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Adopting a diet high in fats may lead to a range of health concerns — not just an increase in weight but also a heightened likelihood of diabetes and other long-term ailments.
At the cellular level, a multitude of alterations occur in reaction to a high-fat diet. Researchers from MIT have now charted some of these modifications, concentrating on the metabolic enzyme dysregulation linked to weight gain.
Their research, carried out in mice, indicated that numerous enzymes involved in glucose, lipid, and protein metabolism are influenced by a high-fat diet, leading to heightened insulin resistance and a buildup of harmful molecules known as reactive oxygen species. These outcomes were more significant in males compared to females.
The researchers also demonstrated that much of the damage could be reversed by administering an antioxidant alongside the high-fat diet to the mice.
“Under conditions of metabolic strain, enzymes can be altered to create a more detrimental state than what was originally present,” states Tigist Tamir, a former postdoctoral researcher at MIT. “Our findings from the antioxidant study show that it’s possible to shift them to a state that is less dysfunctional.”
Tamir, currently an assistant professor of biochemistry and biophysics at the University of North Carolina at Chapel Hill School of Medicine, is the primary author of the new research, which is published 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 study.
Metabolic Networks
In earlier research, White’s laboratory discovered that a high-fat diet prompts cells to activate numerous signaling pathways associated with chronic stress. In the current study, the researchers aimed to investigate the significance of enzyme phosphorylation in these responses.
Phosphorylation, or the addition of a phosphate group, can either activate or deactivate enzyme functions. This process, regulated by enzymes known as kinases, enables cells to quickly adapt to environmental changes by fine-tuning the activity of existing enzymes within the cell.
A variety of enzymes that take part in metabolism — converting food into essential components such as proteins, lipids, and nucleic acids — are recognized to undergo phosphorylation.
The researchers initiated their analysis by examining databases of human enzymes that are subject to phosphorylation, focusing specifically on those involved in metabolism. They discovered that many metabolic enzymes that undergo phosphorylation belong to a category called oxidoreductases, which transfer electrons from one molecule to another. Such enzymes are crucial for metabolic processes such as glycolysis — the conversion of glucose into a smaller compound named pyruvate.
Among the many enzymes identified by the researchers are IDH1, which plays a role in breaking down sugar for energy production, and AKR1C1, which is essential for fatty acid metabolism. The team also noted that numerous phosphorylated enzymes are vital for managing reactive oxygen species, which are necessary for various cellular functions but can be detrimental if they accumulate excessively within a cell.
Phosphorylation of these enzymes can result in either increased or decreased activity as they collectively respond to food intake. Most of the metabolic enzymes identified in this research are phosphorylated at sites located in regions of the enzyme that are significant for binding to the molecules they target or for forming dimers — pairs of proteins that connect to create a functional enzyme.
“Tigist’s research has unequivocally demonstrated the significance of phosphorylation in regulating the flow through metabolic networks. This foundational knowledge emerges from the systemic study she has conducted, and it’s information that is often overlooked in traditional biochemistry textbooks,” White remarks.
Out of Balance
To investigate these impacts in an animal model, the researchers compared two sets of mice, one group given a high-fat diet and the other a standard diet. They found that, overall, phosphorylation of metabolic enzymes resulted in a dysfunctional state where cells experienced redox imbalance, meaning they were generating more reactive oxygen species than they could mitigate. These mice also gained weight and developed insulin resistance.
“In the context of a continuous high-fat diet, we observe a gradual shift away from redox homeostasis towards a more disease-like condition,” White explains.
The effects were significantly more severe in male mice compared to females. The latter were better equipped to adjust to the high-fat diet by activating pathways involved in fat processing and metabolism, according to the researchers.
“One key takeaway is that the overall systemic impact of these phosphorylation events resulted in a greater imbalance in redox homeostasis, particularly in males, who exhibited more stress and a higher degree of metabolic dysfunction compared to females,” Tamir remarks.
The researchers also discovered that administering an antioxidant named BHA to mice on a high-fat diet significantly reversed many of these effects. These mice exhibited a notable decrease in weight gain and did not develop prediabetic conditions, unlike their counterparts on a high-fat diet.
It appears that the antioxidant treatment restores cells to a more balanced state, with fewer reactive oxygen species, the researchers indicate. Furthermore, metabolic enzymes exhibited a systemic rewiring and a modified state of phosphorylation in those mice.
“They’re facing significant metabolic dysfunction, but if you co-administer something that counteracts that, they retain enough reserve to maintain a semblance of normalcy,” Tamir states. “The research suggests a biochemical process occurring in cells that shifts them to a different state — not a normal state, just a different one where, at the tissue and organism levels, the mice are healthier.”
In her new laboratory at the University of North Carolina, Tamir plans to further investigate whether antioxidant treatment could serve as an effective means to prevent or address obesity-related metabolic dysfunction and determine the optimal timing for such treatment.
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.
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