Diet high in fat triggers cellular metabolic disturbances, fostering weight increase.
High-fat diets can precipitate a variety of health issues, beyond just weight gain. These include an elevated risk of diabetes and other chronic conditions. Researchers from MIT have delved into the cellular changes induced by such diets, focusing on metabolic enzyme dysregulation associated with weight gain.
The study, carried out on mice, revealed that thousands of enzymes vital for sugar, lipid, and protein metabolism are impacted by a high-fat diet, leading to increased insulin resistance and an accumulation of reactive oxygen species. These effects were more prominent in male mice than female.
Researchers found that most of the damage caused by a high-fat diet could be partially reversed by administering an antioxidant alongside the diet.
"Under metabolic distress, enzymes can be altered to produce a more detrimental state than initially present," explains Tigist Tamir, a former MIT postdoc and lead author of the study. "The antioxidant study demonstrated that these changes could be steered towards a less dysfunctional state."
Tamir, now an assistant professor of biochemistry and biophysics at the University of North Carolina at Chapel Hill School of Medicine, along with senior author Forest White, have published their findings in Molecular Cell.
In their investigation, the researchers examined the role of enzyme phosphorylation in response to a high-fat diet. Phosphorylation, the addition of a phosphate group, can switch enzyme activity on or off.
Many enzymes involved in metabolism, the conversion of food into essential molecules, are known to undergo phosphorylation. The researchers identified hundreds of such enzymes, particularly oxidoreductases, which transfer electrons from one molecule to another, playing a pivotal role in metabolic reactions.
The phosphorylation of these enzymes can cause them to become more or less active, collectively coordinating responses to food intake. Most of the metabolic enzymes identified in this study were phosphorylated at sites crucial for binding to their target molecules or forming dimers — pairs of proteins essential for enzyme function.
Consequently, the team observed a dysfunctional state characterized by redox imbalance in mice consuming a high-fat diet. In this state, cells produced more reactive oxygen species than they could neutralize, and the mice developed insulin resistance and gain excess weight.
Female mice exhibited better resilience to a high-fat diet, activating pathways involved in processing and metabolizing fat for alternate uses. Surprisingly, male mice bore the brunt of the imbalance in redox homeostasis, experiencing more stress and metabolic dysfunction.
When mice on a high-fat diet were given an antioxidant called BHA, many of the observed effects were reversed. These mice showed a significant decrease in weight gain and did not develop prediabetes, unlike their peers fed a high-fat diet without antioxidants.
The antioxidant treatment appeared to push cells back into a more balanced state, with fewer reactive oxygen species. Metabolic enzymes also showed a systemic rewiring, changing their phosphorylation state in the treated mice.
In her new lab at the University of North Carolina, Tamir plans to further explore whether antioxidant treatment could potentially prevent or address obesity-related metabolic dysfunction and determine optimal timing for such treatment.
The 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.
- High-fat diets can trigger a range of health problems, including diabetes and other chronic conditions, beyond just weight gain.
- Researchers from MIT have investigated the cellular changes that high-fat diets induce, focusing on metabolic enzyme dysregulation associated with weight gain.
- The study, performed on mice, uncovered that thousands of enzymes crucial for sugar, lipid, and protein metabolism are affected by a high-fat diet, leading to increased insulin resistance and an accumulation of reactive oxygen species.
- Most of the damage caused by a high-fat diet could be partially mitigated by administering an antioxidant alongside the diet.
- Researchers discovered that enzyme phosphorylation plays a significant role in response to a high-fat diet, with hundreds of enzymes, particularly oxidoreductases, being identified.
- The phosphorylation of these enzymes can influence their activity, collectively regulating responses to food intake.
- In a dysfunctional state caused by a high-fat diet, cells produce more reactive oxygen species than they can neutralize, leading to insulin resistance and excess weight gain.
- Female mice appear to exhibit better resilience to a high-fat diet, activating pathways that metabolize fat for alternative uses.
- When mice on a high-fat diet were given the antioxidant BHA, many of the observed effects were reversed, leading to a significant decrease in weight gain and the prevention of prediabetes.
