Evaluation of Rgs7 as a key regulator of adipocyte function

Lead Research Organisation: University of Warwick
Department Name: Warwick Medical School

Abstract

Excessive fat storage results from an imbalance between energy intake and energy expenditure. Mammals store excess energy in the form of fat, predominantly in adipocytes. Research over the past 15 years has transformed our view of adipose tissue from a fat-storage depot to an active, multi-hormone producing organ that communicates with a myriad of other tissues including muscle, liver, pancreas, heart, and the brain. Although the majority of fat is normally stored in white adipose tissue, another specialised type of adipose tissue known as brown adipose tissue exists which can convert fat into heat at a very high rate. The ability of brown adipose tissue to effectively burn fat means that it could prove highly effective for treating obesity if fully activated. Although it has recently been demonstrated that most adult humans possess brown adipose tissue it appears to be largely inactive in most individuals under normal conditions. To use brown fat to treat obesity we need to understand more fully the molecules and pathways that control its activation. In this project, we will look at the role of a factor that could have essential actions in controlling the hormonal pathways that affect brown fat activity, energy balance and the conversion of white to brown fat.

Brown fat cells express a unique set of genes that determine the fundamental differences between brown and white fat cells. Rgs7 (Regulator of G protein signalling 7) is a gene that we found was present at high levels in brown fat cells. Furthermore, it was increased in white fat upon prolonged cold exposure, a treatment which induces the appearance of brown fat cells within white fat depots. Importantly, genetic analysis has revealed the RGS7 gene is associated with obesity and diabetes in humans. Rgs7 controls the activity of hormone signalling pathways in cells. As these pathways are essential for the gene regulation required for brown and white fat function, regulators such as Rgs7 are likely to have a vital role in the physiology of fat and the control of energy balance. We will investigate, for the first time, the role of Rgs7 in whole body energy metabolism and fat cell biology by addressing its effects on brown fat activation due to cold exposure and susceptibility to obesity due to high fat diet. We will study how hormone receptor pathways are modulated by Rgs7 in fat cells and how the metabolic function of the cell is affected.

This project proposal to study the metabolic role of Rgs7 is timely given the nature of the obesity epidemic, identification of functional human brown fat as a weight loss target, and our recent study that identified it among genes specifically expressed in brown fat. As obesity and associated metabolic diseases are an increasing health concern the fundamental questions to be addressed in this proposal closely align with the BBSRC's strategic aim to increase understanding of the biology of normal healthy ageing, to improve lifelong health and wellbeing. The targeting of Rgs7 represents a novel approach to modulate receptor-mediated signalling pathways that regulate processes for controlling energy balance. Increasing energy dissipation through signal transduction modulation in adipose tissues has the potential to promote weight loss to assist in treating and preventing metabolic diseases.

Technical Summary

Receptor-mediated signal transduction pathways control essential metabolic processes that modulate whole body energy balance. We have discovered that the gene Regulator of G protein Signalling 7 (Rgs7) is highly expressed in BAT and is induced during the "browning" of WAT by cold exposure. RGS proteins determine the duration of signalling downstream of G protein-coupled receptor (GPCR) activation. As GPCRs serve essential actions in adipocytes including the stimulation of processes such as thermogenesis and lipolysis, Rgs7 has the potential to affect these key G protein-controlled pathways to control adipocyte metabolism.

With increasing rates of obesity and the associated diseases of type 2 diabetes and cardiovascular heart disease, it is important to identify novel approaches to improve metabolic health. Brown adipose tissue (BAT) is recognized as a target to combat obesity and diabetes due to the re-discovery of functional BAT in adult humans and its ability to burn fat and therefore aid weight loss. Adipocytes can be subdivided into two distinct categories; brown adipocytes dissipate energy in the form of heat whereas white adipocytes are specialized in the storage of chemical energy in white adipose tissue (WAT). Adipose tissues are remarkably dynamic in nature and stimuli such as prolonged cold exposure results in the presence of brown adipocytes within WAT depots.

We will determine the pathways that are modulated by Rgs7 in adipocytes and the functional consequences of its actions. The role of Rgs7 in whole body metabolism will be investigated and its actions in brown fat responses to cold exposure and weight gain due to high fat feeding. Rgs7 represents a novel target to modulate the processes that control energy balance. Increasing energy dissipation through signal transduction modulation in adipose tissues has the potential to promote weight loss to assist in treating and preventing metabolic diseases.

