Potential Source of Chronic Inflammation in Patients With Obesity May Lead to Treatment

Chronic, low-level inflammation is one of the main causes of the diseases associated with obesity. For this reason, researchers investigated which cell type was responsible for triggering inflammation in fat tissue.

Chronic, low-level inflammation is one of the main causes of the diseases associated with obesity. For this reason, researchers at UT Southwestern Medical Center investigated which cell type was responsible for triggering inflammation in fat tissue. The results of their research may potentially lead to new methods of treating the inflammation associated with obesity.

"The inflammation of fat cells in obese individuals is linked to many of the comorbidities we associate with being overweight—cancer, diabetes, heart disease, and infection," said study lead Rana Gupta, PhD, associate professor of internal medicine at UT Southwestern Medical Center, in a press release. "By identifying these cells, we've taken a step toward understanding some of the initial events that contribute to that inflammation."

Excess calories in the body are stored as triglycerides within fat tissue or white adipose tissue (WAT). In patients with obesity, WAT can become overworked in the body, leading to the death of fat cells and the activation of immune cells, resulting in inflammation. However, the mechanism that is triggered to cause this inflammation remains unknown.

Although prior research had focused primarily on the signaling molecules in WAT that might cause the inflammation, the researchers at UT Southwestern Medical Center looked instead at the vessels that carry blood, immune cells, and inflammatory molecules into WAT.

In a study conducted in 2018, the researchers identified a new type of adipose progenitor cell (APC) that they called fibro-inflammatory progenitors (FIPs), which they found to be a precursor cell that generates mature fat cells. However, unlike most APCs, FIPs produced signals that promoted inflammation. In the new study, the researchers focused on how FIPs may be able to mediate inflammation.

After a day of observing the FIP levels in mice following a switch to a high-fat diet, the researchers found an increase in the production of inflammatory molecules. After being placed on the high-fat diet for 28 days, the mice demonstrated a substantial increase in the proportion of FIPs compared with other APCs.

"This is the first study to demonstrate that these cells play a very active, early role in being gatekeepers of inflammation in fat tissue," Gupta said in the press release.

In order to demonstrate that the increase in the production and activity of the FIPs was not just a result of the fat cells being inflamed, the team removed Tlr4, a key immune signaling gene, from the FIPs in some of the observed mice. After 5 months on the same high-fat diet, the mice with Tlr4 removed had gained the same amount of weight as the other mice on a high-fat diet.

However, the genetically engineered mice who had FIPs that were no longer able to generate the same signals demonstrated a lower level of inflammation. For these mice, despite their weight gain, the level of inflammation was closer to the levels seen in mice on low-fat diets.

The research also demonstrated that increasing the levels of ZFP423, a related signaling molecule, in FIPs was able to improve inflammation in mouse fat cells. These results may lead to developing effective methods of lowering the risk of disease caused by inflammation in people with obesity.

"It looks like ZFP423 could be an important brake in terms of slowing the inflammatory signals in these cells," Gupta said in the press release. "Of course, it remains to be seen if that's true in humans as well as mice."

Gupta noted that further research is planned to investigate the aspect of a high-fat diet that first triggers the increase in inflammatory signaling in FIPs, as well as whether the results of this study will be consistent when tested in human fat.

REFERENCE

Blood vessel cells implicated in chronic inflammation of obesity. Dallas, TX: UT Southwestern Medical Center; December 31, 2020. sciencedaily.com/releases/2020/12/201231091048.htm. Accessed January 5, 2020.