A new mouse study led by researchers at the University of Chicago (UChicago) and Indiana University demonstrates that a protein called elF5A is necessary for driving inflammation in macrophage cells in obesity. Blocking DHPS, the enzyme that modifies and activates elF5A, led to reduced inflammation and improved glucose control in mice.
Their findings are published in the journal Cell Metabolism in a paper titled, “Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype.”
“The metabolic inflammation (meta-inflammation) of obesity is characterized by proinflammatory macrophage infiltration into adipose tissue,” the researchers wrote.
The team sought to determine DHPS’s role in inflammation and obesity since little was known about the protein.
“When I joined the lab as a postdoc, I was interested to see if the DHS pathway could be a common thread promoting inflammation both in the pancreas, as Dr. Mirmira’s lab had shown, and in the setting of adipose tissue meta-inflammation,” said Emily Anderson-Baucum, PhD, a former postdoctoral scholar at Indiana University.
The researchers focused on the downstream effects on the e1F5A protein, which DHPS activates by modifying a lysine amino acid to generate a rare amino acid called hypusine.
“ElF5A is important in the production of other proteins because of its effects on mRNA translation, but it only does this when cells are under stress,” said Rhagu Mimira, MD, PhD, professor of medicine at UChicago Medicine. “This often is actually protective, but a protective process can become destructive if the stress is ongoing, and can eventually kill the cell. Obesity is an example of an environment that tends to put a lot of stress on our cells, which can trigger these inflammatory pathways that normally would not be triggered. So, we wanted to determine what role these two proteins play in obesity, and in particular in the macrophages—cells that we know play a role in inflammation in obesity.”
In mice that were fed a high-fat diet and became obese, there was an increase in the expression of DHPS, and the activated form of elF5A called elF5AHyp was enriched in macrophages found in adipose tissue.
“We hypothesized that this upregulation was maladaptive, and so we thought that maybe if we blocked DHPS in mice, we could stop this process,” said Mirmira. “And when we blocked this enzyme, we were able to alter the way that the macrophages behaved. They weren’t behaving in an inflammatory way anymore. And even though the animals got obese, they didn’t exhibit metabolic dysfunction, and they didn’t get hyperglycemia.”
The researchers observed that by knocking out DHPS, there was an overall reduction in mRNA translation in inflammatory macrophages, and a reduction in the secretion of some proteins associated with inflammation. In mice, the researchers were able to knock out DHPS only in macrophages, and found that doing so led to a decrease in inflammation and improved glycemic control, even though the mice still became obese after being fed a high-fat diet.
“These results really allow us to dissociate simple weight gain from the subsequent diabetes that often is seen in obesity,” said Mirmira. “Simply knocking out the enzyme in macrophages was enough to have an effect.”
“We know that with a high-fat diet, macrophages are more inclined to be inflammatory,” Mirmira said. “The DHPS enzyme seems to be the trigger that makes those macrophages inflammatory. So, without this enzyme, you don’t get the consequences of inflammation.”
The researchers were surprised to find that a single enzyme could be pivotal in the way that macrophages behave. “There are so many proteins involved in inflammation, and we seem to have distilled it down to a single protein that plays a key role,” said Mirmira.
The researchers are looking forward to investigating at least one small molecule, already approved by the FDA for use in humans, that blocks an enzyme upstream of DHPS.
“Obesity is a complex matter,” said Mirmira. “People can view obesity as an issue of poor choices, but it’s more complicated than that. There are genetic and environmental factors involved. This work shows us that not all of the consequences of obesity are inevitable. And while we do still need to address other aspects of obesity, such as how we can modify our behaviors and our diets, we also need to think about how we can minimize the complications in people who are obese. Obesity doesn’t go away overnight, and half of the United States is either overweight or obese. That’s a huge number. Finding good ways to control blood sugar and treat diabetes in these cases will be crucial for the population and for the healthcare system.”