Regulation of brown adipose tissue activity in humans by glucocorticoids
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Cardiovascular Science
Abstract
Brown fat, also known as brown adipose tissue (BAT), is a unique tissue which functions to promote energy expenditure to raise body temperature. This type of fat has been extensively studied in small animals such as mice and is very important in these animals, as mice lacking BAT become obese. However brown fat has only recently been discovered in adult humans, and the importance of BAT and how it is controlled in humans is unclear. The current methods available to detect BAT activity in humans are inadequate, therefore this proposed project aims to build on existing tools and develop new techniques to determine the importance of BAT to energy expenditure in healthy humans. BAT biopsies will also be obtained from patients undergoing surgery and this tissue will be grown in culture dishes to investigate the important processes controlling its activation. Glucocorticoids are a type of steroid hormone which cause obesity if levels are persistently elevated. Glucocorticoids suppress energy production by brown fat in small animals, and we will use our new techniques to test whether glucocorticoids also suppress BAT activity in humans. The effect of glucocorticoids on the tissue biopsies will also be examined to discover the important pathways controlling energy expenditure in BAT. These studies will tell us whether blocking glucocorticoid action or other pathways in brown fat may increase energy expenditure in humans, and thereby treat obesity.
Technical Summary
To assess macronutrient metabolism by human BAT, PET/CT scanning is currently the only available in vivo technique, but PET does not allow repeated measurements due to radiation exposure and only measures glucose uptake. We aim to measure cold-induced BAT lipid and glucose metabolism in healthy humans using three alternative techniques during stable isotope tracer infusion: 1) intra-adipose microdialysis and 2) selective venous cannulation of BAT (for arterio-interstitial and arterio-venous differences, respectively, in glucose/lipid uptake and energy production); and 3) 13C-magnetic resonance spectroscopy to measure TCA cycle activity. These in vivo techniques will be used to investigate the regulation of human BAT activity by glucocorticoids, which are potent suppressors of BAT in rodents. In parallel, we will use a protocol that we have established for primary culture of human brown adipocytes (obtained from patients undergoing elective neck surgery) to investigate glucocorticoid-sensitive pathways mediating effects on macronutrient metabolism and the role of local glucocorticoid regeneration by 11beta-hydroxysteroid dehydrogenase type 1. If successful, these tools will be vital to dissect BAT metabolic activity in human obesity, its control by other putative regulators, and the key transcription factors controlling differentiation, and to prove the concept that inhibiting glucocorticoid action increases BAT activity in humans.
Planned Impact
Firstly, as stated in the academic beneficiaries, the results from this work will help advance the understanding of the importance and regulation of brown adipose tissue in humans. This will be of benefit to researchers from around the world, as one of the major barriers to developing activators of brown adipose tissue in humans is the unknown contribution of this tissue to whole body energy expenditure. We will utilise cutting edge techniques to investigate a field which has been technologically very challenging, and these tools once created can be used by other researchers/ individuals to dissect in vivo brown adipose tissue physiology.
The private sector will also benefit from this research, namely the pharmaceutical industry. Obesity is considered to be one of the greatest threats to health in the 21st century and research into drug therapies has mainly focused on increasing satiety (decreasing energy input) rather than promoting energy expenditure, and this research will highlight the potential of this alternative strategy. This research may also highlight new candidate pathways in brown adipose tisse which industry may be interested in targeting new drug development. This may lead to collaborations between academia and industry which is critical to improved health outcomes.
Research charities and the government will also benefit from research being performed in this field. A recent call to tackle obesity as one of the major health problems in the UK has highlighted the need for further work in this field. Therefore, being seen to fund research into obesity, which will be performed in the UK, will highlight that we are serious as a nation about exploring novel approaches to tackle this major health burden.
Beneficial effects of this fellowship to the wider population will take much longer to achieve than the duration of this 4-year fellowship. However, if the results from this body of work can either directly lead to new treatments or alternatively stimulate other researchers/ industry to create new drugs to treat obesity, this would be a major improvement for the nation's health as a whole.
Finally, the applicant and technician will benefit hugely from this work. Not only will this secure employment for both individuals for a significant 4-year period, the results generated from this fellowship will place the applicant in a strong position to secure a senior fellowship. In addition, the publications and impact from this work will form the foundation for further research which allow the applicant to expand his research team, providing additional employment and training for others (e.g. PhD students, post-doctoral staff) which can benefit the country as a whole.
