Periodic Reporting for period 1 - IMMUNOBAT (Elucidating the crosstalk between the immune system and brown adipose tissue in humans)
Reporting period: 2022-05-01 to 2025-06-30
Brown fat, also called brown adipose tissue (BAT), is a special type of fat in our bodies that relates to better cardiometabolic health. However, in people with obesity, BAT seems to be dysfunctional. Therefore, it is important to understand what mechanisms regulate human BAT (hBAT) and to find new ways and strategies to improve it.
Research in mice has shown that immune cells - the cells that normally protect us from infections - also play a role in controlling how BAT works. For example, certain immune cells can help activate BAT when exposed to cold temperatures. But in humans, we still do not fully know which immune cells are involved, or whether they could be targeted to make BAT more active and healthier.
The IMMUNOBAT project set out to answer three main questions:
1. Which immune cells are found inside hBAT?
2. Is there inflammation in the hBAT of people with obesity, and does this explain why it works less efficiently?
3. Can cold exposure (for three months) improve BAT activity in people with obesity, and is this linked to changes in hBAT immune cells?
Through this project, we hoped to understand how immune cells and BAT interact in humans, why BAT is less active in obesity, and how cold exposure could be used as a strategy to improve cardiometabolic health.
Research in mice has shown that immune cells - the cells that normally protect us from infections - also play a role in controlling how BAT works. For example, certain immune cells can help activate BAT when exposed to cold temperatures. But in humans, we still do not fully know which immune cells are involved, or whether they could be targeted to make BAT more active and healthier.
The IMMUNOBAT project set out to answer three main questions:
1. Which immune cells are found inside hBAT?
2. Is there inflammation in the hBAT of people with obesity, and does this explain why it works less efficiently?
3. Can cold exposure (for three months) improve BAT activity in people with obesity, and is this linked to changes in hBAT immune cells?
Through this project, we hoped to understand how immune cells and BAT interact in humans, why BAT is less active in obesity, and how cold exposure could be used as a strategy to improve cardiometabolic health.
During the IMMUNOBAT project, I was actively involved in a broad range of tasks. In the first two years, I contributed to the design, planning, and implementation of the clinical trial. My responsibilities included participant recruitment and medical screening, experimental testing, collection and processing of biological samples, dataset creation, data integration, and both statistical and computational analyses. I was also engaged in scientific writing and dissemination activities. Through these efforts, we successfully assessed 28 lean healthy participants and 24 participants with obesity. In addition, I supported the cold intervention study, in which 11 participants with obesity completed the protocol.
In the later phase of my fellowship, I focused more on the project’s in vitro experiments. Since the required infrastructure was initially lacking, I contributed to establishing a wet laboratory to enable these studies. The experimental work included processing hBAT samples for single-cell omics analyses and developing a new model of brown adipocytes, designed to investigate how chronic inflammation influences hBAT regulation.
As a result, we generated the largest single-cell atlas of hBAT to date, analyzing approximately 130,000 cells from samples obtained from 6 lean volunteers and 7 volunteers with obesity. This dataset provides unique insights into hBAT’s cellular composition, the regulatory pathways governing its function, the interactions between different cell types, and the differences between lean and obese individuals. Overall, we identified several thermogenic and non-thermogenic adipocyte populations, as well as diverse immune cell subpopulations. Interestingly, despite the reduced metabolic activity of hBAT in obesity, we found no major differences in overall cell composition between the two groups.
In addition, we developed the first immune single-cell atlas of human brown fat, comprising about 80,000 cells from 6 lean and 6 obese participants. This resource enables the study of which immune cells are present in hBAT and how they may influence its metabolic function in health and obesity. Notably, we found marked heterogeneity in immune cell composition across individuals. Importantly, we identified specific immune cell clusters (validation pending) that were associated with higher hBAT metabolic activity, highlighting potential cellular targets for improving hBAT function.
We also analyzed hBAT samples collected before and after one of the longest human cold-exposure interventions conducted to date (3 months). This provided novel insights into how immune cells, adipocytes, and other hBAT cell types adapt to prolonged cold exposure. Notably, there was substantial inter-individual variability in the cold-acclimation response. An interesting trend emerged: participants with higher BMI tended to show reduced hBAT metabolic activity after the intervention, whereas those with lower BMI showed an increase. When stratifying participants into two groups (BMI <31 kg/m² and BMI >37 kg/m²), we observed that individuals in the lower-BMI group generally increased hBAT metabolic activity, while those in the higher-BMI group decreased it. These findings suggest that cold acclimation may be more effective in individuals with obesity whose hBAT and mitochondrial dysfunction is not yet too advanced.
