for example, sensory perception, metabolism and satiety. Given their involvement in neurological disorders, inflammatory and metabolic diseases, diabetes and cardiac dysfunction they represent the largest and most successful class of "druggable" targets in the human body. However, despite the immense current interest in GPCR biology, the function of numerous members of this family remain poorly understood, but which may well represent important therapeutic targets for treatment of major public health issues, such as obesity, diabetes and cardiovascular disease. This project aims to explore links between a lipid sensing GPCR, called GPR55, and processes influencing adiposity, inflammation, cardiac function and response to insulin within key metabolic tissues, such as white fat, liver, skeletal muscle and heart. These tissues are major targets for insulin in the body and represent the principal sites where sugar (glucose) and fat are stored and metabolised in response to the hormone. GPR55 is stimulated by a circulating lipid called LPI, which we find improves the response of these metabolic tissues to insulin and also helps lower inflammatory drive in cells derived from them. Crucially, this LPI-mediated response is lost if cells are co-treated with a GPR55 inhibitor. Strikingly, we have discovered that animals deficient in this lipid sensor exhibit reduced tissue responsiveness to insulin, impaired metabolic capacity and a decline in cardiac performance. Metabolic capacity is crucially dependent upon mitochondria; structures within cells representing the cell's "energy generator". Significantly, animals lacking GPR55 show changes in mitochondrial biology consistent with a reducedability to "burn" fat. In line with this, we find animals lacking GPR55 develop obesity and that inhibiting the receptor in cultured adipocytes (fat cells) induces proteins that help make more fat, which would augment the process of obesity. Precisely how GPR55 links to the molecular regulation of the above processes is currently unclear. The studies described in this application will utilise cells in culture from rodent and human origin as well as mouse tissues for laboratory-based analysis to help dissect out the role GPR55 plays not only with respect to insulin action and inflammation, but in control of tissue adiposity (fatness) and cardiac function. The project will also explore whether GPR55 activation helps mitigate the increase in fat gain, the loss in tissue sensitivity to insulin and cardiac dysfunction in mice fed a high fat calorie diet. Tissues taken from animals at the end of such studies will be processed for biochemical analysis and state-of-the-art whole cell/tissue protein profiling - an approach that will identify which proteins become up- or down-regulated in tissues of mice lacking GPR55 or in cells in which GPR55 has been activated/inhibited with selective drugs. This methodology will generate a wealth of information, potentially unveiling novel proteins that connect with GPR55 to regulate how insulin works or fat is stored or "burnt". Importantly, the large scale protein profiling may flag-up proteins that have not previously been linked to GPR55, but which may be central to the work of researchers in other fields thus providing an invaluable data resource to the scientific community. Collectively, our pilot studies indicate GPR55 may function as a novel metabolic regulator within tissues and suggest that understanding how it regulates insulin action, lipid metabolism and cardiac function may offer new pharmacological opportunities for treatment of metabolic disorders associated with conditions such as obesity and type II diabetes.

Impact Summary

Who will benefit from this research? Academics: Our understanding of how GPR55 affects key anabolic responses in tissues such as skeletal muscle, adipose tissue, liver and heart is very much in its infancy. Consequently, our findings benefit other academic researchers, especially those working in areas related to metabolic and cardiovascular dysfunction (e.g. obesity and diabetes). Private Sector: Our findings will appeal to pharmaceutical companies with an interest in the endocannabinoid system (ECS), especially with respect to therapies that help maintain/improve tissue response/function, for example, during obesity and Type II diabetes. Government: The findings may help inform national (e.g. DoH) and international (e.g. Healthy Living matters, WHO) policy on healthy living in relation to maintenance of tissue function. Public and Charitable Sectors: Individuals working for public health disciplines (e.g. nutritionists/dieticians etc) and scientific advisors to Medical Charities may benefit from the findings by helping to devise appropriate advice to counter diet-induced decline in tissue health, as well as advising their clients of recent advances. General Public: Target beneficiaries include the public who may lead poor dietary/sedentary life styles and in whom insulin resistance and obesity-related metabolic dysfunction may be an issue. How will they benefit from this research? Our studies reveal that metabolically active tissues (e.g. muscle, fat, liver and heart) lacking GPR55 display reduced insulin sensitivity, heightened tissue inflammation and altered fuel metabolism that promote adiposity and cardiovascular dysfunction. The proposed research will break new ground by unravelling, at the molecular level, how GPR55 links to pathways responsive to insulin or those mediating inflammation and influencing energy metabolism. Such information may inform the design of novel strategies targeting GPR55 to help ameliorate the decline in insulin sensitivity or metabolic function seen in major public health conditions, such as obesity and diabetes, with the ultimate benefit of improved life quality and reduced healthcare costs. We believe our work will be appeal to other academics with an interest in insulin action, tissue inflammation, fuel/energy metabolism and cardiovascular physiology, as well as those involved in pharmaceutical drug discovery programmes focussing on the ECS. Discoveries, materials and expertise made available to other academics and interested commercial beneficiaries via publications, meetings and Material Transfer Agreements will benefit the UK economic competitiveness in biopharmaceutical products. Appointed staff will profit from institutional initiatives promoting career development and training in public engagement. What will be done to ensure that they benefit from this research? Both lead and non-lead institutions are fully committed to maximizing their research impact. This commitment was recognised by the BBSRC "Excellence with Impact" and the first UK Gold Engage Watermark Award by the National Co-ordinating Centre for Public Engagement to the School of Life Sciences (SLS). Impact was also a key measure in REF2014 in which SLS was rated top in biological sciences of any UK University and RGU's UoA3 impact rating was 100% 3*/4*. The applicants have established networks for communicating their research and its benefits via public engagement/outreach activities (e.g. via hosting public visits, Café Science, Royal Society Summer Science Exhibition) and their professional bodies (e.g. Diabetes UK, BHF, British Pharmacological Society and Royal Society of Biology) who interact directly with the public. The impact of our research is publicised on our respective School websites or, where appropriate, through press releases from our Publicity Offices or engagement with our Technology Transfer Offices in matters of Intellectual Property Rights and commercial development.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Diet and Health
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/S000380/1 Delineating the roles of GPR55 in cellular metabolism and energy homeostasis

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