Study Shows How Antioxidants May Undo High-Fat Diet Damage

A new study published in Molecular Cell sheds light on how high-fat diets disrupt cellular metabolism and increase the risk of metabolic diseases. Conducted by researchers at the Massachusetts Institute of Technology (MIT), the study reveals that many of the damaging effects of a high-fat diet can be reversed by the use of antioxidants. The research, led by Tigist Tamir, now a professor at the University of North Carolina, and senior author Forest White of MIT, explores the biochemical disruptions at the cellular level that lead to weight gain and insulin resistance.

Consuming a high-fat diet is already linked to obesity, diabetes, and chronic disease, but the molecular mechanisms behind these risks have remained unclear. To investigate, the researchers used a mouse model to observe the effects of a high-fat diet over time, particularly focusing on how it alters enzyme activity in metabolic pathways. They discovered that hundreds of enzymes involved in sugar, lipid, and protein metabolism became dysregulated through a process called phosphorylation, where enzymes are turned on or off in response to stress or nutrient levels.

Study showed that these changes led to insulin resistance and the accumulation of reactive oxygen species—damaging molecules that indicate cellular stress. Males were found to be more affected than females, who compensated more effectively for the high-fat diet.

“Under metabolic stress conditions, enzymes can be affected to produce a more harmful state than what was initially there,” said Tamir. "Then what we've shown with the antioxidant study is that you can bring them to a different state that is less dysfunctional."

However, when the researchers introduced the antioxidant BHA alongside the high-fat diet, they saw a dramatic reduction in weight gain and prediabetic symptoms. “They’re experiencing a lot of metabolic dysfunction, but if you co-administer something that counters that, then they have enough reserve to maintain some sort of normalcy,” Tamir added.

The findings point to the potential of antioxidant therapies in mitigating metabolic damage caused by unhealthy diets. Tamir now plans to explore whether such treatments could be used to prevent or manage obesity-related disorders in humans.

Reference: Tigist Y. Tamir, Shreya Chaudhary, Annie X. Li, Sonia E. Trojan, Cameron T. Flower, Paula Vo, Yufei Cui, Jeffrey C. Davis, Rachit Mukkamala, Francesca N. Venditti, Alissandra L. Hillis, Alex Toker, Matthew G. Vander Heiden, Jessica B. Spinelli, Norman J. Kennedy, Roger J. Davis, Forest M. White. Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity. Molecular Cell, 2025; DOI: 10.1016/j.molcel.2025.05.007