Newly Found Fat Cell Uses a Different Approach to Heat the Body  

ABOVE: A newly-discovered type of beige fat cell warms the body and may protect against obesity. ©ISTOCK, metamorworks

White fat stores lipids, brown fat generates heat that warms the body, and beige fat exists somewhere in between.¹ However, scientists know little more about how this trinity of adipose cells differ from one another. Publishing in Cell Metabolism, researchers identified 10 different type of fat cells with the help of single-cell RNA sequencing.² One of these, a newly-discovered beige fat cell, uses an unusual approach to generate heat. Its expression was correlated with lower weight in people, suggesting it may help to prevent obesity in some individuals. 

To explore how brown and beige adipocytes generate heat, the researchers started by studying the cells individually. “Single-cell sequencing has been the talk of the town,” said Umesh Wankhade, an adipose tissue biologist at the University of Arkansas who was not involved the work. The method allows scientists to tease apart differences between cells within a population, he explained. In the past, researchers used bulk RNA sequencing, offering a generalized view of adipose cell functions. This oversimplification led to discrepancies in the literature. For example, conflicting studies suggested that either beige or brown fat were the predominant generators of heat in the human neck.^3,4

Moreover, bulk sequencing data led scientists to conclude that brown and beige fat cells express uncoupling protein 1 (Ucp1), which encodes the protein UCP1 that halts adenosine triphosphate (ATP) production inside mitochondria, causing the energy to dissipate as warmth instead.^5,6 However, scientists have increasingly recognized that some brown and beige adipocytes do not express UCP1. “We should look at other ways in which energy expenditure is modulated,” said Christian Wolfrum, a molecular biologist at ETH Zürich and study coauthor.

When Wolfrum and his team used single-cell RNA sequencing on mouse fat cells they found that adipocytes came in 10 varieties. These findings expand the limited white, beige, and brown classification schema. “There are several flavors with different functions that taken together determine the functionality of a tissue,” Wolfrum said. 

Cold temperatures induce an accumulation of heat-producing brown and beige cells, so Wolfrum and his team housed mice at 8°C for one week and compared their adipocyte profiles to mice housed at room temperature. Two subpopulations of beige fat cells burgeoned following cold exposure. However, upon closer examination, the researchers noticed that one of these subpopulations expressed numerous genes involved in ATP synthesis, suggesting that UCP1 had not shut down these energy factories. When the team measured Ucp1 expression, they confirmed that most of the subpopulation of beige cell cells lacked this protein. “This finding challenges the long-held belief that UCP1 is required for thermogenesis,” Wankhade said. Another mechanism must adjust the thermostat.

Wolfrum’s team hypothesized that beige fat cells lacking UCP1 use futile cycles, looping biochemical reactions that synthesize molecules, such as lipids, and break them down again, resulting in no gain on investment.⁷ They discovered increased expression of genes linked to futile cycles, but demonstrating that these looping reactions were active proved challenging. Ideally, they would trace ATP molecules entering the cycle, but Wolfram noted, “This is impossible. There is no experimental paradigm to prove that the ATP is going there.” Instead, they measured the cells' respiration rate by tracking oxygen uptake. Futile cycles break down ATP, requiring increased respiration to replenish the energy molecules. When they treated the cells that lacked UCP1 with drugs that inhibit futile cycles, the cells consumed less oxygen and respired less, indicating that fewer ATP molecules needed replacement. 

Such biochemical circuits serve two purposes—generating heat and using up ATP stores—though Wolfrum remains unsure which is the primary function; either they evolved to warm the body, or they adapted to restrict the amount of available ATP, generating heat only as a byproduct.

To confirm that these beige fat cells use futile cycles to keep the mice warm, Wolfram and his team generated mutant mice that lacked this newly identified cell type. The engineered mice were unable to regulate their body temperature for the first eight hours following cold exposure, after which fat cells that use UCP1 took over, shutting down mitochondria and cranking up the heat.

To find out if humans possess these UCP1-free cells, the team used single-cell RNA sequencing on neck tissue collected from 15 healthy volunteers. They uncovered eight subpopulations of fat cells, including one beige variety that may similarly operate by futile cycling. Individuals with a greater proportion of these cells generally had lower fasting blood sugar levels, lower weight, and higher levels of the appetite-reducing hormone leptin, suggesting this cell type could protect against diabetes or avert obesity. However, additional research is needed to explore causality.

Wankhade suggested that one day scientists may consider administering these cells to counteract weight gain. “But before that, first and foremost, we need to make sure that this particular population can work outside the body when they don’t have their natural environment.” He explained that these cells may only manifest in the presence of other cell types. “We need to do more functional assays to understand more about these cells,” he said.

For a start, Wolfrum wants to determine if these 10 types of mouse adipocytes represent interchangeable states, switching back and forth, or distinct lineages committing to a function for life. Using single-cell approaches, biologists in the future may continue unscrambling details about the dynamic lives of these fat cells.