Planned Impact

The impact of this research program will come from the advancement of knowledge of the molecular mechanisms that control energy homeostasis. This will have a major impact for diverse groups and applications in six main ways:

1-Basic research underpinning health:
The proposed research has potential implications in the field of metabolic wellbeing that could contribute to enhance the quality of life and nation's health. New basic science findings in the signalling mechanisms that affect energy storage are of great interest to this sector. This project will provide new understanding of the signalling pathways that control activation of brown and white adipose tissue. There is a link between absence of detectable brown adipose tissue and obesity. The direct costs to the NHS and other health care providers for treating obesity and related conditions is currently around £10 billion per year (approx. 10% of the NHS budget). Because elevated fat storage in diseases such as obesity and fatty liver disease is linked with increased risk of diabetes, high blood pressure, heart disease and certain cancers, this work will be of importance to the health sector and to the general public, either from a general science education benefit, or for those who are directly impacted by these diseases.

2-Innovative healthcare solutions:
The ability to regulate energy balance has implications not only relevant to obesity, but also to clinical applications associated with weight loss in providing new approaches to treat metabolic disorders including lipodystrophy and cancer cachexia.

3-Biotechnology:
Identification of the molecular role of Rgs7 in adipocytes will be of great interest to the pharmaceutical industry due to the potential for fine-tuning signal transduction pathways or modulating ligand bias to regulate drug action and control which pathways are switched on or off.

4-Education and training:
The bioscience research carried out in the proposed project will contribute towards mantaining the high standard of academic excellence currently enjoyed by the University of Warwick and Cambridge University. This will impact on the ability to offer educational opportunities for undergraduate and post-graduate student training. This is a multidisciplinary project involving groups with renowned expertise in adipocyte biology, in vivo metabolism, cell signalling, gene regulation, bioinformatics, and systems biology. The interactions between researcher partners will facilitate transferable professional, analytical and communication skills, as well as specific scientific and technical skills that will contribute to their development and future prospects.

5-UK international competitiveness:
This research program will contribute to deliver the BBSRC's mission especially the strategic research priority 3 - Bioscience for Health as well as supporting the general UK strategy for combating increased incidence in obesity.

6-Science communication:
The conceptual advances and material (e.g. pictures and illustrations) generated to present the results of the proposed research will add to the resources used during outreach activities such as school open days and available for visitors to Warwick Medical School. We will raise awareness of the latest advances in the fields of metabolic medicine amongst diverse audiences within the general public and to educate and inspire interest in scientific careers in secondary school students. The pathway towards academic impact will be based on the classical instruments of scientific communication. Publication of our results in peer reviewed journals and presentations at international scientific meetings of relevance to the field will be the preferred means of communicating our results and conclusions.

Publications

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Description Fat consumption in brown adipose tissue is activated by the ligand TUG-891 that activates receptors present on adipocytes. The ligand in addition to activating cell surface receptors to affect signaling pathways also directly activates the protein UCP1 to increase energy consumption.
Exploitation Route Further ligand development for treatment of obesity/diabetes.
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Title Generation of Conditionally Immortalised Rgs7 knockout cell lines 
Description Cell lines were generated from brown adipose tissue, gonadal white adipose tissue and subcutaneous white adipose tissue. Both Rgs7 knockout and wild type cell lines were generated from the three adipose tissue depots. 
Type Of Material Cell line 
Year Produced 2018 
Provided To Others? No  
Impact The application of these cell lines allows us to investigate the role of Rgs7 in adipocytes and serves to reduce the requirement of animals in this research path. 
 
Description In vivo and in vitro investigation of Rgs7 in metabolism 
Organisation Scripps Research Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Expertise on metabolism and identification of importance of Rgs7 in brown adipose tissue
Collaborator Contribution Kirill Martemyanov has provided Rgs7 KO mice that will be used to investigate the in vivo role of Rgs7 in metabolism. In addition primary cultures will be prepared to investigate in vitro cell autonomous actions of Rgs7.
Impact There are no outputs as yet. The mice are currently being re-derived.
Start Year 2017
 
Description In vivo metabolic phenotyping 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise in planning and concept of in vivo studies
Collaborator Contribution Rgs7 KO mice are presently being re-derived in Cambridge to be taken into the Phenotyping unit where the experiments will be performed.
Impact No impact yet
Start Year 2017