The private sector will also benefit from this research, namely the pharmaceutical industry. Obesity is considered to be one of the greatest threats to health in the 21st century and research into drug therapies has mainly focused on increasing satiety (decreasing energy input) rather than promoting energy expenditure, and this research will highlight the potential of this alternative strategy. This research may also highlight new candidate pathways in brown adipose tisse which industry may be interested in targeting new drug development. This may lead to collaborations between academia and industry which is critical to improved health outcomes.
Research charities and the government will also benefit from research being performed in this field. A recent call to tackle obesity as one of the major health problems in the UK has highlighted the need for further work in this field. Therefore, being seen to fund research into obesity, which will be performed in the UK, will highlight that we are serious as a nation about exploring novel approaches to tackle this major health burden.
Beneficial effects of this fellowship to the wider population will take much longer to achieve than the duration of this 4-year fellowship. However, if the results from this body of work can either directly lead to new treatments or alternatively stimulate other researchers/ industry to create new drugs to treat obesity, this would be a major improvement for the nation's health as a whole.
Finally, the applicant and technician will benefit hugely from this work. Not only will this secure employment for both individuals for a significant 4-year period, the results generated from this fellowship will place the applicant in a strong position to secure a senior fellowship. In addition, the publications and impact from this work will form the foundation for further research which allow the applicant to expand his research team, providing additional employment and training for others (e.g. PhD students, post-doctoral staff) which can benefit the country as a whole.
People |
ORCID iD |
Roland Stimson (Principal Investigator / Fellow) |
Publications
Nixon M
(2016)
ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy.
in Science translational medicine
Ramage LE
(2016)
Glucocorticoids Acutely Increase Brown Adipose Tissue Activity in Humans, Revealing Species-Specific Differences in UCP-1 Regulation.
in Cell metabolism
Stimson RH
(2017)
Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct.
in Diabetes, obesity & metabolism
Stimson RH
(2014)
Glucocorticoids Increase Glucose Uptake By Human Brown Adipose Tissue in Vivo but Decrease Oxidative Phosphorylation and Inhibit Uncoupling Protein 1
in Endocrine Reviews
Stimson Roland H.
(2014)
Glucocorticoids Increase Glucose Uptake By Human Brown Adipose Tissue in Vivo but Decrease Oxidative Phosphorylation and Inhibit Uncoupling Protein 1
in ENDOCRINE REVIEWS
Stimson, Roland
Glucocorticoids decrease UCP-1 in human primary brown adipocytes
in Adipocyte Biology, Keystone symposium
Suchacki K
(2023)
The serotonin transporter sustains human brown adipose tissue thermogenesis
in Nature Metabolism
Suchacki KJ
(2021)
Nutritional Regulation of Human Brown Adipose Tissue.
in Nutrients
Suchacki KJ
(2020)
Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis.
in Nature communications
Suchacki KJ
(2022)
The diverse and distinct roles of adipose tissue on metabolic heath
Suchacki, KJ
(2020)
Serotonin suppresses brown adipose tissue activation in humans.
Thompson A
(2017)
Hypoxia determines survival outcomes of bacterial infection through HIF-1a-dependent reprogramming of leukocyte metabolism
in Science Immunology
Weng X
(2020)
Collagen 24 a1 Is Increased in Insulin-Resistant Skeletal Muscle and Adipose Tissue.
