Modern weight loss medications have a dirty little secret: they can also reduce muscle mass. But researchers at the Weizmann Institute of Science have identified a protein called MTCH2 - affectionately nicknamed "Mitch" - that may one day help solve that problem while also cranking up the body's fat-burning furnace.

In a study published in the EMBO Journal, the team found that disabling Mitch in human cells accelerates the burning of fats and carbohydrates while simultaneously reducing the formation of new fat cells. The findings build on earlier mouse studies that showed animals lacking Mitch in their muscles became more physically fit, developed greater endurance, and were remarkably resistant to obesity. Because of course they did.

Prof. Atan Gross and his colleagues first noticed something strange years ago: when they suppressed Mitch in mouse muscle tissue, the animals not only avoided obesity but also developed more muscle fibers that consume large amounts of oxygen, improving stamina and heart function. The obvious question: how does disabling one protein both protect against obesity and enhance endurance?

The answer lies in mitochondria, the cellular power plants. Mitch regulates mitochondrial fusion - when it's absent, mitochondria break apart into smaller, less efficient units. Cells compensate by burning more fuel, including fats, carbohydrates, and proteins. In the new study, led by doctoral student Sabita Chourasia, the team used genetic engineering to delete Mitch from human cells. Without Mitch, the mitochondrial network shattered, leaving cells in a constant energy shortage. "After deleting Mitch, we examined, every few hours, the effect on more than 100 substances taking part in metabolism," Chourasia explains. "We saw an increase in cellular respiration." The altered cells consumed more fuel, especially fat. "We discovered that deleting Mitch led to a major drop in fats in membranes," Gross says. "Mitch determines the fate of fat in human cells."

But wait, there's more. Previous studies showed that women with obesity tend to have elevated Mitch levels. When the researchers removed Mitch from fat precursor cells (called progenitor cells), those cells struggled to become mature fat-storing cells. "The environment created in these cells was not conducive to the synthesis of new fats," Gross explains. Cells lacking Mitch not only burned more fat but also had trouble creating new fat cells. It's like a two-for-one deal on metabolic mischief.

Although the work is still far from becoming a treatment - conducted in cells, not people - the findings reveal a biological pathway that influences both energy use and fat storage. Targeting Mitch could eventually provide a new strategy for combating obesity while preserving muscle mass, addressing one of the most persistent drawbacks of modern weight loss therapies. The study involved researchers from the Weizmann Institute, the University of Pennsylvania, and the University of Texas at San Antonio. Prof. Gross holds the Marketa & Frederick Alexander Professorial Chair, and his research is also supported by Amnon Shoham. Materials provided by the Weizmann Institute of Science.