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.

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.

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.
 
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 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 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 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 Dr Tavares to explore metabolic networks in mice. 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution We contributed our PET analysis techniques and undertook analysis of various regions of interest to identify these networks
Collaborator Contribution They performed the in vivo murine studies
Impact Original manuscript under review
Start Year 2020
 
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 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