Modern weight loss medications have transformed the treatment of obesity and have helped many people lose significant amounts of weight. But these medications often have a major drawback: they can also reduce muscle mass. Now, researchers have discovered a biological mechanism that could one day help address that challenge while boosting the body’s ability to burn fat.
Scientists at the Weizmann Institute of Science have identified a protein called MTCH2, nicknamed “Mitch,” that appears to play an important role in how cells manage energy and store fat. In a recent study published in the EMBO MagazineThe team found that turning off this protein in human cells increases the rate at which fats and carbohydrates are burned while reducing the formation of new fat cells.
The findings build on previous research in mice that produced a surprising result. Animals that lacked Mitch in their muscles became more physically fit, developed greater endurance, and were remarkably resistant to obesity.
A surprising discovery in mice
Several years ago, Professor Atan Gross and his colleagues made an unexpected observation while studying Mitch. When the researchers suppressed protein production in mouse muscle tissue, the animals showed significant improvements in body composition.
The mice not only avoided obesity but also developed more muscle fibers. These fibers consume large amounts of oxygen and are associated with greater endurance and athletic performance. The animals performed better during physical stress tests and also showed better heart function.
The discovery raised an important question. How could knocking out a single protein protect against obesity and improve physical endurance?
To answer that question, researchers turned their attention to mitochondria, the small structures inside cells often described as their power plants. Mitochondria generate the energy that cells need to function and play a central role in metabolism, the set of chemical processes that convert food into usable energy.
How mitochondria influence fat burning
The shape and organization of mitochondria can reveal a lot about how cells produce energy.
Sometimes mitochondria fuse into large interconnected networks that generate energy efficiently. In other situations, they remain separated into smaller individual units that are less efficient. When energy production becomes less efficient, cells compensate by consuming greater amounts of fuel, including fats, carbohydrates, and proteins.
After years of research, Gross’s team in the Weizmann Department of Immunology and Regenerative Biology discovered that Mitch helps control this process by regulating mitochondrial fusion. This finding offered a possible explanation for the unusual results observed in mice.
The next step was to determine if the same mechanism operates in human cells.
What happens when Mitch is eliminated?
The new study, led by PhD student Sabita Chourasia, used genetic engineering techniques to remove the Mitch protein from human cells.
The results were dramatic.
Without Mitch, the normal mitochondrial network split into separate units. Energy production became less efficient, leaving cells in what the researchers describe as a constant state of energy shortage.
At first glance, this might seem harmful. However, when the goal is to increase energy expenditure and reduce fat accumulation, this type of inefficiency can work in the body’s favor. Cells struggling to produce energy must consume more fuel to meet their needs.
“After eliminating Mitch, we examined every few hours the effect he had on more than 100 substances involved in the metabolism of human cells,” explains Chourasia. “We saw 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 muscle endurance in previous experiments with mice.”
Human cells begin to consume more fat
Because the altered cells required more energy, they increased their consumption of available fuel sources.
The researchers observed increased breakdown of fats, carbohydrates and amino acids. They also found a significant change in the way cells generate energy.
Ordinary cells tend to rely more on carbohydrates and proteins. However, cells lacking Mitch were much more dependent on fat as their primary fuel source.
“We found that removing Mitch caused a significant decrease in fats in the membranes,” explains Gross. “At the same time, we saw an increase in fatty substances used for energy production and realized that fat was being broken down from the membrane to be used as fuel. In other words, we showed that Mitch determines the fate of fat in human cells.”
The findings suggest that Mitch acts as an important regulator that helps decide whether fat is stored or burned.
Block the formation of new fat cells
The researchers discovered another important effect of eliminating Mitch.
Previous studies have shown that women with obesity tend to have elevated protein levels. That observation led the team to investigate whether Mitch could also influence the creation of new fat cells.
Fat cells originate from precursor cells known as progenitor cells. Under the right conditions, these immature cells accumulate fat and become mature fat-storing cells through a process called differentiation.
When the researchers removed Mitch from the progenitor cells, that transformation became much more difficult.
“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,” explains Gross. “The reduction in 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 shortage of energy. In addition, the expression of genes necessary for differentiation is suppressed and there is a shortage of substances vital for this process to occur. As a result, the differentiation of new fat cells is reduced, along with the accumulation of fat.”
In other words, cells lacking Mitch not only burned more fat but were also less able to create new cells to store fat.
A possible new direction for obesity research
Although the work was done in cells and is still far from becoming a treatment, the findings reveal a powerful biological pathway that influences both energy use and fat storage.
By increasing fat burning while limiting the formation of new fat cells, targeting Mitch could eventually provide researchers with a new strategy to combat obesity. The discovery may also help address one of the most persistent challenges associated with modern weight loss therapies: preserving healthy muscles while reducing excess body fat.
Researchers from the Weizmann Institute of Science, the University of Pennsylvania and the University of Texas at San Antonio participated in the study.
Professor Atan Gross holds the Marketa & Frederick Alexander Chair. His research is also supported by Amnon Shoham.