Leading international research from Ben-Gurion University discovers unique subpopulations of fat cells and provides innovative treatment approaches to prevent obesity complications
A new international study led by scientists from Ben-Gurion University of the Negev has characterized the populations of fat cells in different adipose tissues in the human body. Using cutting-edge technology, the researchers were able to identify for the first time unique subpopulations of fat cells, with putative functions more complex than previously known, and even identified differences between human adipose tissues in intercellular communication. The findings were published in the prestigious journal Nature Genetics, and form the basis for further research to promote personalized medicine in obesity.
The research team led by Prof. Estee Yager-Lotem and Prof. Assaf Rodich from the Department of Clinical Biochemistry and Pharmacology in the Faculty of Health Sciences at Ben-Gurion University of the Negev, in collaboration with researchers from the Hebrew University of Jerusalem, Leipzig, Germany, and Auckland, New Zealand, studied the diversity of fat cells in human subcutaneous and intra-abdominal adipose tissue. This study is part of an international effort to map all the types and subtypes of cells that make up the human body (The Human Cell Atlas Project), which has many other laboratories around the world as partners.
The study used cutting-edge technology that maps the molecules of RNA which form the basis for building proteins. The technology is based on attaching a unique "barcode" to all molecules of the RNA originating from the same cell, simultaneously for many thousands of cells produced from the same tissue. Thus, it is possible to classify according to the molecules of RNA From each cell, the different cell types that make up the tissue under study. Applying the technology to samples of adipose tissue obtained from donors made it possible to identify known types of cells found in the tissue, such as fat cells, blood vessel cells, immune system cells, and surprisingly – also subtypes that had not been characterized before.
In the last thirty years, there has been a revolution in the way we view adipose tissue and fat cells in particular. In the past, adipose tissue was seen as a "boring" tissue, whose sole purpose was to store excess energy in the form of fat (triglycerides) and break them down as an available energy source for the body. Today, we know that adipose tissue produces and secretes into the bloodstream hundreds of proteins and other substances, which control a wide variety of processes through communication with the brain, blood vessels, liver, and pancreas. For example, the hormone leptin, which is produced almost exclusively by fat cells, is a central controller of appetite, eating, and the rate of energy expenditure through communication through the bloodstream with the brain's control centers.
At the same time, it turned out that adipose tissue is not a single tissue, and that adipose tissue in different locations in the body – for example, under the skin, as opposed to inside the abdominal cavity and around the internal organs (visceral fat), are tissues that function differently and have different effects, both in healthy and diseased states. For example, visceral adipose tissue develops in obesity as a more inflammatory tissue, containing more immune system cells, the communication between which and fat cells contributes to the complications of obesity, especially metabolic (diabetes, fatty liver) and in the cardiovascular system.
"The diversity of fat cells in the different adipose tissues in humans is more complex, interesting and surprising than we thought. For example, in addition to the "classical" fat cells, we found populations of fat cells, characterized here for the first time, that express RNA molecules that indicate unique functions such as controlling inflammatory processes, blood vessel formation, deposition of extracellular proteins and scarring (fibrosis)," explained Prof. Yager-Lotem. "After we found them computationally, we were also able to detect them in microscopic examinations. We thought that the unique cells were created from the classic cells by "adopting" additional, unique functions, but we discovered that the differentiation pathway was actually the opposite - from the unique fat cells to the classic ones, while "losing" the unique functions."
In searching for the source of the differences between subcutaneous and visceral fat, it was found that most subpopulations of fat cells are found in both subcutaneous and intra-abdominal fat, but significant, albeit more subtle, differences were identified between fat cells from the two tissues. For example, intercellular communication in the two tissues was different: fat cells in intra-abdominal tissue expressed genes indicating more active communication with immune system cells in the tissue and involvement 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 intra-abdominal tissue.
"The new insights into the cellular composition and function of human adipose tissue form the basis for further applied research, the purpose of which is to promote more personalized medicine in obesity," explains Prof. Rodich. "We found that the prevalence of the unique fat cells we identified is related to the metabolic complications of obesity: their relative proportion in the tissue is higher the more severe the insulin resistance. If it turns out that the prevalence of unique fat cells also predicts the degree of individual risk of developing obesity complications over time, 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 adipose tissue and identifying unique fat cells by a pathologist."
The research team included from Ben-Gurion University the research group of Prof. Esti Yager Lotem, led by doctoral students Or Lazarsko and Maya Ziv-Agam together with Dr. Idan Hexelman, Dr. Juman Joubran and Ariel Shneur, the research group of Prof. Assaf Rodich led by doctoral students Or Lazarsko and Maya Ziv-Agam together with Dr. Idan Hexelman and Dr. Juman Joubran and Mr. Ariel Shneur, the research group of Prof. Assaf Rodich, led by Dr. Yulia Haim and with the contribution of doctoral students Habib Mualem, Marina Rosengarten-Levin and Alon Zemer, Dr. Liron Levin from the Bioinformatics Unit, and the physicians members of the Faculty of Health Sciences and employees of Soroka University Medical Center – Dr. Uri Yoel, Dr. Idit Liberty, and Dr. Oleg Dohno. From the Hebrew University, Prof. Naomi Habib's group participated. International partners were from the University of Leipzig in Germany, and the University of Auckland in New Zealand.
This research was supported by the Chan Zuckerberg Foundation through the Human Cell Atlas project, and by the German Science Foundation.
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