Scientists have discovered new fat cell subpopulations with specialized functions, revealing differences between subcutaneous and visceral fat.
A groundbreaking international study, led by scientists from Ben-Gurion University of the Negev, has mapped the diverse populations of fat cells across different human fat tissues. Using advanced technology, researchers identified distinct subpopulations of fat cells with more complex functions than previously understood. They also discovered variations in how fat tissues communicate at the cellular level.
Published in Nature Genetics, these findings lay the foundation for future research aimed at advancing personalized medicine for obesity.
The research team, led by Prof. Esti Yeger-Lotem and Prof. Assaf Rudich from the Department of Clinical Biochemistry and Pharmacology at the Faculty of Health Sciences at Ben-Gurion University of the Negev, in collaboration with Prof. Naomi Habib from the Hebrew University of Jerusalem, Profs. Matthias Bluher, Antje Korner and Martin Gericke from the University of Leipzig, Germany, and Prof. Rinki Murphy from the University of Auckland, New Zealand, studied the diversity of fat cells in subcutaneous and intra-abdominal (visceral) fat tissues in humans.
This study is part of an international effort, The Human Cell Atlas Project, to generate a comprehensive map (“create atlases”) of all types and subtypes of cells that make up the human body, in partnership with many other laboratories around the world.
Innovative RNA Mapping Technology
The study used innovative technology that maps RNA molecules, which are the basis for translating the genome into proteins. The technology is based on attaching a unique single-cell-specific “barcode” to RNA molecules originating from each cell.
Thousands of cells comprising the tissue are thereby barcoded simultaneously enabling to detect cells containing similar subsets of RNA molecules, which belong to the same cell type, and cells with distinct subsets of RNA molecules, that belong to different cell types. Applying the technology to samples of adipose tissue obtained from donors made it possible to identify known types of cells comprising the tissue, such as fat cells, blood vessel cells, immune system cells, and surprisingly – also previously uncharacterized subtypes.
In the last thirty years, our views of fat tissues and fat cells have transformed. In the past, adipose tissue was perceived as a “boring” tissue, whose sole purpose was to store excess energy in the form of fat (triglycerides) and break it down as a readily available energy source for the body.
Today, we know that adipose tissue produces and secretes hundreds of proteins and other substances into the bloodstream, which regulate a wide variety of processes through intercellular communication within the fat tissue, and with the brain, blood vessels, liver, and pancreas tissues. For example, the leptin hormone, produced almost exclusively by fat cells, is a central regulator of appetite, eating, and the rate of energy expenditure, that travels through the bloodstream reaching control centers in the brain.
At the same time, it became clear that adipose tissue is not a single tissue. Instead, fat tissues in separate locations in the body – for example, under the skin, or inside the abdominal cavity and around the internal organs (visceral fat) –function differently and have a diverse impact on health and disease. For example, visceral adipose tissue develops in obesity as a more inflammatory tissue, containing more immune system cells, whose communication with fat cells contributes to the metabolic (diabetes, fatty liver) and cardiovascular complications of obesity.
Diverse Functions of Fat Tissues
“The diversity of fat cells in the different fat tissues in humans is more complex, interesting, and surprising than we previously thought. For example, in addition to the ‘classical’ fat (adipocyte) cells, we found subpopulations of adipocytes, characterized here for the first time, that express RNA molecules indicating unique functions, such as regulation of inflammatory processes, blood vessel formation, extracellular protein deposition, and scarring (fibrosis),” explained Prof. Yeger-Lotem. “After we found them computationally, we were also able to see them under the microscope. We initially thought that these unique cells were created from the classical cells by ‘adopting’ additional, unique functions, but we discovered that the differentiation pathway is actually the opposite: the unique fat cells seem to “lose” their unique functions to become classical fat cells.”
Searching for the source of the differences between subcutaneous and visceral fat, the researchers found that most of the fat cell subpopulations were similar between subcutaneous and intra-abdominal fat. Nevertheless, significant, albeit more subtle, differences were identified between fat cells from the two tissues.
For example, intercellular communication in the two tissues differs: fat cells in the intra-abdominal tissue express genes indicating more active communication with immune system cells within the tissue and are involved in pro-inflammatory processes. In contrast, in subcutaneous fat, fat cells communicate more with each other and participate in anti-inflammatory processes. In addition, one of the unique types of fat cells, discovered for the first time in this study, appeared only in the intra-abdominal tissue.
“The new insights into the cellular composition and function of human fat tissues provide a basis for further applied research aimed at promoting personalized medicine in obesity,” explains Prof. Rudich. “We found that the prevalence of the unique fat cells we identified was related to the metabolic complications of obesity: their relative proportion in the tissue is higher the more severe the insulin resistance is. If it turns out that the prevalence of unique fat cells also predicts the degree of personal risk for future development of obesity complications, and/or can predict the individual response to treatment – the findings may have great significance in the pursuit of more personalized treatment for obesity. To this end, we are already working to develop tools that can bring our findings to clinical medicine, for example, developing microscopic examinations of fat tissue and identifying unique fat cells by a clinical pathologist.”
Reference: “Human subcutaneous and visceral adipocyte atlases uncover classical and nonclassical adipocytes and depot-specific patterns” by Or Lazarescu, Maya Ziv-Agam, Yulia Haim, Idan Hekselman, Juman Jubran, Ariel Shneyour, Habib Muallem, Alon Zemer, Marina Rosengarten-Levin, Daniel Kitsberg, Liron Levin, Idit F. Liberty, Uri Yoel, Oleg Dukhno, Miriam Adam, Julia Braune, Claudia Müller, Nora Raulien, Martin Gericke, Antje Körner, Rinki Murphy, Matthias Blüher, Naomi Habib, Assaf Rudich and Esti Yeger-Lotem, 24 January 2025, Nature Genetics.
DOI: 10.1038/s41588-024-02048-3
This research was supported by the Chan-Zuckerberg Initiative through the Human Cell Atlas Project, and by the German Research Foundation (DFG).
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