Delineating the regulation and function of gamma-synuclein in adipocyte lipid metabolism
Lead Research Organisation:
University of Aberdeen
Department Name: Rowett Institute of Nutrition and Health
Abstract
Obesity represents one of the biggest current medical challenges worldwide and so there is a clear need to find new potential therapies to combat this increasingly prevalent condition. Fat tissue is comprised of adipocytes which are cells specialised to allow the safe storage of fat in one large lipid droplet occupying most of the cell. The bigger the lipid droplet is the larger the fat cell becomes and the greater the overall mass of fat tissue. In obesity, it appears that the safe lipid storage capacity of fat tissue may be exceeded and lipids then instead go to other tissues causing harmful effects. Many prevalent diseases are linked to the negative effects of these lipids including diabetes, heart disease and some forms of dementia.
We have recently found that inhibiting a protein called gamma-synuclein might prevent the development of obesity. The gamma-synuclein protein is particularly highly expressed in fat cells. In fat cells lacking gamma-synuclein the breakdown of the lipid droplet is increased. However, this does not cause a problematic rise in lipids going to other tissues because it seems that the lipid that comes from the lipid droplet in the fat cell can be preferentially burnt as a fuel to provide energy in a way that lipids from the diet are not.
This burning of lipids particularly occurs in specialised brown fat cells which are capable of doing this and then dissipating the energy generated as heat. Activating this process is seen a potential way to treat obesity by effectively burning excess lipids and wasting energy. We have found that inhibiting gamma-synuclein may help brown fat cells to do this more efficiently. Therefore, overall the effect of gamma-synuclein inhibition may be both to break down fat stores and then to burn the lipid in the brown fat cells.
In this study we aim to understand 1) how the gamma-synuclein gene is switched on and off in fat cells, 2) how precisely gamma-synuclein controls the breakdown of the lipid droplet and 3) how losing gamma-synuclein makes brown fat cells burn more lipids. All of these may suggest ways to change levels of gamma-synuclein or alter the way it works to reduce body weight and/or treat the diseases associated with obesity.
We have recently found that inhibiting a protein called gamma-synuclein might prevent the development of obesity. The gamma-synuclein protein is particularly highly expressed in fat cells. In fat cells lacking gamma-synuclein the breakdown of the lipid droplet is increased. However, this does not cause a problematic rise in lipids going to other tissues because it seems that the lipid that comes from the lipid droplet in the fat cell can be preferentially burnt as a fuel to provide energy in a way that lipids from the diet are not.
This burning of lipids particularly occurs in specialised brown fat cells which are capable of doing this and then dissipating the energy generated as heat. Activating this process is seen a potential way to treat obesity by effectively burning excess lipids and wasting energy. We have found that inhibiting gamma-synuclein may help brown fat cells to do this more efficiently. Therefore, overall the effect of gamma-synuclein inhibition may be both to break down fat stores and then to burn the lipid in the brown fat cells.
In this study we aim to understand 1) how the gamma-synuclein gene is switched on and off in fat cells, 2) how precisely gamma-synuclein controls the breakdown of the lipid droplet and 3) how losing gamma-synuclein makes brown fat cells burn more lipids. All of these may suggest ways to change levels of gamma-synuclein or alter the way it works to reduce body weight and/or treat the diseases associated with obesity.
Technical Summary
The incidence of obesity has increased dramatically and is linked to the development of conditions such as diabetes and cardiovascular disease. Altered lipid homeostasis due to adipocyte dysfunction in obesity is believed to significantly contribute to the development of these conditions. We recently found that knockout of gamma-synuclein can increase energy expenditure and prevent the development of high fat diet induced obesity. This appears to involve increased lipolysis in white adipose tissue (WAT) and increased lipid oxidation in brown adipose tissue (BAT), both significant sites of gamma-synuclein expression. This proposal will investigate the molecular mechanisms underlying these effects and determine how gamma-synuclein expression is regulated. Specifically:
1) We will interrogate prexisting genome wide ChIP-seq and DHS-seq data sets from adipocytes, to identify putative transcriptional regulators of gamma-synuclein expression in these cells. Their importance will then be examined in both white and brown adipocyte cell lines using targeted promoter/reporter assays, ChIP assays and transcription factor knockdown.
2) We will determine the molecular mechanisms via which gamma-synuclein regulates lipolysis in adipocytes. We will investigate the interaction of gamma-synuclein with regulators of lipolysis including ATGL, for which we have already demonstrated binding. These studies will employ co-IPs and immunofluorescent cell imaging techniques to reveal the subcellular localisation and dynamic regulation of any interactions.
