Newly discovered fat cells use a different approach to warm the body

WHite fat stores lipids, brown fat produces heat It warms the body, but beige fat is somewhere in between.¹ However, scientists know little about how this trinity of fat cells differs from each other. Publication in cell metabolismresearcher 10 types of fat cells identified With the help of single-cell RNA-seq.² One of these, the newly discovered beige fat cells, uses an unusual approach to generate heat. Its expression correlates with weight loss in people, and it has been suggested that it may help prevent obesity in some people.

To find out how brown and beige fat cells generate heat, researchers started by studying the cells individually. “Single-cell sequencing is a hot topic,” he said. Umesh Wankadean adipose tissue biologist at the University of Arkansas, was not involved in the study. This method allows scientists to distinguish differences between cells within a population, he explained. Previously, researchers used bulk RNA sequencing to provide a general view of fat cell function. This oversimplification has led to inconsistencies in the literature. For example, conflicting studies suggest that either: beige or brown Fat was the main source of thermogenesis in the human neck.^3,4

Additionally, large amounts of sequencing data have led scientists to the following conclusions: brown and beige fat Cells express uncoupling protein 1 (UCP1), encodes the protein UCP1 that stops adenosine triphosphate (ATP) production in mitochondria; energy dissipated as warmth Instead.^5,6 However, scientists are increasingly recognizing that some brown and beige fat cells do not express UCP1. “We should look at other ways to regulate energy consumption,” he said. christian wolframa molecular biologist at ETH Zurich and co-author of the study.

When Wolfrum and his team performed single-cell RNA sequencing on mouse fat cells, they discovered that there are 10 types of fat cells. These findings extend the limited white, beige, and brown classification scheme. “There are several flavors with different functions that together determine the function of the tissue,” Wolfram said.

Because cold temperatures induce the accumulation of heat-producing brown and beige cells, Wolfram and his team kept mice at 8 degrees Celsius for a week and compared their adipocyte profiles with those kept at room temperature. did. Two subpopulations of beige adipocytes rapidly increased after cold exposure. However, upon closer inspection, the researchers noticed that one of these subpopulations expressed a large number of genes involved in ATP synthesis, suggesting that UCP1 was not shutting down these energy factories. . When the team measured UCP1 They confirmed that most of the beige cell subpopulation lacked this protein. “This finding challenges the long-held idea that UCP1 is required for thermogenesis,” Wankade said. You need to adjust the thermostat with a different mechanism.

Wolfrum’s team hypothesized that beige adipocytes lacking UCP1 use wasteful cycles and are stuck in a loop. biochemical reaction There is no return on investment because molecules such as lipids are synthesized and then broken down again.⁷ They found increased expression of genes associated with wasteful cycles, but proving that these loop reactions are active has proven difficult. Ideally, Wolfram points out, we would track ATP molecules as they enter the cycle. No experimental paradigm exists to prove that ATP goes there. ” Instead, they measured the cells’ respiration rate by tracking their oxygen uptake. Wasted cycles require increased respiration to break down ATP and replenish energy molecules. When cells lacking UCP1 were treated with drugs that inhibit wasteful cycles, the cells consumed less oxygen and respired, indicating that fewer ATP molecules needed to be replaced.

Such biochemical circuits serve dual purposes: generating heat and consuming stored ATP, but it is still unclear which function is their primary function. Either they evolved to keep the body warm, or they adapted to limit the amount of ATP available and produce heat only as a byproduct.

To confirm that these beige fat cells use wasted cycles to keep mice warm, Wolfram and his team created mutant mice lacking this newly identified cell type. The genetically engineered mice were unable to regulate their body temperature for the first eight hours after cold exposure, but then fat cells that use UCP1 took over, shutting down mitochondria and raising body temperature.

To find out whether humans have these UCP1-free cells, the research team used single-cell RNA sequencing on neck tissue taken from 15 healthy volunteers. They found eight subpopulations of fat cells, including a beige type that may function by futile cycling as well. People with a higher proportion of these cells generally have lower fasting blood sugar levels, lower body weight, and higher levels of the appetite-suppressing hormone leptin, suggesting that this cell type may protect against diabetes and stave off obesity. is suggested. However, additional research is needed to investigate the causal relationship.

Dr. Wankade suggested that scientists may one day consider administering these cells to reduce weight gain. “But first and foremost, we need to make sure that this particular population can work outside the body in the absence of a natural environment.” I explained that it can only occur in “To understand more about these cells, we need to perform further functional assays,” he said.

First, Professor Wolfram wants to determine whether these 10 types of mouse fat cells represent interchangeable states, whether they switch back and forth, or whether they represent distinct lineages that serve functions throughout life. Masu. In the future, biologists may continue to use single-cell approaches to uncover details about the dynamic lives of these adipocytes.