The Fat Trap: How Rich Diets Cause Cellular Dysfunction and Weight Gain

Researchers also found these effects can be reversed by treatment with an antioxidant.

High-fat diets trigger numerous health complications beyond simple weight gain, including elevated diabetes risk and various chronic conditions. Now, MIT researchers have unveiled the intricate cellular mechanisms behind these harmful effects while discovering a potential therapeutic solution.

The comprehensive study, performed on laboratory mice, demonstrates that high-fat diets disrupt hundreds of metabolic enzymes responsible for processing sugars, fats, and proteins. These disruptions result in insulin resistance and dangerous accumulation of reactive oxygen species—harmful molecules that damage cells. Notably, male subjects experienced more severe effects than females.

The research team also made a promising discovery: administering antioxidants alongside high-fat diets could reverse most of the cellular damage.

“When cells face metabolic stress, enzymes can shift into states that are more harmful than their original condition,” explains Tigist Tamir, formerly a postdoc at MIT and now assistant professor of biochemistry and biophysics at the University of North Carolina at Chapel Hill School of Medicine. “Our antioxidant research demonstrates that these enzymes can be guided toward less dysfunctional states.”

Tamir leads this groundbreaking study, published in Molecular Cell, with Forest White, the Ned C. and Janet C. Rice Professor of Biological Engineering and Koch Institute for Integrative Cancer Research member at MIT, serving as senior author.

Metabolic Networks

Previous research from White’s laboratory established that high-fat diets activate cellular signaling pathways similar to those triggered by chronic stress. This new investigation delved deeper into enzyme phosphorylation’s role in these cellular responses.

Phosphorylation involves adding phosphate groups to enzymes, which can activate or deactivate them. Kinase enzymes control this process, enabling cells to rapidly adapt to environmental changes by adjusting existing enzyme activity levels.

Numerous metabolism-related enzymes—those converting food into essential molecular building blocks like proteins, fats, and nucleic acids—undergo phosphorylation modifications.

The research team began by examining databases of phosphorylatable human enzymes, concentrating on those involved in metabolism. They discovered that many phosphorylated metabolic enzymes belong to oxidoreductases, a class that transfers electrons between molecules. These enzymes play crucial roles in metabolic processes like glycolysis, where glucose breaks down into pyruvate.

The identified enzymes include IDH1, essential for sugar breakdown and energy production, and AKR1C1, necessary for fatty acid metabolism. Many phosphorylated enzymes also manage reactive oxygen species—molecules vital for cellular functions but harmful when accumulated excessively.

Enzyme phosphorylation can increase or decrease their activity as they collectively respond to food intake. Most metabolic enzymes in this study undergo phosphorylation at sites critical for binding target molecules or forming dimers—protein pairs that create functional enzymes.

“Tigist’s research definitively demonstrates phosphorylation’s importance in controlling metabolic network flow. This fundamental knowledge from her systematic study isn’t traditionally covered in biochemistry textbooks,” White notes.

Out of Balance

To examine these effects in living organisms, researchers compared mice groups receiving high-fat versus normal diets. They found that metabolic enzyme phosphorylation created dysfunctional cellular states characterized by redox imbalance—cells producing more reactive oxygen species than they could neutralize. These mice gained weight and developed insulin resistance.

“With continued high-fat diet consumption, we observe gradual movement away from redox homeostasis toward more disease-like conditions,” White explains.

Male mice experienced significantly more pronounced effects than females. Female mice demonstrated better high-fat diet compensation by activating fat-processing and metabolic pathways.

“We learned that these phosphorylation events’ overall systemic effects created increased redox homeostasis imbalance, particularly in males. They showed considerably more stress and metabolic dysfunction compared to females,” Tamir reports.

The researchers discovered that giving high-fat diet mice the antioxidant BHA reversed many harmful effects. These treated mice showed dramatically reduced weight gain and avoided becoming prediabetic, unlike untreated high-fat diet mice.

Antioxidant treatment appears to restore cellular balance by reducing reactive oxygen species. Additionally, metabolic enzymes displayed systematic rewiring and altered phosphorylation states in treated mice.

“They experience significant metabolic dysfunction, but co-administering something that counteracts this allows them sufficient reserves to maintain relative normalcy,” Tamir explains. “The study suggests biochemical cellular changes bring them to a different state—not normal, but different—where mice are healthier at tissue and organism levels.”

In her new University of North Carolina laboratory, Tamir plans to further investigate whether antioxidant treatment could effectively prevent or treat obesity-related metabolic dysfunction, including determining optimal treatment timing.

The research received partial funding from the Burroughs Wellcome Fund, National Cancer Institute, National Institutes of Health, MIT’s Ludwig Center, and MIT Center for Precision Cancer Medicine.

TO READ MORE, OPEN THE LINK BELOW:

https://news.mit.edu/2025/high-fat-diet-metabolic-dysfunction-cells-weight-gain-0528