Finally, we established a new laboratory model: a 3D culture system of human primary brown adipocytes. This model enables controlled investigation of the mechanisms regulating hBAT function and has potential applications in future drug screening.
In the later phase of my fellowship, I focused more on the project’s in vitro experiments. Since the required infrastructure was initially lacking, I contributed to establishing a wet laboratory to enable these studies. The experimental work included processing hBAT samples for single-cell omics analyses and developing a new model of brown adipocytes, designed to investigate how chronic inflammation influences hBAT regulation.
As a result, we generated the largest single-cell atlas of hBAT to date, analyzing approximately 130,000 cells from samples obtained from 6 lean volunteers and 7 volunteers with obesity. This dataset provides unique insights into hBAT’s cellular composition, the regulatory pathways governing its function, the interactions between different cell types, and the differences between lean and obese individuals. Overall, we identified several thermogenic and non-thermogenic adipocyte populations, as well as diverse immune cell subpopulations. Interestingly, despite the reduced metabolic activity of hBAT in obesity, we found no major differences in overall cell composition between the two groups.
In addition, we developed the first immune single-cell atlas of human brown fat, comprising about 80,000 cells from 6 lean and 6 obese participants. This resource enables the study of which immune cells are present in hBAT and how they may influence its metabolic function in health and obesity. Notably, we found marked heterogeneity in immune cell composition across individuals. Importantly, we identified specific immune cell clusters (validation pending) that were associated with higher hBAT metabolic activity, highlighting potential cellular targets for improving hBAT function.
We also analyzed hBAT samples collected before and after one of the longest human cold-exposure interventions conducted to date (3 months). This provided novel insights into how immune cells, adipocytes, and other hBAT cell types adapt to prolonged cold exposure. Notably, there was substantial inter-individual variability in the cold-acclimation response. An interesting trend emerged: participants with higher BMI tended to show reduced hBAT metabolic activity after the intervention, whereas those with lower BMI showed an increase. When stratifying participants into two groups (BMI <31 kg/m² and BMI >37 kg/m²), we observed that individuals in the lower-BMI group generally increased hBAT metabolic activity, while those in the higher-BMI group decreased it. These findings suggest that cold acclimation may be more effective in individuals with obesity whose hBAT and mitochondrial dysfunction is not yet too advanced.
Finally, we established a new laboratory model: a 3D culture system of human primary brown adipocytes. This model enables controlled investigation of the mechanisms regulating hBAT function and has potential applications in future drug screening.
The IMMUNOBAT project has moved research on hBAT a big step forward. Until now, very little was known about BAT cell composition and how works in people, especially in those with obesity.
With IMMUNOBAT, we have for the first time created a detailed “map” of the different cells inside hBAT, including immune cells. This is important because studies in animals suggest that immune cells play a key role in controlling how well brown fat works. Understanding this in humans may help us find new ways to activate BAT, either through medicines or lifestyle approaches.
We also tested a Nordic tradition - cold-water immersion - to see if it can improve BAT activity in people with obesity. Results showed that in some participants (“responders”) BAT metabolic activity increased, while in others it decreased. Overall, there were no clear improvements in blood sugar, cholesterol, or other health markers after 3 months, which means longer, or stronger programs may be needed.
In addition to advancing science, participants benefited directly. They received very detailed health check-ups, reports about their metabolism and lifestyle, and personalized feedback. This helped raise awareness about their health and provided advice for positive changes.
Looking ahead, more research is needed to understand how to safely and effectively activate hBAT, and whether this can truly improve overall health. If successful, such approaches could provide affordable ways to help reduce obesity and related diseases, which remain major health challenges worldwide.
With IMMUNOBAT, we have for the first time created a detailed “map” of the different cells inside hBAT, including immune cells. This is important because studies in animals suggest that immune cells play a key role in controlling how well brown fat works. Understanding this in humans may help us find new ways to activate BAT, either through medicines or lifestyle approaches.
We also tested a Nordic tradition - cold-water immersion - to see if it can improve BAT activity in people with obesity. Results showed that in some participants (“responders”) BAT metabolic activity increased, while in others it decreased. Overall, there were no clear improvements in blood sugar, cholesterol, or other health markers after 3 months, which means longer, or stronger programs may be needed.
In addition to advancing science, participants benefited directly. They received very detailed health check-ups, reports about their metabolism and lifestyle, and personalized feedback. This helped raise awareness about their health and provided advice for positive changes.
Looking ahead, more research is needed to understand how to safely and effectively activate hBAT, and whether this can truly improve overall health. If successful, such approaches could provide affordable ways to help reduce obesity and related diseases, which remain major health challenges worldwide.