Weight-loss medicines in the GLP-1 class, including Ozempic, have proved strikingly effective in helping people shed weight in recent years. However, researchers have also flagged bone and muscle loss as potential side effects.
Against that backdrop, scientists are continuing to look for ways to support weight management that might avoid those drawbacks. One possible lead is a protein called MTCH2 – often referred to informally as "Mitch" – which could represent a different route to treatment.
From mouse studies to a human question
Evidence for Mitch’s influence on body weight first gained traction in a 2016 study. In that work, scientists switched off Mitch production in mouse muscle, and the animals were shielded from obesity. At the same time, the mice showed improvements in measures linked to stamina and endurance.
Those results, alongside earlier research on Mitch, set the stage for a newly published study led by researchers at the Weizmann Institute of Science in Israel. The team set out to test whether comparable effects might also appear in humans.
MTCH2 (“Mitch”) knockout in human cells
To explore this, the researchers removed (knocked out) the gene responsible for producing Mitch in human cells grown in the laboratory.
"After deleting Mitch, we examined, every few hours, the effect that had on more than 100 substances taking part in metabolism in human cells," says biologist Sabita Chourasia from the Weizmann Institute of Science.
"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."
Looking more closely, the researchers were able to describe Mitch’s role in far greater detail. Their analysis indicates that Mitch interferes with the ability of mitochondria – the cell’s energy-producing machinery – to fuse together. When mitochondria are less able to fuse, the cell becomes less efficient at converting nutrients into usable energy.
In practice, this suggests that cells lacking Mitch behave as though their energy supplies are constantly depleted, driving them to hunt for fuel. As a result, compounds such as carbohydrates, fats, and amino acids are used up more quickly. This helps clarify why mice missing Mitch in their muscles did not become obese.
What Mitch changes about fat use and fat-cell formation
The team also found that, without Mitch, cells leaned especially heavily on fats for energy. In effect, they began consuming fatty components associated with cell membranes.
"We discovered that deleting Mitch led to a major drop in fats in membranes," says biologist Atan Gross from the Weizmann Institute of Science.
"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."
Beyond that, the researchers uncovered a broader fat-related effect: when Mitch is absent, it also interrupts the process by which whole cells develop into fat tissue – a phenomenon known as fat cell differentiation.
"The process of fat accumulation requires a large amount of available energy, but in cells without Mitch, there is a shortage of energy," says Gross.
"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."
Why therapies are still a long way off
Even with these insights, the work is still far from delivering a practical treatment. Still, because Mitch appears to sit at the centre of both fat burning and fat accumulation, it stands out as a compelling target for future investigation.
Considerably more research will be needed to pin down what the presence or absence of Mitch means in real biological systems. For example, forcing cells into an intense, energy-deprived mode could place tissues and organs under stress, potentially to the point of harm-an outcome any future therapy would need to avoid.
"Our findings demonstrate that MTCH2 knockout induces a hypermetabolic state, leading to an imbalance in cellular energy flow and activating multiple metabolic pathways to meet the heightened energy utilization and demand," write the researchers in their published paper.
"These results underscore MTCH2's role as a crucial regulator of cellular energy flow."
The research has been published in the EMBO Journal.
This article was fact-checked by Rachel Garner and edited by Peter Dockrill. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.
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