3) We will elucidate the molecular mechanisms via which gamma-synuclein may increase lipid oxidation and energy expenditure in BAT. We hypothesize that gamma-synuclein loss in BAT cells increases lipolysis providing lipid species that may be preferred for oxidation in this tissue. In addition, lipids from the increased lipolysis caused by gamma-synuclein loss may selectively activate an oxidative gene expression profile.
1) We will interrogate prexisting genome wide ChIP-seq and DHS-seq data sets from adipocytes, to identify putative transcriptional regulators of gamma-synuclein expression in these cells. Their importance will then be examined in both white and brown adipocyte cell lines using targeted promoter/reporter assays, ChIP assays and transcription factor knockdown.
2) We will determine the molecular mechanisms via which gamma-synuclein regulates lipolysis in adipocytes. We will investigate the interaction of gamma-synuclein with regulators of lipolysis including ATGL, for which we have already demonstrated binding. These studies will employ co-IPs and immunofluorescent cell imaging techniques to reveal the subcellular localisation and dynamic regulation of any interactions.
3) We will elucidate the molecular mechanisms via which gamma-synuclein may increase lipid oxidation and energy expenditure in BAT. We hypothesize that gamma-synuclein loss in BAT cells increases lipolysis providing lipid species that may be preferred for oxidation in this tissue. In addition, lipids from the increased lipolysis caused by gamma-synuclein loss may selectively activate an oxidative gene expression profile.
Planned Impact
Academic impact:
Research into metabolic health and disease is continually expanding and the UK has major strength and expertise in this field. This field involves multidisciplinary research from fundamental molecular and cellular biology to whole organism physiology, multi-tissue crosstalk, systems biology, genetics, epigenetics, pharmacology, nutrition and public health.
The work proposed spans several of these areas and would be of significant interest to a wide range of investigators from basic to clinical scientists. By increasing the UK's research output, skills training and profile in the area of metabolic disease the work will contribute to the building of new capacity on this area. The research will also apply new techniques and generate new reagents that will be of significant benefit to other academic researchers. These will be made available to other academic researchers to accelerate the pace of discovery in this field.
Economic and societal impacts:
Obesity is a major health problem in the UK, leading to increased risk of disease and a health service burden in excess of a half billion pounds a year in direct costs. Current pharmacological therapies are extremely limited and so the identification of new potential therapeutic avenues is essential. The work proposed aims to uncover novel pathways via which adipocyte function and lipid metabolism might be regulated. This has the power to reveal new targets for the development of molecular or pharmacological therapies for the treatment of insulin resistance, dyslipidaemia, obesity and metabolic disease.
The majority of the work addresses the fundamental questions regarding the molecular mechanisms controlling adipocyte lipolysis and lipid oxidation. When amenable and relevant pathways are identified through these studies, therapeutic drugs are likely to be 10 years or more from clinical use. However, the novel findings of this research may be of significant value to pharmaceutical companies with an interest in this area. The insights gained into novel regulators of these processes may reveal new candidates to be screened in individuals with unsolved lipodystrophy or who appear likely to have severe monogenic forms of insulin resistance, dyslipidaemia or obesity. As such it may be valuable in genetic diagnosis of these individuals, aiding their appropriate treatment. This could provide a significant benefit in the short-term to the health of affected individuals. In addition we aim to determine how gamma-synuclein is nutritionally regulated in adipose tissue. If, as our preliminary data suggests, altering gamma-synuclein levels could have some beneficial effects on metabolic health this might also provide insights into how this might be achieved by altered nutrition.
Intellectual property arising from the proposed research will be exploited through the University of Cambridge's technology transfer company Cambridge Enterprise and the BBSRC. The proposed research may inform and benefit the bioscience sector through access to new knowledge, technology development and data. Thus it may enhance the knowledge economy and economic competitiveness of the UK. The research is also readily accessible to the public, given its clear relevance to the well-publicised problem of obesity. Advances in this area have the potential to improve health, lifespan and quality of life.
Research into metabolic health and disease is continually expanding and the UK has major strength and expertise in this field. This field involves multidisciplinary research from fundamental molecular and cellular biology to whole organism physiology, multi-tissue crosstalk, systems biology, genetics, epigenetics, pharmacology, nutrition and public health.
The work proposed spans several of these areas and would be of significant interest to a wide range of investigators from basic to clinical scientists. By increasing the UK's research output, skills training and profile in the area of metabolic disease the work will contribute to the building of new capacity on this area. The research will also apply new techniques and generate new reagents that will be of significant benefit to other academic researchers. These will be made available to other academic researchers to accelerate the pace of discovery in this field.
Economic and societal impacts:
Obesity is a major health problem in the UK, leading to increased risk of disease and a health service burden in excess of a half billion pounds a year in direct costs. Current pharmacological therapies are extremely limited and so the identification of new potential therapeutic avenues is essential. The work proposed aims to uncover novel pathways via which adipocyte function and lipid metabolism might be regulated. This has the power to reveal new targets for the development of molecular or pharmacological therapies for the treatment of insulin resistance, dyslipidaemia, obesity and metabolic disease.
