Scientists have identified a remarkable protein switch that influences how cells burn or store fat. Disabling this protein increases fat consumption and interferes with the formation of new fat cells, raising the possibility of a different approach to treating obesity. Subsequent research reinforced this finding, revealing that the same protein helps regulate the amount of energy burned by the body.
What if one of the keys to fighting obesity wasn’t suppressing appetite, but changing the way the body’s cells use energy?
Researchers at the Weizmann Institute of Science have identified a protein called MTCH2, nicknamed “Mitch”, which plays an important role in controlling metabolism. When scientists turned off this protein in laboratory experiments, cells began to consume more fuel, including fats and carbohydrates. They also discovered that removing Mitch could interfere with the process by which immature cells turn into fat cells.
The finding builds on previous experiments in mice, in which silencing Mitch in muscle tissue increased energy expenditure, improved endurance and protected the animals from diet-related obesity.
The results, published in EMBO magazine in January 2025, suggest that manipulating this protein could potentially offer a way to influence both fat burning and fat accumulation. Additional research published later that year provided further evidence of its importance in regulating body fat and metabolism.
Why scientists are looking for better treatments for obesity
Over the past decade, medications to promote weight loss have transformed the treatment of obesity. Drugs such as semaglutide and tirzepatide have helped many patients significantly reduce their body weight, largely by influencing the body’s appetite and responses to food.
But losing weight doesn’t necessarily mean losing just fat.
Weight loss can also involve a decrease in lean body mass, which includes muscle and other tissues. Preserving muscle is especially important because it promotes strength, mobility and metabolic health.
A 2026 analysis of 20 clinical trials involving 15,782 participants found that lean mass accounted for about 25 to 39 percent of the weight lost with several widely used weight-loss drugs. Importantly, researchers found that comparable proportional losses also occurred with lifestyle interventions, while adding resistance training helped preserve more lean tissue.
These concerns have encouraged scientists to look for ways to reduce body fat while protecting the muscles needed for long-term health.
Professor Atan Gross and his colleagues at the Weizmann Institute arrived at a possible lead thanks to an unexpected discovery involving Mitch.
Shutting down a mouse protected by an obesity protein
In previous experiments, Gross’s team reduced MTCH2 activity in mouse muscles. The effects were striking.
The genetically modified animals showed increased metabolic activity and were resistant to obesity caused by their diet. Their muscles also developed more fibers with a high capacity to use oxygen, helping to improve physical endurance.
The mice performed better on exercise and stress tests and showed improvements in heart function. In addition to resisting excess fat accumulation, they experienced favorable changes in their overall body composition.
The results suggest that Mitch was doing much more than controlling a single metabolic reaction. In one way or another, this protein appears to influence the body’s ability to use energy, store fat, and maintain physical activity.
This raised an intriguing question: How could silencing a protein produce such widespread effects?
To investigate, the researchers turned their attention to mitochondria, the microscopic structures responsible for providing much of the energy cells need to function.
The Mitochondria Connection Behind Fat Burning
Mitochondria are often described as the powerhouses of cells because they convert energy from food into a usable form called ATP, or adenosine triphosphate.
ATP acts as a cellular energy currency. Muscles use it to contract, cells need it to grow and repair, and countless biological processes depend on a constant supply.
However, mitochondria are not static structures. They are constantly changing shape, coming together into larger networks or breaking up into smaller units.
When mitochondria fuse, they can form interconnected systems that help coordinate energy production. When they divide, the resulting structures can function differently, changing the efficiency with which cells produce and consume energy.
Gross’s team previously established that Mitch plays a major role in mitochondrial fusion, the process that allows separate mitochondria to fuse together.
Without this protein, the mitochondrial network fragments. Although cells can still produce energy, they experience changes in their energy efficiency and demand that may force them to consume more fuel.
This offers a possible explanation for the unusual metabolism observed in mice. Instead of efficiently conserving energy, their cells appeared to be operating in a more energy-hungry state.
But would disabling Mitch have a similar effect on human cells?
Human Cells Start Burning More Fat Without Mitch
To answer this question, researchers led by doctoral student Sabita Chourasia used genetic engineering to eliminate MTCH2 from human cells grown in the laboratory.
The change disrupted the normal structure of their mitochondrial networks. Individual mitochondria became more separated and the balance between energy production and energy demand shifted.
The cells developed a persistent lack of readily available energy relative to their needs, even as their mitochondria increased their oxygen-consuming activity.
To compensate, they started consuming more nutrients.
“After removing Mitch, we looked, every few hours, at the effect it had on more than 100 substances involved in the metabolism of human cells,” says Chourasia. “We found an increase in cellular respiration, the process by which the cell produces energy from nutrients, such as carbohydrates and fats, using oxygen. This explains the increase in muscular endurance in previous experiments using mice.”
Cellular respiration is a series of chemical reactions that allow cells to extract usable energy from nutrients. Increasing this activity generally requires a larger supply of fuel.
The researchers found that cells lacking Mitch consumed more fats, carbohydrates and amino acids, the building blocks of protein.
Fat metabolism was particularly revealing.
Rather than relying on their usual mix of energy sources, the engineered cells increased their use of fatty acids for fuel. This indicates that MTCH2 influences not only the amount of energy consumed by cells, but also the nutrients they use to meet this demand.
“We found that removing Mitch caused a significant drop in fats in the membranes,” Gross says. “At the same time, we saw an increase in fats used for energy and realized that fat was broken down from the membrane for use as fuel. In other words, we showed that Mitch determines the fate of fat in human cells.”
Cell membranes are thin, flexible barriers made largely of fatty molecules called lipids. They protect cells and organize many of their essential functions.
The results suggest that Mitch-deprived cells were changing how they distributed and used these lipids, drawing on some of their available fat resources to support increased energy consumption.
Detailed analysis also revealed changes in stored lipids, demonstrating that the effect was more complex than simply removing cellular fat. Overall, the results showed that MTCH2 is a potent regulator of how cells partition nutrients between energy production and other biological needs.
Block the formation of new fat cells
The researchers then investigated whether Mitch also influenced the development of fat cells.
This question was particularly interesting because previous studies had found elevated levels of MTCH2 in the adipose tissue of obese women.
Fat cells, also called adipocytes, do not appear fully formed. They develop from immature precursor cells through a process called adipogenesis or fat cell differentiation.
As these precursor cells mature, they must build new cellular structures, produce fats, and activate genes that allow them to specialize in energy storage.
All this requires a lot of energy and raw materials.
Gross’s team suspected that removing Mitch might disrupt the process by creating an environment in which cells would be too busy consuming fuel to build the components needed for fat storage.
Experiments using mouse fat precursor cells supported this idea. When the researchers deleted MTCH2, far fewer cells successfully developed into mature fat cells.
In published experiments, about 80 to 90 percent of normal precursor cells differentiated within six days, compared with only 5 to 10 percent of cells lacking MTCH2. The modified cells also accumulated far fewer lipid droplets, the structures used to store fat.
“When we removed Mitch from the progenitor cells, we discovered that the environment created in these cells was not conducive to the synthesis of new fats,” says Gross. “Reducing the ability to synthesize membranes prevents cells from growing, developing and reaching the point where differentiation is possible. The process of fat accumulation requires a large amount of available energy, but in cells without Mitch there is a lack of energy. In addition, the expression of genes necessary for differentiation is suppressed and there is a lack of vital substances for this process to occur. As a result, the differentiation of new fat cells is reduced, as well as the accumulation of fat.”
In other words, turning off Mitch seemed to affect fat metabolism in two distinct ways. This increased the consumption of…
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