Targeting the serotonergic pathway in humans to treat metabolic disease
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Cardiovascular Science
Abstract
The number of people who are overweight or obese continues to rise. Obesity is associated with other conditions such as high blood pressure, type 2 diabetes and heart disease. Therefore, new treatments for obesity are urgently required. While most treatments for obesity aim to reduce the amount of food we eat, an alternative approach is to increase the amount of energy we burn. There is a special type of fat tissue in our bodies called brown fat. Brown fat's role is to burn energy to make heat to keep us warm when we are in a cold environment. Developing new treatments to activate brown fat is a new strategy to try to treat obesity and the associated conditions. However, we do not fully understand how brown fat activation is controlled.
In this research we are determining how a substance in the body called serotonin controls how brown fat is activated. Serotonin is very important in the brain and controls different processes in the body such as our mood and our appetite. We will recruit healthy volunteers to different studies to test how altering their serotonin levels controls their brown fat activity. We will measure brown fat activity using different techniques such as PET imaging (which we use to see the active brown fat deep in the body), infrared imaging (which measures the heat produced by brown fat) and microdialysis (where we place special tubes in brown fat to measure the substances it uses and produces). We will also determine how serotonin alters energy expenditure by human brown fat cells in culture. By understanding how serotonin controls how much energy we burn, we may be able to identify new treatments for obesity that increase our energy expenditure.
In this research we are determining how a substance in the body called serotonin controls how brown fat is activated. Serotonin is very important in the brain and controls different processes in the body such as our mood and our appetite. We will recruit healthy volunteers to different studies to test how altering their serotonin levels controls their brown fat activity. We will measure brown fat activity using different techniques such as PET imaging (which we use to see the active brown fat deep in the body), infrared imaging (which measures the heat produced by brown fat) and microdialysis (where we place special tubes in brown fat to measure the substances it uses and produces). We will also determine how serotonin alters energy expenditure by human brown fat cells in culture. By understanding how serotonin controls how much energy we burn, we may be able to identify new treatments for obesity that increase our energy expenditure.
Technical Summary
The continuing rise in the prevalence of obesity and associated metabolic disease highlights the need for new treatments. Pharmacotherapy for obesity has mainly focused on limiting food intake and been largely ineffective. An alternative approach is to increase energy expenditure and the recent identification of brown adipose tissue (BAT) in adult humans has highlighted the potential to activate BAT as a novel treatment for metabolic disease. However, most of our knowledge of BAT is based on data from rodents and we have recently identified substantial species-specific differences in the regulation of BAT activation. This underlines the need to study this physiology in humans to understand how to activate BAT as a novel therapeutic strategy.
We have discovered high expression of the serotonin transporter (SERT) in human BAT and that inhibition of SERT enhances serotonin-induced suppression of human brown adipocyte activation. We will perform three separate in vivo experimental medicine and parallel in vitro studies to dissect serotonergic signalling in human BAT and determine whether manipulation of this pathway is a novel therapeutic strategy to treat metabolic disease. These studies will investigate 3 key aspects of this biology by inhibiting 1) the SERT transporter, 2) the serotonin receptor and 3) peripheral serotonin synthesis. To measure the effect on BAT activity and wider metabolism we will use a combination of in vivo techniques we have developed such as PET/MR scanning, thermal imaging, microdialysis, indirect calorimetry and stable isotope infusions and in vitro techniques such as primary human adipocyte culture, cell sorting and respirometry. In addition, we will develop an entirely novel in vivo technique using microdialysis to directly administer drugs to human BAT and quantify activation using PET/CT. This research may reveal a novel approach to treat obesity and associated metabolic disease by reducing peripheral serotonin action.
