Body weight and body mass index (BMI) don’t solely determine the likelihood of developing metabolic diseases. New research featuring an atlas of cells found in fat tissue sheds light on why some people with obesity remain healthy while others face health issues.
Even though individuals with obesity have a higher chance of developing conditions such as diabetes, hypertension, or high cholesterol, not all of them will experience these metabolic disorders. In fact, about 25% of obese individuals are considered healthy. Scientists are investigating the reasons behind the differing health outcomes in those who are obese.
A recent extensive study conducted by researchers from Zurich and Leipzig has made significant contributions to understanding this issue. They created a detailed atlas using data from both healthy and unhealthy overweight individuals, focusing on their fat (adipose) tissue and the gene activity occurring in those cells. “Our findings can assist in identifying cell markers that indicate the likelihood of developing metabolic diseases,” states Adhideb Ghosh, a researcher within ETH Professor Christian Wolfrum’s team and one of the lead authors. “This data is also valuable for fundamental research and could lead to new treatment options for metabolic diseases.”
Exploring a large biobank
In their study, Ghosh and his colleagues utilized the Leipzig Obesity Biobank, which contains a vast array of biopsies from obese patients. Compiled by University of Leipzig scientists, these samples were sourced from obese individuals who agreed to donate adipose tissue during planned surgical procedures. The biobank includes comprehensive medical records related to the patients’ health.
Because the collected tissue samples come from both healthy and unhealthy obese individuals, they allow for meaningful comparisons. The researchers studied samples from 70 volunteers to assess which genes were active and to what extent, examining two types of adipose tissue: subcutaneous (under the skin) and visceral (deep abdominal fat).
Medical experts believe that visceral fat, found deep in the abdomen and surrounding vital organs, is primarily linked to metabolic diseases, while subcutaneous fat is generally seen as less harmful.
A crucial aspect of the study involved ensuring that adipose tissue cells were not combined indiscriminately since this tissue comprises various cell types alongside fat cells (adipocytes). “In fact, adipocytes are comparatively rare,” notes Isabel Reinisch, a postdoc in Wolfrum’s group and co-lead author. A significant portion of adipose tissue consists of immune cells, blood vessel cells, and immature precursor cells of adipocytes. Additionally, mesothelial cells, which are located only in visceral adipose tissue, help delineate its outer boundary.
Changes in abdominal fat
The researchers identified notable functional alterations in the visceral adipose tissue cells of individuals with metabolic diseases, affecting nearly all cell types within this tissue. For instance, genetic tests revealed that the adipocytes in unhealthy individuals became less efficient at burning fats and produced more immunological signaling molecules. “These substances provoke an immune response in the visceral fat of obese individuals,” explains Reinisch. “It’s possible that this immune response contributes to the onset of metabolic diseases.”
Furthermore, the researchers observed distinct variations in the number and functioning of mesothelial cells: Healthy obese individuals exhibited a higher proportion of mesothelial cells in their visceral fat, which displayed greater functional versatility. These cells can adapt to a stem cell-like state, allowing them to transform into different cell types, such as adipocytes, in healthy individuals. “This ability of fully differentiated cells to revert to stem cells is typically associated with cancer,” remarks Reinisch. Thus, she was intrigued to discover this flexibility in adipose tissue as well. “We suspect that these adaptable cells at the edges of adipose tissue in healthy obese individuals facilitate smooth tissue expansion.”
Lastly, the study uncovered gender-specific differences: a particular kind of progenitor cell exists solely in the visceral fat of women. “This might help to explain the variances in the development of metabolic diseases seen between men and women,” Reinisch adds.
Searching for new biomarkers
This new atlas detailing gene activity in overweight people outlines the composition and function of various cell types within adipose tissue. “However, we cannot determine if these differences are responsible for a person’s metabolic health or if metabolic diseases alter these features,” Ghosh clarifies. Instead, the scientists view this research as a foundational step for future investigations. They have made all their findings available through a public web app for other researchers to utilize.
Importantly, this atlas enables the discovery of new markers that can indicate the risk of developing metabolic diseases. Currently, ETH researchers are actively seeking such markers, which may help improve disease management. There is a new class of drugs designed to suppress appetite and stimulate insulin production in the pancreas, yet these medications are limited in availability. “Biomarkers derived from our data could help pinpoint patients who would benefit the most from this treatment,” notes Reinisch.