The majority of the work addresses the fundamental questions regarding the molecular mechanisms controlling adipocyte lipolysis and lipid oxidation. When amenable and relevant pathways are identified through these studies, therapeutic drugs are likely to be 10 years or more from clinical use. However, the novel findings of this research may be of significant value to pharmaceutical companies with an interest in this area. The insights gained into novel regulators of these processes may reveal new candidates to be screened in individuals with unsolved lipodystrophy or who appear likely to have severe monogenic forms of insulin resistance, dyslipidaemia or obesity. As such it may be valuable in genetic diagnosis of these individuals, aiding their appropriate treatment. This could provide a significant benefit in the short-term to the health of affected individuals. In addition we aim to determine how gamma-synuclein is nutritionally regulated in adipose tissue. If, as our preliminary data suggests, altering gamma-synuclein levels could have some beneficial effects on metabolic health this might also provide insights into how this might be achieved by altered nutrition.
Intellectual property arising from the proposed research will be exploited through the University of Cambridge's technology transfer company Cambridge Enterprise and the BBSRC. The proposed research may inform and benefit the bioscience sector through access to new knowledge, technology development and data. Thus it may enhance the knowledge economy and economic competitiveness of the UK. The research is also readily accessible to the public, given its clear relevance to the well-publicised problem of obesity. Advances in this area have the potential to improve health, lifespan and quality of life.
Publications
D'Agostino G
(2018)
Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake.
in Cell metabolism
Castro IG
(2019)
Promethin Is a Conserved Seipin Partner Protein.
in Cells
Burke LK
(2016)
Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons.
in Molecular metabolism
Burke LK
(2017)
Lorcaserin improves glycemic control via a melanocortin neurocircuit.
in Molecular metabolism
Description | We have made significant advances in understanding the function of the protein being investigated in this project, called gamma-synuclein. We have found that reducing the levels of gamma-synuclein in mature fat cells is enough to make them use more fats as a fuel source. This makes them use up these fats instead of storing them. Overall this makes the fat cells more metabolically healthy. We have worked out several details regarding how gamma-synuclein does this and the proteins it regulates to achieve this effect. In a complementary PhD project we collaborated with colleagues with expertise in medicinal chemistry to generate potential drugs to manipulate gamma-synuclein function. This was based on original data from the researcher working on this BBSRC funded project. In addition we have uncovered some details about how the levels of gamma-synuclein are controlled in fat cells and how gamma-synuclein can regulate the type of fat cells we have. This tells us how some circulating factors such as hormones and nutrients regulate the amount of gamma-synuclein in a fat cell. It also gives us the detailed information that may make it possible to artificially control the levels of gamma-synuclein to increase the burning of fat as a fuel source and protect against obesity. We have also determined the effects of inhibiting gamma-synuclein on metabolic health in the whole organism and have now examined this is a well known in vivo model of cardiovascular disease. In addition we have tested the ability of a potential peptide inhibitor of gamma-synuclein to bring about the health benefits of gamma-synuclein loss. We have two manuscripts in preparation reporting these findings which include data from this original award as well as subsequent data from the related PD studentship |
Exploitation Route | We are currently preparing publications from this work and expect to have three further papers in addition to existing publications. These are likely to inform future work by others in this area as well as forming the basis for more work from our laboratory. |
Sectors | Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | NHS Grampian Endowment Research Grant 2018 |
Amount | £9,350 (GBP) |
Funding ID | Project No:17/045 |
Organisation | NHS Grampian |
Department | NHS Grampian Endowment Fund |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2018 |
End | 03/2019 |
Description | University of Aberdeen/BBSRC Eastbio PhD Studentship |
Amount | £92,000 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2017 |
End | 09/2021 |
Title | Gene edited cells lacking gamma synuclein |
Description | gene editing used to generate adipocyte lines lacking gamma-synuclein |
Type Of Material | Cell line |
Year Produced | 2017 |
Provided To Others? | No |
Impact | None yet |
Description | Analysing adipose tissues by FFC-MRI |
Organisation | University of Aberdeen |
Department | Department of Biomedical Physics & Bioengineering |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in adipose tissue biology and tissue samples for analysis |
Collaborator Contribution | Expertise in FFC-MRI imaging and NMR |
Impact | manuscript in preparation |
Start Year | 2016 |
Description | Determining the effects of adipose tissue on cardiovascular health |
Organisation | University of Aberdeen |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Genetically modified mouse lines allowing us to examine the effect either of adipose tissue loss or increase adipose tissue lipid oxidation on cardiovascular health. Expertise in adipose tissue lipid handling and the endocrine functions of adipose tissue. |
Collaborator Contribution | Murine models of cardiovascular disease and expertise in assessing cardiovascular health. |