We have discovered high expression of the serotonin transporter (SERT) in human BAT and that inhibition of SERT enhances serotonin-induced suppression of human brown adipocyte activation. We will perform three separate in vivo experimental medicine and parallel in vitro studies to dissect serotonergic signalling in human BAT and determine whether manipulation of this pathway is a novel therapeutic strategy to treat metabolic disease. These studies will investigate 3 key aspects of this biology by inhibiting 1) the SERT transporter, 2) the serotonin receptor and 3) peripheral serotonin synthesis. To measure the effect on BAT activity and wider metabolism we will use a combination of in vivo techniques we have developed such as PET/MR scanning, thermal imaging, microdialysis, indirect calorimetry and stable isotope infusions and in vitro techniques such as primary human adipocyte culture, cell sorting and respirometry. In addition, we will develop an entirely novel in vivo technique using microdialysis to directly administer drugs to human BAT and quantify activation using PET/CT. This research may reveal a novel approach to treat obesity and associated metabolic disease by reducing peripheral serotonin action.
Planned Impact
This project will determine whether circulating and tissue serotonin levels are an important regulator of brown adipose tissue function and wider metabolic health in humans. This research may then identify manipulation of this pathway as novel treatment strategy for obesity and associated metabolic diseases such as type 2 diabetes and dyslipidaemia. We will inhibit several different key steps in the serotonergic pathway to determine the best target for therapeutic manipulation and this research may, in time, lead to the development of new medications to treat obesity and associated metabolic disease.
In addition, this research may identify a novel mechanism through which certain antidepressants cause adverse side effects such as weight gain and type 2 diabetes mellitus. At present, the mechanisms responsible for this are unknown so identifying the cause is extremely important to many patients taking these medications. This research could then highlight the need to use alternative antidepressants which cause fewer adverse metabolic side effects and prevent the negative health consequences associated with obesity and type 2 diabetes mellitus.
Activating brown adipose tissue is an exciting new strategy to treat obesity and associated metabolic disease, however our understanding of how this tissue is activated is limited in part by the number of techniques available to study BAT activation. This research may develop an entirely new technique to specifically activate and measure brown adipose tissue activity in humans, which could be used in the future by the wider research community to improve understanding of human brown adipose tissue physiology and importantly test the efficacy of new drugs to activate this tissue. This technique may speed up the development of new medications by providing a technique to specifically activate the tissue in humans.
Finally, this research may create a new technique to be able to specifically culture human brown adipocytes. This could benefit the wider research community and pharmaceutical industry by improving this cell culture model and make results using this technique more reproducible. This would improve our ability to test the efficacy of novel medications to activate human brown adipocytes in vitro, which could improve selection of appropriate candidates for subsequent in vivo testing.
In addition, this research may identify a novel mechanism through which certain antidepressants cause adverse side effects such as weight gain and type 2 diabetes mellitus. At present, the mechanisms responsible for this are unknown so identifying the cause is extremely important to many patients taking these medications. This research could then highlight the need to use alternative antidepressants which cause fewer adverse metabolic side effects and prevent the negative health consequences associated with obesity and type 2 diabetes mellitus.
Activating brown adipose tissue is an exciting new strategy to treat obesity and associated metabolic disease, however our understanding of how this tissue is activated is limited in part by the number of techniques available to study BAT activation. This research may develop an entirely new technique to specifically activate and measure brown adipose tissue activity in humans, which could be used in the future by the wider research community to improve understanding of human brown adipose tissue physiology and importantly test the efficacy of new drugs to activate this tissue. This technique may speed up the development of new medications by providing a technique to specifically activate the tissue in humans.
Finally, this research may create a new technique to be able to specifically culture human brown adipocytes. This could benefit the wider research community and pharmaceutical industry by improving this cell culture model and make results using this technique more reproducible. This would improve our ability to test the efficacy of novel medications to activate human brown adipocytes in vitro, which could improve selection of appropriate candidates for subsequent in vivo testing.
