Protein 'Mitch' Discovery Could Boost Fat Burning, Block New Fat Cells

Researchers at the Weizmann Institute of Science have pinpointed a protein named MTCH2, or "Mitch," that plays a crucial role in cellular energy management and fat storage. A recent study published in the EMBO Journal reveals that deactivating this protein in human cells significantly accelerates the burning of fats and carbohydrates, while simultaneously hindering the development of new fat cells. These findings build upon prior research in mice, which demonstrated that eliminating Mitch in muscles led to enhanced physical fitness, greater endurance, and a remarkable resistance to obesity.

Several years ago, Professor Atan Gross and his team at the Weizmann Institute made a striking observation during their work on Mitch. When they suppressed the protein's production in mouse muscle tissue, the animals exhibited substantial improvements in their body composition. Beyond warding off obesity, these mice also developed more muscle fibers, which are known for their high oxygen consumption and association with improved stamina and athletic performance. The mice performed notably better on physical stress tests and displayed enhanced heart function. This unexpected outcome prompted the researchers to investigate the underlying mechanisms, specifically focusing on the role of mitochondria, the powerhouses of the cell.

Mitochondria's Role in Energy Expenditure

The shape and organization of mitochondria are key indicators of cellular energy production. Mitochondria can fuse into large, interconnected networks for efficient energy generation, or remain as smaller, separate units with less efficiency. When cellular energy production becomes less efficient, cells compensate by consuming more fuel, including fats, carbohydrates, and proteins. Professor Gross's research group discovered that Mitch helps regulate this process by controlling mitochondrial fusion. This mechanism provided a potential explanation for the observed effects in mice and guided the subsequent investigation into human cells.

In the new study, led by doctoral student Sabita Chourasia, the team utilized genetic engineering to remove the Mitch protein from human cells. The consequences were dramatic: without Mitch, the interconnected mitochondrial network fragmented into individual units. This led to less efficient energy production, creating a state of perceived energy shortage within the cells. While seemingly counterintuitive, this inefficiency can be beneficial for energy expenditure and fat reduction. Cells requiring more energy must burn more fuel. "After deleting Mitch, we examined, every few hours, the effect that had on more than 100 substances taking part in metabolism in human cells," Chourasia explained. "We saw an increase in cellular respiration, the process in 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."

The altered cells, driven by their heightened energy demands, ramped up their consumption of available fuel. Researchers observed increased breakdown of fats, carbohydrates, and amino acids. Crucially, cells lacking Mitch relied significantly more on fat as their primary energy source, a departure from ordinary cells that favor carbohydrates and proteins. "We discovered that deleting Mitch led to a major drop in fats in membranes," Professor Gross stated. "At the same time, we saw an increase in fatty substances used to produce energy, and we realized that the 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." This suggests that Mitch acts as a critical regulator, dictating whether fat is stored or burned.

Furthermore, the team noted another significant impact of Mitch removal. Previous studies had indicated higher levels of Mitch in women with obesity, prompting an investigation into its role in the creation of new fat cells. Fat cells develop from precursor progenitor cells through a process called differentiation. When Mitch was removed from these progenitor cells, their transformation into mature fat-storing cells was considerably inhibited. "When we deleted Mitch from the progenitor cells, we discovered that the environment created in these cells was not conducive to the synthesis of new fats," Gross elaborated. "Reducing the ability to synthesize membranes prevents the 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 the substances vital for this process to occur. As a result, differentiation of new fat cells is reduced, along with fat accumulation." Therefore, cells deficient in Mitch not only burned existing fat more effectively but also exhibited a reduced capacity to generate new fat cells.

While this research is still in its early stages and far from clinical application, the discovery of the protein's influence on energy expenditure and fat storage presents a promising new biological pathway. By potentially enhancing fat burning and limiting the formation of new adipocytes, targeting MTCH2 protein could offer a novel strategy for addressing obesity. This breakthrough may also contribute to tackling a persistent challenge in weight management therapies: preserving lean muscle mass while reducing body fat. The study involved collaboration between the Weizmann Institute of Science, the University of Pennsylvania, and the University of Texas at San Antonio. Professor Atan Gross holds the Marketa & Frederick Alexander Professorial Chair, with research support from Amnon Shoham.