Scientists discover a cell that is responsible for stimulating persistent low-grade inflammation in fat tissue

When fat cells in the body are filled with too much fat, the surrounding tissue becomes inflamed. That persistent, low – grade inflammation is one of the factors behind many of the diseases associated with obesity.

Now, UT Southwestern scientists have discovered a type of cell responsible, at least in mice, for stimulating this inflammation in fat tissue. Their conclusions, published in The metabolism of nature, ultimately that could lead to new ways of treating obesity.

Inflammation of fat cells in obese people is linked to many of the comorbidities we associate with being obese – cancer, diabetes, heart disease, and infection. By recognizing these cells, we have taken a step to understand some of the initial events that contribute to that inflammation.. “

Rana Gupta, Ph.D, Director of Research and Associate Professor of Internal Medicine, UT Southwestern Medical Center

When a person eats more calories than necessary, the excess calories are stored in the form of triglycerides within a fatty tissue, also known as white adipose (WAT). Researchers know that in obese people, WAT gets overworked, fat cells begin to die, and immune cells activate them. But the exact manner in which this inflammation occurs is not understood.

While many studies have focused on the signaling molecules produced by the fat cells or immune cells in WAT that may contribute to inflammation, the Gupta team took a different approach. They instead focused on the blood-carrying vessels – as well as immune cells and inflammatory molecules – into WAT.

In 2018, Gupta and his colleagues identified a new type of cell lining these blood vessels in mice – an adipose progenitor cell (APC), or a progenitor cell that goes on to develop mature fat cells generation. But unlike most APCs, the new cells – black fibro-inflammatory progenitors, or FIPs – produced inflammation-inducing signals. In the new work, the researchers took a closer look at the role of FIPs in mediating inflammation.

Within just one day of switching young male mice to a high-fat diet, Gupta and his colleagues found that the FIPs were rapidly increasing the number of inflammatory molecules removed. After 28 days on a high-fat diet, they found a significant increase in the proportion of FIPs compared to other APCs.

“This is the first study to show that these cells play an active, early role in the gatekeepers of inflammation in fat tissue,” Gupta says.

To show that the increase in the number and activity of FIPs was not just a side effect of already inflamed fat cells, the team removed a key immune signal gene, Tlr4, from the FIPs in some mice. After five months on a high-fat diet, mice with Tlr4 deficiency had gained as much weight, and as much fat, as other mice on a high-fat diet.

But the mice did not have high levels of inflammation – with FIPs the same symptoms could no longer be generated. Instead, the levels of inflammatory molecules in their WAT were closer to those seen in mice on a low-fat diet.

Gupta and his colleagues went on to show that increasing levels of a related sign molecule, ZFP423, in FIPs can also reduce the inflammation in mouse fat cells. The findings identify potential pathways to reduce the risk of disease in obese people.

“It looks like ZFP423 could be an important brake in slowing down the inflammatory signals in those cells,” Gupta says. “Of course, it remains to be seen whether that is true in humans as well as mice.”

Gupta group is planning future experiments to better understand which side of a high-fat diet triggers more bloating symptoms in FIPs, as well as whether the results are true in human fat.