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Do you store fat or burn it?Targeting a single protein toggles the switch

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As obesity has become a global problem and has nearly tripled in the last half century, scientists are trying to better understand the state at the molecular level. A new study, led by scientists at the University of California, San Francisco, now suggests that a single protein can play a major role in weight gain.

As reported in Natural metabolism February 18, 2021, UCSF Davide Ruggero, Ph.D. They found that in mice in which the activity of a protein called eIF4E was genetically or pharmacologically reduced, all mice gained only half the weight of other mice. Eat a high-fat diet.

“These mice were basically protected from weight gain, and their livers were healthier and not full of fat droplets,” said the Helendyler Family Chair for UCSF Basic Cancer Research. Senior author Lugero said.

The eIF4E protein plays an important role in initiating protein synthesis and is found in all cells of the body. During a process called translation, the strands of messenger RNA (mRNA) carry instructions from genes to the ribosome, the machine of the cell in which the protein is made. In organisms ranging from yeast to mammals, eIF4E binds to the cap at the end of each mRNA strand and forms an important part of the complex that directs the mRNA to the ribosome. Therefore, eIF4E is considered essential for the production of all proteins.

Due to its importance, until recently, the complete complement of eIF4E was considered essential to life. However, in 2015, Ruggero’s research group developed a mouse that was genetically modified to carry only one copy of the eIF4E gene, that is, it could synthesize only half the amount of the eIF4E protein found in normal mice. I made an amazing discovery that it was done. Normally.

However, the Ruggero team investigated whether eIF4E removal had a more subtle effect on certain living conditions. Former UCSF postdoctoral researcher Crystal S. Conn, Ph.D. Haojun Yang, Ph.D., currently an assistant professor at the Perelman School of Medicine at the University of Pennsylvania, and a postdoc at the current Ruggero Lab. In an experiment led by the team, regular eIF4E-modified mice were on a high-fat diet for 5 months. They found that the weight of the modified mouse was only half that of the corresponding mouse, as explained in Nature Metabolism. This suggests that eIF4E activity is involved in fat accumulation.

“Targeting mRNA translations may be a new way to cure obesity,” said Yang, co-lead author of the new treatise.

Obesity develops when you consume more energy than an individual consumes. In particular, excess dietary fat deposits in what is known as lipid droplets in organs such as the liver. Compared to the livers of other mice fed a high-fat diet, the livers of eIF4E-modified mice contained far fewer and smaller droplets. With these findings in hand, the Ruggero group has taken a closer look at how eIF4E controls obesity.

Alma Burlingame, Ph.D. of UCSF, a professor of medicinal chemistry. Used mass spectrometry to profile proteins in both normal and modified mice. From these data, researchers found that many of the proteins present in eIF4E-modified mice not only reduce lipid storage in the liver, but also promote lipid metabolism. In essence, mice can eat more and burn more fat.

“When you put each type of mouse on a treadmill or run a marathon, the eIF4E-modified mouse always wins. It can burn lipids so it can keep moving,” Ruggero said. I will.

In 2012, Ruggero co-founded eFFECTOR Therapeutics, a biopharmacy company that develops anti-cancer drugs for translation. Among the small molecules he has already developed is a translation inhibitor called eFT508 (tomivosertib). Currently, in clinical trials of various forms of cancer, eFT508 inhibits the action of eIF4E.

eFT508 selectively blocks eIF4E phosphorylation. This is the mechanism that proteins use to regulate each other and effectively act as a light switch that turns proteins “on” or “off.” In the case of eIF4E, phosphorylation encourages cells to store fat, but blocking phosphorylation causes cells to burn fat as fuel. As a result, mice treated with this inhibitor and fed a high-fat diet lost much more weight than mice fed a control.

This newly discovered fat-burning mechanism can be attractive to athletes who want to increase their endurance, said Conn, co-lead author of the Nature Metabolism treatise.

Obesity is a risk factor for cancer, and new discoveries associated with eIF4E provide an interesting new perspective on this link, Ruggero said. He wants researchers to investigate the role of this translator in obesity, cancer, and their relationship.

In the future, Ruggero will ask whether eFT508 translation inhibitors can prevent or treat other features of obesity, such as non-alcoholic fatty liver disease and NAFLD (severe liver damage due to obesity that can lead to liver cancer). I am also enthusiastic about my research.


Cancer blocked by halving the level of proteins that are considered “untouchable”


For more information:
The major cap-binding protein, eIF4E, regulates lipid homeostasis and dietary obesity. Natural metabolism (2021). DOI: 10.1038 / s42255-021-00349-z, dx.doi.org / 10.1038 / s42255-021-00349-z

Courtesy of the University of California, San Francisco

Quote: Do you store fat or burn it? Targeting a single protein, the switch obtained from https: //medicalxpress.com/news/2021-02-fat-protein-flips.html on February 18, 2021 (2021, February 18) Will switch.

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