Publications
Choong K
(2021)
The serotonin transporter SLC6A4 protects human brown adipose tissue from serotonin-mediated suppression of thermogenesis.
in Endocrine Abstracts
Choong K
(2023)
Human brown adipose tissue activity is regulated by the parasympathetic nervous system
in Endocrine Abstracts
Choong K
(2021)
Measurements of skin temperature in lean and obese humans at thermoneutrality and following cold exposure
in Endocrine Abstracts
Choong K
(2022)
UCP1 expression in human brown adipose tissue is inversely associated with cardiometabolic risk factors
in Endocrine Abstracts
Kwok T
(2023)
OR07-03 UCP1 Expression In Human Brown Adipose Tissue Is Inversely Associated With Cardiometabolic Risk Factors
in Journal of the Endocrine Society
Kwok TC
(2023)
Human brown adipose tissue function: insights from current in vivo techniques.
in The Journal of endocrinology
McNeill B
(2023)
FRI025 Succinate Receptor Activation Increases Respiration In Human But Not Murine Brown Adipocytes
in Journal of the Endocrine Society
McNeill BT
(2020)
Substrate Utilization by Brown Adipose Tissue: What's Hot and What's Not?
in Frontiers in endocrinology
McNeill BT
(2021)
MECHANISMS IN ENDOCRINOLOGY: Human brown adipose tissue as a therapeutic target: warming up or cooling down?
in European journal of endocrinology
Suchacki K
(2023)
The serotonin transporter sustains human brown adipose tissue thermogenesis
in Nature Metabolism
Suchacki K
(2022)
Human brown adipose tissue demonstrates substantial choline uptake for incorporation into phosphatidylcholines
in Endocrine Abstracts
Suchacki K
(2021)
A Systems-Level Analysis of Total-Body PET Data Reveals Complex Skeletal Metabolism Networks in vivo
in Frontiers in Medicine
Suchacki KJ
(2022)
The diverse and distinct roles of adipose tissue on metabolic heath
Suchacki KJ
(2021)
Nutritional Regulation of Human Brown Adipose Tissue.
in Nutrients
Suchacki, KJ
(2020)
Serotonin suppresses brown adipose tissue activation in humans.
Description | Panel member of the Chief Scientist Office postdoctoral fellowship committee |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | We awarded 4 highly promising postdoctoral researchers fellowships in 2022 and will do again this year. |
URL | https://www.cso.scot.nhs.uk/fellowship-funding/early-postdoctoral-fellowship/ |
Description | Participation in Society for Endocrinology Clinical Research Strategy working group to identify priorities for funding endocrine research in the UK |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Description | Participation in Society for Endocrinology working group to develop the Careers Skills sessions for clinical and basic science PhD and postdoctoral researchers |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | Society for endocrinology leadership and development committee work |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
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 | Development of a LC-MS assay to quantify multiple metabolic intermediates to assess thermogenesis. |
Amount | £4,991 (GBP) |
Funding ID | BT-000087 |
Organisation | The Bioscientifica Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2022 |
End | 08/2022 |
Description | Dissecting thermogenesis by brown adipose tissue and skeletal muscle in lean and obese subjects |
Amount | £1,110,785 (GBP) |
Funding ID | MR/W01937X/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2022 |
End | 03/2025 |
Description | Parasympathetic regulation of brown adipose tissue, a novel therapeutic target for type 2 diabetes. |
Amount | £8,000 (GBP) |
Organisation | J T Borland Charitable Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2020 |
End | 11/2021 |
Description | The extracellular matrix remodelling and receptor activation drives adipose tissue malfunction in obesity |
Amount | £329,367 (GBP) |
Funding ID | 21/0006329 |
Organisation | Diabetes UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2022 |
End | 12/2024 |
Description | The role of matrix-gla protein (MGP) in brown adipose tissue |
Amount | £9,968 (GBP) |
Organisation | Society for Endocrinology |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2022 |
End | 11/2023 |
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 | 09/2023 |
End | 09/2027 |
Description | Towards a novel treatment targeting obesity in women with polycystic ovary syndrome (PCOS) |
Amount | £468,272 (GBP) |
Funding ID | MR/W015439/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2021 |
End | 03/2024 |
Description | Wellcome Trust institutional translational partnership award |
Amount | £18,000 (GBP) |
Organisation | University of Edinburgh |
Sector | Academic/University |
Country | United Kingdom |
Start | 11/2020 |
End | 10/2021 |
Description | Collaboration with Cecile Benezech on B cells in obesity |
Organisation | University of Edinburgh |
Department | Queen's Medical Research Institute Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have provided human adipose tissue for analysis of B cells in obesity and diabetes |