in International journal of molecular sciences
Title | Cover artwork for Cell Metabolism |
Description | The cover image of the issue of Cell Metabolism relating to our paper was a piper with the heading from the editors stating 'A new vista on human brown adipose tissue', highlighting the importance of our novel technique we developed and the innovative research occurring in Scotland. |
Type Of Art | Artwork |
Year Produced | 2018 |
Impact | Improved awareness of our research. |
URL | https://www.cell.com/cell-metabolism/issue?pii=S1550-4131(17)X0010-7# |
Description | Membership of UK Society for Endocrinology Clinical Committee |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Due to my clinical fellowships I was invited to join hte Society for Endocrinology clinical committee in 2018 for a 5 year term. We have published several guidelines for management of endocrine conditions, such as guidelines on the acute management of diabetes insipidus and the endocrine complications of checkpoint inhibitors. In addition, I am the lead clinician for developing guidelines in the committee. Furthermore, during the covid pandemic we created several guidance documents to ensure that clinicians were able to manage endocrine conditions appropriately within the constraints of the healthcare system caused by the pandemic. |
URL | https://www.endocrinology.org/clinical-practice/clinical-guidelines/ |
Description | Reduction in radiation dosage for CT-guided biopsies locally |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | British Heart Foundation Centre of Research Excellence Award |
Amount | £10,520 (GBP) |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2017 |
End | 12/2017 |
Description | British Heart foundation Centre of Research Excellence Award |
Amount | £13,200 (GBP) |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 11/2017 |
Description | Call for projects for IFCAH |
Amount | € 60,000 (EUR) |
Organisation | International Fund raising for Congenital Adrenal Hyperplasia (IFCAH) |
Sector | Charity/Non Profit |
Country | Global |
Start | 04/2016 |
End | 03/2017 |
Description | Centre for Cardiovascular Science public engagement fund for 'The many faces of fat' |
Amount | £500 (GBP) |
Organisation | University of Edinburgh |
Sector | Academic/University |
Country | United Kingdom |
Start | 02/2020 |
End | 06/2020 |
Description | Edinburgh and Lothians Health Foundation |
Amount | £19,988 (GBP) |
Organisation | Edinburgh & Lothians Health Foundation |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2015 |
End | 04/2017 |
Description | Edinburgh and Lothians Health Foundation Diabetes REsearch Fund |
Amount | £62,691 (GBP) |
Organisation | Edinburgh & Lothians Health Foundation |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2016 |
End | 11/2017 |
Description | MRC Confidence in Concept scheme |
Amount | £90,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2016 |
End | 09/2017 |
Description | Medical Research Council - Human Experimental Medicine Challenge Grant |
Amount | £1,212,985 (GBP) |
Funding ID | MR/S035761/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2019 |
End | 02/2023 |
Description | Scottish Senior Clinical Academic Fellowship |
Amount | £1,032,371 (GBP) |
Organisation | Chief Scientist Office |
Sector | Public |
Country | United Kingdom |
Start | 03/2018 |
End | 02/2023 |
Description | The role of the lactate receptor in adipose tissue thermogenesis |
Amount | £123,799 (GBP) |
Funding ID | PhD-50544-2022 |
Organisation | Medical Research Scotland |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2023 |
End | 09/2027 |
Description | Wellcome Trust Institutional Strategic Support Fund |
Amount | £50,650 (GBP) |
Organisation | Wellcome Trust |
Department | Wellcome Trust Institutional Strategic Support Fund |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2015 |
End | 01/2016 |
Description | Wellcome Trust Institutional Translational Partnership Award |
Amount | £19,440 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2018 |
End | 04/2019 |
Description | Wellcome Trust Institutional support Funding |
Amount | £19,800 (GBP) |
Organisation | Wellcome Trust |
Department | Wellcome Trust Institutional Strategic Support Fund |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2017 |
End | 04/2018 |
Title | Culture of in vivo human brown adipocytes |
Description | We have developed a novel primary culture system of human brown pre-adipocytes for study of the regulation of human brown adipose tissue. |
Type Of Material | Model of mechanisms or symptoms - in vitro |
Provided To Others? | No |
Impact | We have used this technique to determine the mechanisms of how glucocorticoids regulate brown adipose tissue activity in humans and determine species-specific differences in the regulation of brown adipose tissue function. This paper is currently under revision at Cell Metabolism. |
Title | Edinburgh Adipose Tissue Bank |
Description | I have set up an adipose tissue bank to provide a valuable resource. This bank comprises adipose tissue from several depots (e.g. subcutaneous, visceral, brown adipose tissue, bone marrow adipose) from a variety of subjects, which can be used by local and European collaborators to answer important questions. In addition, we collect anthropometric data, genetic information and plasma samples from subjects to maximise the benefit of this resource. |
Type Of Material | Biological samples |
Year Produced | 2013 |
Provided To Others? | Yes |
