Beige fat cells with a “Sisyphus mechanism”

Fat cells come in three colours: white, brown, and beige. White fat cells store fat in our body as an energy reserve. We need these cells, but having too many creates health problems. Brown fat cells are particularly active in infants. They produce heat and thus maintain the baby’s body temperature. However, the amount of brown adipose tissue decreases over a person’s lifetime; adults have very little of it. Then, finally, the beige fat cells. These can also produce heat, albeit somewhat less well than brown fat cells. Beige fat cells occur in adults as well: scattered throughout the white fatty tissue, especially in the neck and shoulder area, they help in using up excess energy.

Now an international research team – including scientists at the University of Basel – has discovered and described a new type of beige fat cells. “Certain groups of fat cells can expend energy using inefficient metabolic processes. We describe a new population of beige cells that use different mechanisms than previously described,” says Matthias Betz, head of the research group Translational Metabolism at the University of Basel and University Hospital Basel. “This inefficiency if beneficial for human metabolism and could help to avoid obesity and type 2 diabetes.”

The study was led by the ETH Zurich, the University of Basel and the University Hospital Basel, the University of Leipzig Medical Center and the Dana-Farber Cancer Institute in Boston. Numerous other hospitals and research institutions around the world were involved in the project.

Independent of a known protein

The beige fat cells that researchers were already familiar with generate heat via a protein called UCP1 which also exists in brown fat cells. This protein is located in the inner of two membranes that surround the mitochondria, the structural units often referred to as the powerhouse of the cell. As part of their normal function, mitochondria pump electrically charged particles (protons) from their interior into the space between the two membranes. The protein UCP1 forms a very narrow channel in the inner membrane through which the protons flow back into the mitochondria, thereby generating heat from friction.

In recent years, scientists have discovered that there are also beige fat cells without the UCP1 protein, and that these also consume energy and thus produce heat. The international research team has now precisely characterised the new class of beige fat cells and shown how they do this: by means of a “Sisyphus mechanism”.

Here’s how it works: All biochemical processes that take place in cells always generate some heat. The new class of beige fat cells takes advantage of this and allows individual processes to run back and forth, seemingly without purpose. This primarily involves two conversion processes. In one, the cells break fats down into their components (fatty acids) at full speed and then assemble them into new fats just as quickly. In the other, they apply an enzyme to convert molecules of creatine into creatine phosphate, a related molecule, only to immediately convert it back into creatine. Scientists call these back-and-forth processes “futile cycles”. They don’t add anything to the biochemical budget overall, but they consume energy and generate heat.

Preventing diabetes and obesity

The research team first described the new type of beige fat cells in mice. They then examined human adipose tissue and were able to show that these fat cells occur there, too. While less than half the population has the previously known type of classical beige fat cells, almost all humans have the new futile-cycle type, albeit in differing amounts.

As the researchers were able to show, people with a high number of beige fat cells – of either the previously known type or this new type – are slimmer and tend to have better metabolic health. That makes them less prone to obesity and metabolic disorders such as diabetes. “Because beige fat cells can convert energy into heat, they help to break down excess fat,” explains Tongtong Wang, first author of the study and a doctoral student at ETH Zurich.

Original publication

Wang T, Sharma AK, Wu C et al.:
Single Nucleus Transcriptomics Identifies Separate Classes of UCP1 and Futile Cycle Beige Cells.
Cell Metabolism (2024), doi: 10.1016/j.cmet.2024.07.005