Get rid of the fat and lose weight

Research from the Weizmann Institute reveals that silencing the Mitch protein in human cells increases the rate of cellular respiration, prevents fat accumulation, and increases muscle endurance

They have taken our lives by storm in the last decade, promising to make the world slimmer and healthier, but the new weight loss drugs have a problem – they cause muscle loss. Unintentionally, Prof. found Eitan Gross In 2016, a possible solution was discovered. He identified in his lab at the Weizmann Institute of Science that if the muscle protein Mitch, or by its official name MTCH2, is silenced, mice enter high physical fitness and become immune to obesity due to increased metabolism throughout the body. In a new article published in the scientific journal EMBO JournalProf. Gross' group has taken another step towards a new treatment for obesity: they have shown that silencing Mitch in human cells also increases the burning of fats and carbohydrates and inhibits the development of new fat cells.

The mice from Prof. Gross' original experiment enjoyed a positive change in their body composition – in addition to not becoming obese, they also developed a large number of muscle fibers that consume large amounts of oxygen and increase endurance. These welcome developments led to improved results in the mice's stress tests and improved heart function, but left the researchers with a mystery – how does silencing a single protein manage to "immunize" the body from obesity while at the same time improving muscle endurance? This question led the scientists to the "cellular power plants" of mitochondria, the tiny organelles responsible for energy production and metabolism in the cell.

A lot can be learned about mitochondria simply by observing their shape and arrangement in the cell: the ability of these organelles to fuse together to form an extensive network of power plants that produce energy very efficiently or to exist as separate organelles that produce energy less efficiently. To cope with the decline in their efficiency, the organelles in their separate configuration are forced to utilize diverse energy stores, such as fat, carbohydrates, and proteins, at a higher rate. Over the years, Prof. Gross' group in the Department of Immunology and Biological Regeneration discovered that Mitch is one of the factors that controls mitochondrial fusion, hence the findings in mice. But will silencing Mitch lead to similar results in humans?

In the new study, the researchers, led by doctoral student Savita Chorcia, examined what happens to human cells when Mitch is deleted from them using genetic engineering methods. When this is done, the mitochondrial network collapses, the organelles separate, the efficiency of energy production decreases – and the cell enters a permanent state of energy deficiency. This may sound like a scary scenario, but sometimes inefficiency in energy production and a deficiency may be desirable, for example in a state of overeating or when you want to encourage the utilization of body fat stores and inhibit their accumulation. "We deleted Mitch and checked every few hours how this affected more than 100 substances that participate in the metabolism of human cells," describes Chorcia. "We saw an increase in the rate of cellular respiration – the process by which the cell produces energy from food substances, such as carbohydrates and fats, with the help of oxygen. This increase explains the increase in muscle endurance previously observed in mice."

To increase the rate of cellular respiration, cells need more food to use as "fuel" in the process of energy production. The scientists identified that the high demand for fuel causes human cells lacking Mitch to "burn" more of their stores, such as fats, carbohydrates, and amino acids. Moreover, while normal cells depend on the utilization of carbohydrates and proteins for energy production and less on the utilization of fat, the same cells lacking Mitch were found to be more dependent on the utilization of fat for energy production and growth. "We observed that deleting Mitch caused a marked decrease in the amount of fat in the membranes," explains Prof. Gross. "At the same time, we saw an increase in fatty substances used for energy production and we understood that fat is broken down from the membranes in order to be utilized as "fuel." In other words, we showed that Mitch controls the fate of fat in human cells."

In the next stage of the study, the scientists discovered that Mitch's involvement in body fat accumulation goes even further. It was known that obese women have high levels of Mitch, and the scientists concluded from this that the protein is essential not only for mitochondrial fusion but also for fat cell differentiation – a process in which stem cells accumulate a lot of fat and become mature fat cells. "When we deleted Mitch in stem cells, we saw that an environment was created in them that was not suitable for the synthesis of new fats," explains Prof. Gross. "A reduction in the ability to assemble membranes prevents the cells from growing, developing and reaching a starting point that allows differentiation. The process of fat synthesis requires available energy, but in cells without Mitch, it is in short supply. In addition, there is a suppression of the expression of genes necessary for the differentiation process and there is a shortage of substances important for the process. The result was a delay in the differentiation of new fat cells and a delay in the accumulation of fat stores."

In a study whose findings were published in the scientific journal EMBO Journal Also participating were Dr. Christopher Petucci, Clarissa Schoffler and Dina Abassian from the University of Pennsylvania in Philadelphia, USA; Hu Wang and Prof. Xianlin Han from the University of Texas Health Science Center at San Antonio; Dr. Ehud Sivan, Dr. Alexander Brandis, Tabi Melman, Dr. Sergey Melitsky, Dr. Maxim Itkin, Dr. Ayla Sharp, Dr. Ron Rotkopf and Dr. Barkat Dassa from the Department of Life Sciences Research Infrastructures; Dr. Limor Regev and Dr. Yehudit Salzman from the Department of Immunology and Biological Regeneration at the Institute.

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