Collaborator Contribution | They have undertaken the murine work looking at the effect of diet induced obesity and the microbiome on B cell function |
Impact | Wellcome Trust funded PhD |
Start Year | 2022 |
Description | Collaboration with Colin Duncan to look at inhaled insulin in PCOS patients. |
Organisation | University of Edinburgh |
Department | MRC Centre for Reproductive Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We bring expertise in experimental medicine techniques and study design/ management along with use of some of our equipment. |
Collaborator Contribution | They will run the study and bring expertise in PCOS. |
Impact | MRC grant awarded commenced 2021, PI Colin Duncan and co-I Roland Stimson. |
Start Year | 2021 |
Description | Collaboration with Dr Mark Nixon regarding tissue cortisol delivery |
Organisation | University of Edinburgh |
Department | Queen's Medical Research Institute Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have taught their team how to perform primary culture of adipocytes, in addition to advising on their protocol to improve the clinical relevance of this project. |
Collaborator Contribution | They are undertaking the murine in vivo work to dissect the mechanism of action. |
Impact | We have been awarded a BHF project grant to undertake this work. |
Start Year | 2023 |
Description | Collaboration with Mandy Drake regarding epigenetic regulation of brown adipose tissue |
Organisation | University of Edinburgh |
Department | Centre for Cardiovascular Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have collaborated with Dr Drake to help design, undertake and interpret the effects of cold exposure on epigenetic markers in adipose tissue. We aided our collaborator in obtaining an early career award to undertake this research project. |
Collaborator Contribution | They have performed rodent in vivo and in vitro experiments. |
Impact | The PhD student (Bonnie Nicholson) obtained an early career grant for ~£10000 from the Society for Endocrinology to undertaker this project. An original research article is under review. |
Start Year | 2019 |
Description | Collaboration with Shingo Kajimura |
Organisation | Harvard University |
Department | Harvard Medical School |
Country | United States |
Sector | Academic/University |
PI Contribution | We are undertaking the human research aspects of this project |
Collaborator Contribution | They are undertaking the murine in vivo work relating to this project |
Impact | Nil to date |
Start Year | 2022 |
Description | Collaboration with Will Cawthorn regarding caloric restriction in mice |
Organisation | University of Edinburgh |
Department | Queen's Medical Research Institute Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have provided support on protocol development, data analysis and interpretation |
Collaborator Contribution | They undertook the murine in vivo work and analysis of the human data |
Impact | Nil to date |
Start Year | 2021 |
Description | Comment on new technique to activate brown fat activity for 'The Scientist' magazine |
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 | Media (as a channel to the public) |
Results and Impact | I was contacted as a relevant expert in the area to read and discuss the strengths/ weaknesses of a new approach to activate brown fat that was to be published in Cell to time with the press release. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.the-scientist.com/news-opinion/heat-may-melt-away-white-fat-69773 |
Description | Daily Mail article on cold exposure and metabolic health |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Email interview with journalist for the Daily Mail about the potential for cold exposure and brown fat activation to improve metabolic health. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.dailymail.co.uk/health/article-9135949/The-cold-truth-losing-weight-keeping-germ-free.ht... |
Description | Demonstration at the Edinburgh Science festival entitled 'The many faces of fat'. |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | We were awarded local funds to prepare an activity for the Edinburgh Science Festival to publicise the positive role of fat as evidenced by our work on brown adipose tissue, along with other researchers in our institute promoting the benefits of other adipose tissue depots. We created this activity for the Science festival which was then cancelled due to covid, we will be able to undertake this activity at the next Edinburgh Science Festival. |
Year(s) Of Engagement Activity | 2021 |
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 | School interview on STEM to encourage engagement and careers in sicence |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Invited interview with Down House school for girls discussing my career, specifically my role, highlights, positive experiences, insights and tips on how to succeed in this career. This led to a magazine article. |
Year(s) Of Engagement Activity | 2023 |