Impact | Generation of preliminary data, currently forming the basis of applications in preparation for funding in this area. |
Start Year | 2016 |
Description | Aberdeen Cardiovascular and Diabetes Centre launch |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Launch event/day for a new Cardiovascular and Diabetes Centre based at the University of Aberdeen. Attendees were a divers mix of funders, patients, healthcare professionals, researchers, donors and other stakeholders. |
Year(s) Of Engagement Activity | 2018 |
Description | Patient group workshop (Diabetes Scotland Peer Support Group Aberdeen) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Organised and hosted a workshop for diabetes patients, carers, professionals and other stakeholders at the Rowett Institute, University of Aberdeen. Included patient discussions, discussion of local NHS service and research presentations |
Year(s) Of Engagement Activity | 2019 |
Description | Public Engagement Lecture, Aberdeen Sience Festival 2015 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Approximately 60-80 people attended a 30 minute presentation "Mad, bad and dangerous to grow. Are we making our body fat angry?". This was followed by discussions with the audience about obesity, metabolic health and how to adopt a healthier lifestyle. |
Year(s) Of Engagement Activity | 2015 |
Description | Public Engagement Talk at Satrosphere Aberdeen ads part of Aberdeen Techfest Sept 2014 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Talk entitled "Good or bad: Can we learn to love our fat?" attended by around 50 members of the public with Q&A afterwards Requests for further similar talks in future. |
Year(s) Of Engagement Activity | 2014 |
Description | Public lecture Jan 2018 "Stuff worth knowing: Handling energy from food. Where did my Christmas dinner go (and is it still with me)?" |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Talk of approx 50 mins to general audience with extensive questions and discussions afterwards. Request for participation in future similar programs. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.aberdeencity.gov.uk/events/where-did-my-christmas-dinner-go-stuff-worth-knowing |
Description | Public lecture at Aberdeen Techfest Sept. 2017 "Handling energy in the body. Are we storing up trouble for the future?" |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Public talk discussing how obesity leads to diabetes and other metabolic diseases, the involvement of different tissues and organs and how different diets may alter health. The purpose was principally to widen knowledge of our research, inform the public regarding the causes and consequences of obesity and encourage discussion of the topic.The talk of around 50 minutes was followed by a comprehensive discussion driven by questions from the audience which lasted around 45 minutes. The level of interest led to a request to give a subsequent presentation at a different venue in Jan 2018 |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.aberdeenperformingarts.com/events/techfest-handling-energy-in-the-body-are-we-storing-up-... |
Description | Secondary School Visit (Aberdeen) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Visit to a secondary school to discuss obesity, diabetes and nutrition research and the science around body weight regulation and metabolism. |
Year(s) Of Engagement Activity | 2018 |
Description | Talk Aberdeen Science Festival 2016: "Obesity and Diabetes, a conflict of organs" |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | This presentation was made jointly with a colleague who also works in this field and discussed obesity, why it causes ill health and approaches to reduce rates of obesity and the conditions associated with it. The presentation of approximately 1 hour led to a lively and extended discussion afterwards that lasted over an hour after the talk concluded. Indeed the organisers were had to conclude the discussions because of a need to close the venue. Feedback was extremely strong for this event and suggested we had informed the public regarding research in this topic, challenged preconceptions and prejudices and may lead to altered behaviour. |
Year(s) Of Engagement Activity | 2014,2016 |
URL | http://www.techfestsetpoint.org.uk/tis/ |
Description | Talk to Grampian Branch of The Society of Chiropodists and Podiatrists. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Talk sparked discussion after the presentation Participants reported that the talk had improved their understanding of factors affecting body weight and metabolic health which would inform their approach to patient advice and care. |
Year(s) Of Engagement Activity | 2014 |
Description | Talk to clinical geneticists Aberdeen Royal Infirmary |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Talk gave rise to discussion and questions. I was asked by a family member of an attendee who is a school student if they could join my laboratory for a summer placement. |
Year(s) Of Engagement Activity | 2014 |
Description | Talk to secondary school students Jan 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Talk to secondary school science class regarding obesity, diabetes and heart disease. Talk was given to approx 40-50 children followed by discussion regarding obesity and associated diseases, diet, exercise and science and research more broadly. Has led to a request to return to speak to other classes in the future. |
Year(s) Of Engagement Activity | 2006,2018 |
Description | Video to discuss new research regarding adipose tissue development and function |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Video posted on the University of Aberdeen website regarding novel work from our group identifying a new type of adipocyte stem cell |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.abdn.ac.uk/clsm/research/issf/projects/defining-a-novel-population-of-stem-cells-and-the-... |