Modern weight loss drugs have revolutionized obesity treatment, allowing many people to lose significant amounts of weight. However, these drugs often have significant drawbacks. That means it can also reduce muscle mass. Now, researchers have discovered a biological mechanism that may one day help meet that challenge while increasing 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 a key role in how cells manage energy and store fat. In a recent study published in EMBO JournalThe research team found that disabling this protein in human cells increased the rate of fat and carbohydrate burning, while simultaneously reducing the formation of new fat cells.
This discovery builds on previous research in mice that yielded surprising results. Animals lacking Mitch in their muscles were physically fitter, had increased endurance, and were significantly more resistant to obesity.
Amazing discovery in mice
Several years ago, Professor Eitan Gross and his colleagues made an unexpected observation while studying Mitch. When the researchers inhibited protein production in the muscle tissue of mice, they saw significant improvements in the animals’ body composition.
The mice not only avoided obesity, but also developed more muscle fibers. These fibers consume large amounts of oxygen, leading to increased stamina and athletic performance. The animals performed better during physical stress tests and also showed improved heart function.
This finding raises important questions. How can we prevent obesity and improve physical endurance by disabling a single protein?
To answer that question, researchers turned to mitochondria. Mitochondria are small structures within cells that are often referred to as their powerhouses. Mitochondria generate the energy cells need to function and play a central role in metabolism, the collection of chemical processes that convert food into usable energy.
How mitochondria affect fat burning
The shape and organization of mitochondria can reveal a lot about how a cell produces energy.
In some cases, mitochondria fuse to form large interconnected networks that efficiently produce energy. In other situations, they remain isolated into small, individual units that are less efficient. When energy production becomes less efficient, cells compensate by consuming large amounts of fuels such as fats, carbohydrates, and proteins.
After years of research, Gross’ team in Weitzman’s Department of Immunology and Regenerative Biology discovered that Mitch helps control this process by regulating mitochondrial fusion. This finding provided a possible explanation for the unusual results seen in mice.
The next step was to see if the same mechanism was at work in human cells.
What happens if Mitch is removed?
The new study, led by PhD student Savita Chaurasia, 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. The efficiency of energy production decreased, leaving cells in what researchers called a permanent state of energy starvation.
At first glance, it may seem harmful. But if your goal is to increase energy expenditure and reduce fat storage, this kind of inefficiency can actually work to your body’s advantage. Cells that are struggling to produce energy must consume more fuel to meet their needs.
“After we removed Mitch, we examined its effects on more than 100 substances involved in human cell metabolism every few hours,” Chaurasia explains. “We observed an increase in cellular respiration, the process by which cells use oxygen to generate energy from nutrients such as carbohydrates and fats. This explains the increase in muscle endurance in previous experiments with mice.”
Human cells begin to consume more fat
The modified cells required more energy, thus increasing the consumption of available fuel sources.
Researchers observed more breakdown of fats, carbohydrates, and amino acids. They also discovered major changes in the way cells produce energy.
Normal cells usually rely heavily on carbohydrates and proteins. However, cells lacking Mitch were much more dependent on fat as their main fuel source.
“We found that removing Mitch significantly reduced the fat within the membrane,” Gross explains. “At the same time, we saw an increase in fatty substances used to generate energy, and we found that fat was being broken down from membranes to be used as fuel. In other words, we showed that Mitch determines the fate of fat within human cells.”
The findings suggest that Mitch acts as an important regulator that helps determine whether fat is stored or burned.
Block the formation of new fat cells
The researchers discovered another important effect of removing Mitch.
Previous research has shown that obese women tend to have elevated protein levels. This observation led the team to investigate whether Mitch could also influence the production of new fat cells.
Fat cells are derived from progenitor cells known as progenitor cells. Under the right conditions, these immature cells accumulate fat and develop into mature fat storage cells through a process called differentiation.
When the researchers removed Mitch from the progenitor cells, their transformation became even more difficult.
“When we removed Mitch from the progenitor cells, we found that the environment created within these cells was not suitable for the synthesis of new fat,” Gross explains. “The reduced capacity for membrane synthesis prevents cells from reaching a state in which they can grow, develop, and differentiate. The process of fat accumulation requires large amounts of available energy, and cells without Mitch lack energy. Furthermore, the expression of genes required for differentiation is suppressed, resulting in a lack of substances essential for the occurrence of this process. As a result, along with fat accumulation, differentiation of new adipocytes is reduced.”
In other words, cells lacking Mitch not only burn more fat, but also have a reduced ability to generate new fat storage cells.
Potential new directions for obesity research
Although the research was carried out inside cells and is still far from a cure, the findings reveal a powerful biological pathway that influences both energy use and fat storage.
Targeting Mitch could ultimately provide researchers with a new strategy to combat obesity by promoting fat burning while simultaneously inhibiting the formation of new fat cells. The discovery may also help address one of the most persistent challenges associated with modern weight loss therapies: maintaining healthy muscle while reducing excess body fat.
The study involved researchers from the Weizmann Institute of Science, the University of Pennsylvania, and the University of Texas at San Antonio.
Professor Atan Gross holds the Marketa and Frederick Alexander Professorship Chair. His research is also supported by Amnon Shoham.
