High-fat diet sets off metabolic dysfunction in cells, leads to weight gain: Study

Washington DC [US], May 30 : Researchers find high-fat diets set off metabolic dysfunction in cells, leading to weight gain, but these effects can be reversed by treatment with an antioxidant.

Consuming a high-fat diet can lead to a variety of health problems not only weight gain but also an increased risk of diabetes and other chronic diseases.

At the cellular level, hundreds of changes take place in response to a high-fat diet. MIT researchers have now mapped out some of those changes, with a focus on metabolic enzyme dysregulation that is associated with weight gain.

Their study, conducted in mice, revealed that hundreds of enzymes involved in sugar, lipid, and protein metabolism are affected by a high-fat diet, and that these disruptions lead to an increase in insulin resistance and an accumulation of damaging molecules called reactive oxygen species.

These effects were more pronounced in males than in females.

The researchers also showed that most of the damage could be reversed by giving the mice an antioxidant along with their high-fat diet.

"Under metabolic stress conditions, enzymes can be affected to produce a more harmful state than what was initially there," says Tigist Tamir, a former MIT postdoc.

"Then what we've shown with the antioxidant study is that you can bring them to a different state that is less dysfunctional," added Tigist Tamir.

Tamir, who is now an assistant professor of biochemistry and biophysics at the University of North Carolina at Chapel Hill School of Medicine, is the lead author of the new study, which appears today in Molecular Cell.

Forest White, the Ned C. and Janet C. Rice Professor of Biological Engineering and a member of the Koch Institute for Integrative Cancer Research at MIT, is the senior author of the paper.

In previous work, White's lab has found that a high-fat diet stimulates cells to turn on many of the same signalling pathways that are linked to chronic stress.

In the new study, the researchers wanted to explore the role of enzyme phosphorylation in those responses.

Phosphorylation, or the addition of a phosphate group, can turn enzyme activity on or off. This process, which is controlled by enzymes called kinases, gives cells a way to quickly respond to environmental conditions by fine-tuning the activity of existing enzymes within the cell.

Many enzymes involved in metabolism the conversion of food into the building blocks of key molecules such as proteins, lipids, and nucleic acids are known to undergo phosphorylation.

The researchers began by analysing databases of human enzymes that can be phosphorylated, focusing on enzymes involved in metabolism.

They found that many of the metabolic enzymes that undergo phosphorylation belong to a class called oxidoreductases, which transfer electrons from one molecule to another.

Such enzymes are key to metabolic reactions such as glycolysis the breakdown of glucose into a smaller molecule known as pyruvate.

Among the hundreds of enzymes the researchers identified are IDH1, which is involved in breaking down sugar to generate energy, and AKR1C1, which is required for metabolising fatty acids.

The researchers also found that many phosphorylated enzymes are important for the management of reactive oxygen species, which are necessary for many cell functions but can be harmful if too many of them accumulate in a cell.

Phosphorylation of these enzymes can lead them to become either more or less active, as they work together to respond to the intake of food.

Most of the metabolic enzymes identified in this study are phosphorylated on sites found in regions of the enzyme that are important for binding to the molecules that they act upon or for forming dimers pairs of proteins that join together to form a functional enzyme.

"Tigist's work has really shown categorically the importance of phosphorylation in controlling the flux through metabolic networks. It's fundamental knowledge that emerges from this systemic study that she's done, and it's something that is not classically captured in the biochemistry textbooks," White says.

To explore these effects in an animal model, the researchers compared two groups of mice, one that received a high-fat diet and one that consumed a normal diet.

They found that overall, phosphorylation of metabolic enzymes led to a dysfunctional state in which cells were in redox imbalance, meaning that their cells were producing more reactive oxygen species than they could neutralise.

These mice also became overweight and developed insulin resistance.

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