Impact | This bank forms the basis for my own research developing human brown adipocyte cultures, a primary aim of my fellowships. In addition, the bank has been used to answer important questions on adipose tissue biology in other depots such as subcutaneous, visceral and bone marrow. This bank has contributed to important publications in Nature Cell Biology, Cell Metabolism (2) and Science Translational Medicine and has allowed new important collaborations to develop. |
Title | Microdialysis measurement of in vivo brown adipose tissue activity in humans |
Description | We have developed a novel technique to measure brown adipose tissue (BAT) activity in humans using microdialysis, following localisation of brown adipose tissue deposits using PET/CT. Insertion of these catheters into supraclavicular brown adipose tissue has not been performed previously, and we have recently published this technique (Cell Metabolism 2018) and used it to quantify substrate utilisation by human brown adipose tissue during thermoneutrality and during cold activation. This technique can be used by other groups in order to better understand BAT function. |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | This technique has highlighted crucial new understanding of BAT physiology in humans and provides the only published technique to directly assess tissue levels in vivo. |
URL | https://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30304-8 |
Description | Collaboration with Brian Walker reagarding ABCC1 transport of glucocorticoids |
Organisation | University of Edinburgh |
Department | Centre for Cardiovascular Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have obtained subcutaneous and visceral adipose tissue and paired plasma samples from humans to determine the levels of cortisol and corticosterone in these samples and relative expression of ABCC1 transporter in adipose tissue in humans. |
Collaborator Contribution | They have looked at the effect of inhibiting or knocking out ABCC1 transporter in mice to determine that this transporter exports corticosterone but not cortisol to show how ABCC1 protects adipose tissue from the adverse metabolic effects of corticosterone. |
Impact | Paper published in Science Translational Medicine (Nixon et al, 2016). Funding from the International Fund for the treatment of Congenital Adrenal Hyperplasia (IFCAH) and MRC Confidence in Concept scheme obtained to determine whether corticosterone is a novel treatment for this condition. |
Start Year | 2014 |
Description | Collaboration with Dave Newby/ Marc Dweck |
Organisation | University of Edinburgh |
Department | Centre for Cardiovascular Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have generated data determining that glucocorticoids regulate myocardial metabolism in both humans and in mice. |
Collaborator Contribution | They have brought their expertise in cardiac PET/CT imaging to help us determine whether glucocorticoids may aid in the diagnosis of unstable coronary artery disease. |
Impact | We have obtained pilot funding to test whether glucocorticoids can aid in the diagnosis of unstable coronary artery disease, involving . |
Start Year | 2014 |
Description | Collaboration with Fredrik Karpe |
Organisation | University of Oxford |
Department | Department of Physics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Developed microdialysis as a novel technique to measure in vivo brown adipose tissue activity. |
Collaborator Contribution | Provided valuable insight and training into adipose tissue vein cannulations and use of xenon to measure adipose tissue blood flow. |
Impact | Original research article in preparation. Oral communication at Keystone Meeting 2017 on Adipocyte Biology. |
Start Year | 2015 |
Description | Collaboration with Gudmundur Johannsson on miRNAs regulated by glucocorticoids |
Organisation | University of Gothenburg |
Department | Sahlgrenska Academy |
Country | Sweden |
Sector | Academic/University |
PI Contribution | We performed a clinical study testing regulation of glucocorticoids on plasma parameters |
Collaborator Contribution | They tested the plasma for microRNAs and performed the statistical analyses |
Impact | Original research article published in e Life |
Start Year | 2018 |
Description | Collaboration with Li Kang on ILKs |
Organisation | University of Dundee |
Department | School of Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We provided fat tissue from human subjects with a range of BMI to determine the effect of obesity on integrin linked kinase |
Collaborator Contribution | They undertook the murine experiments to determine the role of ILK in adipose tissue |
Impact | One manuscript published in 2020 i IJMS, another published in Molecular Metabolism in 2021. I am a co-I on Dr Kang's new Diabetes UK grant to explore the role of ILK and ECM in brown adipose tissue function, awarded in 2022. |
Start Year | 2018 |
Description | Collaboration with Nick Hastie/ You-Ying |
Organisation | University of Edinburgh |
Department | Institute of Genetics & Molecular Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We obtained and provided samples of human brown adipose tissue to determine the developmental origins of these cells |
Collaborator Contribution | Collaborators performed the experiments with this tissue we provided |
Impact | Original research article published in Nature Cell Biology in 2014. Further research is planned with Dr Chau to explore this in more detail, this is dependent on obtaining funding (Dr Stimson down as collaborator on her grant application). |
Start Year | 2013 |
Description | Collaboration with Phil Coan regarding Camk2n1 |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We provided human adipose tissue samples to determine whether Camk2n1 expression is dysregulated in adipose tissue in obesity and type 2 diabetes mellitus |
