Have you ever considered how a high-fat diet affects your health? Beyond weight gain, it can significantly heighten the risk of diabetes and various chronic conditions. Recent research at MIT has illuminated the myriad cellular changes that occur in response to such diets, particularly focusing on the dysregulation of metabolic enzymes linked to weight increase.
The study, which was performed on mice, uncovered that a high-fat diet alters hundreds of enzymes that play vital roles in sugar, lipid, and protein metabolism. Notably, these disruptions can elevate insulin resistance and lead to an accumulation of harmful molecules known as reactive oxygen species, with the adverse effects being more pronounced in male mice than in females.
Interestingly, the researchers discovered that many of these harmful impacts could be mitigated by administering an antioxidant alongside the high-fat diet. “Under conditions of metabolic stress, enzymes may shift to a more detrimental state than initially present,” explains Tigist Tamir, a former MIT postdoctoral researcher. “Our findings reveal that the addition of an antioxidant can help restore these enzymes to a less dysfunctional state.”
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 study published in Molecular Cell. Forest White, a prominent professor of Biological Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, serves as the senior author of this groundbreaking research.
Understanding Metabolic Networks
White’s lab has previously found that high-fat diets activate several signaling pathways associated with chronic stress. In their latest research, the team aimed to delve deeper into the role of enzyme phosphorylation within these responses. Phosphorylation—the addition of a phosphate group—can toggle enzyme activity on or off. This process, governed by kinases, enables cells to adjust quickly to changing environmental conditions by modulating the activity of existing enzymes.
Investigating databases of human enzymes that can undergo phosphorylation, the researchers concentrated on those linked to metabolism. They identified that many metabolic enzymes subject to phosphorylation belong to a category known as oxidoreductases, which facilitate electron transfer between molecules. This class is crucial for metabolic reactions, such as glycolysis, where glucose is broken down into pyruvate.
Within the multitude of enzymes explored, destacan IDH1, vital for sugar breakdown to produce energy, and AKR1C1, essential for fatty acid metabolism. The team also noted that many phosphorylated enzymes play important roles in managing reactive oxygen species, necessary for various cell functions but detrimental in excessive amounts.
Phosphorylation can either enhance or diminish the activity of these enzymes as they collectively respond to food intake. Most metabolic enzymes highlighted in this study are phosphorylated in regions critical for binding to their substrates or forming functional dimers—pairs of proteins that work together.
“Tigist’s work demonstrates unequivocally the significance of phosphorylation in controlling metabolic flux. It’s fundamental knowledge that emerges from this comprehensive study, yet it’s often overlooked in traditional biochemistry education,” comments White.
The Imbalance of Metabolism
To further investigate these effects, the researchers compared two groups of mice: one group on a high-fat diet and another on a standard diet. The findings revealed that the phosphorylation of metabolic enzymes led to a dysfunctional state characterized by redox imbalance, wherein cells produced more reactive oxygen species than they could handle. This condition culminated in weight gain and insulin resistance among the high-fat diet group.
White notes, “In the context of a continued high-fat diet, we observe a gradual shift away from redox homeostasis toward a more disease-like state.” Male mice exhibited these effects more severely than their female counterparts, who managed to compensate for the high-fat diet by activating pathways related to fat processing and metabolism.
“One key takeaway is that phosphorylation events systemically led to greater redox imbalance and metabolic dysfunction, particularly in males,” Tamir remarks.
Furthermore, when the high-fat diet mice were given an antioxidant known as BHA, many detrimental effects were reversed. This treatment resulted in significant weight loss for these mice, preventing them from becoming prediabetic—unlike their high-fat counterparts without antioxidant intervention.
The researchers concluded that the antioxidant treatment helped restore cells to a more balanced state, reducing the levels of reactive oxygen species. Additionally, metabolic enzymes displayed a systemic reorganization and a change in their phosphorylation state.
“While they experienced substantial metabolic dysfunction, co-administering a counteracting substance enabled them to maintain a semblance of normalcy,” Tamir explains. “Our study suggests a biochemical shift within cells that leads to a different—but healthier—state at both tissue and organism levels.”
In her new position at the University of North Carolina, Tamir aims to further investigate the potential of antioxidant treatments in preventing or managing obesity-related metabolic dysfunction and determine the optimal timing for such interventions.
This research was partially funded by the Burroughs Wellcome Fund, the National Cancer Institute, the National Institutes of Health, the Ludwig Center at MIT, and the MIT Center for Precision Cancer Medicine.
Photo credit & article inspired by: Massachusetts Institute of Technology
