Delineating the roles of GPR55 in cellular metabolism and energy homeostasis
Lead Research Organisation:
Robert Gordon University
Department Name: School of Pharmacy and Life Sciences
Abstract
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Technical Summary
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.
Planned Impact
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.
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.
Organisations
People |
ORCID iD |
| Cherry Lindsey Wainwright (Principal Investigator) |
| Description | The background hypothesis to this study was that the orphan receptor GPR55 plays an important role in energy regulation in metabolically active tissues, including the heart, and that activation of this receptor with a drug (ML184) would improve both insulin responses and ameliorate heart dysfunction in the setting of metabolic disruption in mice caused by intake of a high fat diet. So far in this project we have made a number of novel findings that suggest that activation of GPR55 results in different outcomes in normal-fed and high fat-fed mice. For example: 1. In normal fed mice, by performing protein arrays on heart tissue we have found that ML184 appears to suppress some of the insulin responses in heart tissue, suggesting that prolonged activation of this receptor reduces the metabolic response of the heart. This is borne out by findings that ML184 reduces some measures of heart function, such as the ability to expel blood from the ventricles during cardiac contraction. This suggests that in the presence of this drug the heart has "remodelled", making the walls of the heart stiffer. 2. In contrast, in mice fed a high fat diet where the responses to insulin are depressed, ML184 does not worsen these responses further, but neither does it improve insulin sensitivity. However, while high fat diet reduces heart function, animals treated with ML184 exhibited better measures of cardiac contractility than animals given the drug vehicle. 3. ML184 resulted in a modest reduction in the total plasma levels of the endogenous ligand at GPR55 (lysophosphatidylinositol; LPI), largely due to reductions in specific isoforms (18:0 and 18:2) of this mediator. Conversely, high fat feeding caused a marked increase in total levels of LPI, resulting from increases in the 18:0, 18:1, 20:3 and 20:4 isoforms, which was partially reversed by ML184. All of the above changes are absent in mice with a gene deletion for GPR55 (GPR55-/- mice), indicating that the effects we have seen are mediated via this receptor and opens up numerous questions as to the role of GPR55 in energy regulation (and therefore function) in the heart under differing metabolic conditions. The final experiments in this project have been studying the effects of ML184 on the increase in cAMP in response to isoprenaline in cultured cardiomyocytes to determine if the reduction in cardiac function can be attributed to a reduction in downstream signalling of the beta-adrenoceptor. This data is currently being fully anlaysed. |
| Exploitation Route | The key findings of the project have shown a complex role of chronic GPR55 activation, dependent upon whether this under physiological or pathophysiological settings. In the normal heart, chronic GPR55 activation suppresses the insulin response (i.e. induces metabolic dysregulation) and reduces contractile function; in contrast ML184 appears to partially ameliorate some of the metabolic and functional consequences of obesity/metabolic syndrome. This suggests that GPR55 activation is an attractive approach for a programme of drug development to improve heart function in individuals with obesity-related heart failure. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |