Targeting the serotonergic pathway in humans to treat metabolic disease

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.

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.

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.