Consuming a high-fat food plan can result in a wide range of well being issues — not solely weight achieve but in addition an elevated threat of diabetes and different continual illnesses.
On the mobile stage, a whole lot of adjustments happen in response to a high-fat food plan. MIT researchers have now mapped out a few of these adjustments, with a deal with metabolic enzyme dysregulation that’s related to weight achieve.
Their research, carried out in mice, revealed that a whole lot of enzymes concerned in sugar, lipid, and protein metabolism are affected by a high-fat food plan, and that these disruptions result in a rise in insulin resistance and an accumulation of damaging molecules known as reactive oxygen species. These results have been extra pronounced in males than females.
The researchers additionally confirmed that many of the injury might be reversed by giving the mice an antioxidant together with their high-fat food plan.
“Beneath metabolic stress circumstances, enzymes will be affected to provide a extra dangerous state than what was initially there,” says Tigist Tamir, a former MIT postdoc. “Then what we have proven with the antioxidant research is that you could deliver them to a special state that’s much less dysfunctional.”
Tamir, who’s now an assistant professor of biochemistry and biophysics on the College of North Carolina at Chapel Hill Faculty of Drugs, is the lead creator of the brand new research, which seems at the moment in Molecular Cell. Forest White, the Ned C. and Janet C. Rice Professor of Organic Engineering and a member of the Koch Institute for Integrative Most cancers Analysis at MIT, is the senior creator of the paper.
Metabolic networks
In earlier work, White’s lab has discovered {that a} high-fat food plan stimulates cells to activate lots of the identical signaling pathways which can be linked to continual stress. Within the new research, the researchers wished to discover the function of enzyme phosphorylation in these responses.
Phosphorylation, or the addition of a phosphate group, can flip enzyme exercise on or off. This course of, which is managed by enzymes known as kinases, provides cells a technique to rapidly reply to environmental circumstances by fine-tuning the exercise of current enzymes inside the cell.
Many enzymes concerned in metabolism — the conversion of meals into the constructing blocks of key molecules resembling proteins, lipids, and nucleic acids — are recognized to endure phosphorylation.
The researchers started by analyzing databases of human enzymes that may be phosphorylated, specializing in enzymes concerned in metabolism. They discovered that lots of the metabolic enzymes that endure phosphorylation belong to a category known as oxidoreductases, which switch electrons from one molecule to a different. Such enzymes are key to metabolic reactions resembling glycolysis — the breakdown of glucose right into a smaller molecule referred to as pyruvate.
Among the many a whole lot of enzymes the researchers recognized are IDH1, which is concerned in breaking down sugar to generate power, and AKR1C1, which is required for metabolizing fatty acids. The researchers additionally discovered that many phosphorylated enzymes are essential for the administration of reactive oxygen species, that are mandatory for a lot of cell capabilities however will be dangerous if too lots of them accumulate in a cell.
Phosphorylation of those enzymes can make them turn out to be both kind of lively, as they work collectively to answer the consumption of meals. A lot of the metabolic enzymes recognized on this research are phosphorylated on websites present in areas of the enzyme which can be essential for binding to the molecules that they act upon or for forming dimers — pairs of proteins that be a part of collectively to type a purposeful enzyme.
“Tigist’s work has actually proven categorically the significance of phosphorylation in controlling the flux by metabolic networks. It is basic information that emerges from this systemic research that she’s executed, and it is one thing that’s not classically captured within the biochemistry textbooks,” White says.
Out of stability
To discover these results in an animal mannequin, the researchers in contrast two teams of mice, one which obtained a high-fat food plan and one which consumed a traditional food plan. They discovered that total, phosphorylation of metabolic enzymes led to a dysfunctional state by which cells have been in redox imbalance, that means that their cells have been producing extra reactive oxygen species than they may neutralize. These mice additionally turned obese and developed insulin resistance.
“Within the context of continued excessive fats food plan, what we see is a gradual drift away from redox homeostasis in the direction of a extra disease-like setting,” White says.
These results have been far more pronounced in male mice than feminine mice. Feminine mice have been higher capable of compensate for the excessive fats food plan by activating pathways concerned in processing fats and metabolizing it for different makes use of, the researchers discovered.
“One of many issues we discovered is that the general systemic impact of those phosphorylation occasions led to, particularly in males, an elevated imbalance in redox homeostasis. They have been expressing much more stress and much more of the metabolic dysfunction phenotype in comparison with females,” Tamir says.
The researchers additionally discovered that in the event that they gave mice who have been on a high-fat food plan an antioxidant known as BHA, many of those results have been reversed. These mice confirmed a big lower in weight achieve and didn’t turn out to be prediabetic, in contrast to the opposite mice fed a high-fat food plan.
It seems that the antioxidant therapy leads cells again right into a extra balanced state, with fewer reactive oxygen species, the researchers say. Moreover, metabolic enzymes confirmed a systemic rewiring and altered state of phosphorylationin these mice.
“They’re experiencing loads of metabolic dysfunction, however if you happen to co-administer one thing that counters that, then they’ve sufficient reserve to keep up some type of normalcy,” Tamir says. “The research means that there’s something biochemically taking place in cells to deliver them to a special state — not a traditional state, only a completely different state by which now, on the tissue and organism ranges, the mice are more healthy.”
In her new lab on the College of North Carolina, Tamir now plans to additional discover whether or not antioxidant therapy might be an efficient technique to stop or deal with obesity-associated metabolic dysfunction, and what the optimum timing of such a therapy can be.
The analysis was funded partially by the Burroughs Wellcome Fund, the Nationwide Most cancers Institute, the Nationwide Institutes of Well being, the Ludwig Middle at MIT, and the MIT Middle for Precision Most cancers Drugs.