Collaborator Contribution | They generated a Camk2n1 knockout rat and performed the in vivo rodent experiments using this model. |
Impact | Original research article published in Hypertension. |
Start Year | 2018 |
Description | Collaboration with Sarah Walmsley |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have aided Sarah's group in understanding the metabolic phenotype of her mouse, designing experiments to determine effect of hypoxia on adipose tissue function and thermogenesis. |
Collaborator Contribution | They have generated a HIF-1alpha knockout mouse and looked at metabolic health in the presence of infection, hypoxia and hypoxic pre-conditioning. |
Impact | Publication in Science Immunology DOI: 10.1126/sciimmunol.aal2861 |
Start Year | 2016 |
Description | Collaboration with Steve O'Railly regarding regulation of GDF15 by glucocorticoids |
Organisation | University of Cambridge |
Department | Institute of Metabolic Science (IMS) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have provided human plasma samples and analysed adipose tissue GDF15 levels to determine the regulation of GDF15 by glucocorticoids |
Collaborator Contribution | They have analysed these samples for GDF15 in plasma and have performed rodent in vitro experiments looking at regulation of glucocorticoids |
Impact | Original research article published in 202 in the Journal of Clinical Endocrinology & Metabolism. |
Start Year | 2018 |
Description | Collaboration with Will Cawthorne regarding PET/CT analysis of bone marrow uptake in humans |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We provided PET/CT scans performed during cold exposure and at room temperature of subjects to quantify bone marrow fat glucose uptake and compare against brown adipose tissue |
Collaborator Contribution | They performed the rodent and rabbit studies looking at the effect of cold on bone marrow glucose uptake. |
Impact | Publication in Nature Communications |
Start Year | 2018 |
Description | Will Cawthrone for marrow adipose tissue research |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are providing human marrow adipose tissue and other human adipose depots for our collaborator to determine if key differences between depots are maintained across species. |
Collaborator Contribution | Our collaborator is determining the importance of bone marrow adipose tissue in rodents and determining the differences between this and other adipose tissue depots. |
Impact | Nil to date, collaboration just commenced |
Start Year | 2014 |
Description | Faculty member and speaker at Career Development Workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Due to my MRC Clinician Scientist and CSO Senior fellowships, I was asked to become a faculty member of the Career Development Workshop run by the Society for Endocrinology to talk about how to further your career during and post-PhD to try and obtain independence and set up your own research team. This was attended by approximately 15 PhD and early post-doctoral scientists/ clinicians and I was involved in teaching them about appraising papers, writing grants and providing advice on how to obtain a fellowship. |
Year(s) Of Engagement Activity | 2016,2018 |
URL | https://www.endocrinology.org/meetings/2016/cdw2016/ |
Description | How and when to apply for an intermediate fellowship |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | National |
Primary Audience | Health professionals |
Results and Impact | The Young Diabetologists form Research Day is an annual event aimed at junior clinicians with an interest in Endocrinology which aims to spark interest in research and provide them with the practical information on how to undertake a period of research and pursue a research career thereafter. As a new MRC Clinician Scientist I was asked to give a lecture about my research career and top tips on how to obtain a research fellowship, and spent the day with this group to answer questions and offer advice on how to obtain an PhD and further funding. I have met several of these young clinicians again at a recent conference and some have already set up plans for a period of research (either undertaking a PhD or MD) which is encouraging. |
Year(s) Of Engagement Activity | 2013 |
Description | News interest in microdialysis paper |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Our publication in Cell Metabolism in 2018 attracted interest from the media and was reported by 8 online providers |
Year(s) Of Engagement Activity | 2018 |
Description | O The Oprah Magazine article entitled 'The skinny on fat' |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Interview with journal for O The Oprah magazine about brown fat about the metabolic improvements from brown fat activation in humans and the potential for BAT activation as a therapeutic target. Contributed to the final article. |
Year(s) Of Engagement Activity | 2020 |
Description | Report on our research to CAH patient group |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I wrote a piece on our research about a potential new treatment for congenital adrenal hyperplasia after discussing this with the head of the patient group. This was to make the community aware of the potential new treatment, the need for ongoing research to determine whether this is better than current practice, and to get valuable advice from this patient cohort about the important outcomes for us to monitor to determine the success of the treatment such as efficacy and side effects. |
Year(s) Of Engagement Activity | 2017 |