Scientists have discovered a type of cell responsible for triggering inflammation in fat tissue


When fat cells in the body are stuffed with excess fat, the surrounding tissue becomes inflamed. That chronic, low-level inflammation is one of the driving 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 triggering this inflammation in fat tissue. Their findings, published in Nature Metabolism, could eventually lead to new ways to treat 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,” says study leader Rana Gupta, Ph.D., associate professor of internal medicine.

“By identifying these cells, we’ve taken a step toward understanding some of the initial events that contribute to that inflammation.”

When a person consumes more calories than needed, the excess calories are stored in the form of triglycerides inside fat tissue, also known as white adipose tissue (WAT).

Researchers know that in obese people, WAT becomes overworked, fat cells begin to die, and immune cells become activated. But the exact mechanism by which this inflammation occurs isn’t fully understood.

While many studies have focused on the signaling molecules produced by the fat cells or immune cells in WAT that might contribute to inflammation, Gupta’s team took a different approach. They focused instead on the vessels that carry blood – 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 precursor cell that goes on to generate mature fat cells.

But unlike most APCs, the new cells – dubbed fibro-inflammatory progenitors, or FIPs – produced signals that encouraged inflammation. In the new work, the researchers looked more closely at the role of the FIPs in mediating inflammation.

Within just one day of switching young male mice to a high-fat diet, Gupta and his colleagues discovered that the FIPs quickly increased the number of inflammatory molecules produced.

After 28 days on a high-fat diet, they found 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,” says Gupta.

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

But the genetically engineered mice – with FIPs that could no longer generate the same signals – no longer had high levels of inflammation.

Instead, the levels of inflammatory molecules in their WAT were closer to the levels seen in mice on low-fat diets.

Gupta and his colleagues went on to show that increasing levels of a related signaling molecule, ZFP423, in FIPs can also ameliorate the inflammation in mouse fat cells. The findings point toward possible avenues to pursue to lower the risk of disease in people with obesity.

“It looks like ZFP423 could be an important brake in terms of slowing the inflammatory signals in these cells,” says Gupta. “Of course, it remains to be seen if that’s true in humans as well as mice.”

Gupta’s group is planning future experiments to better understand what aspect of a high-fat diet initiates the increased inflammatory signaling in FIPs, as well as whether the results hold true in human fat.

Obesity is a pandemic public health problem, especially in developing countries, where the prevalence is increasing exponentially in the last decades [1]. Obesity is considered the leading cause of risk for cardiovascular disease (CVD) and metabolic diseases [2].

It is a complex disorder with multifactorial etiology, characterized by an imbalance between energy intake and energy expenditure, which, in turn, induces a pathological growth of adipose tissue [3, 4]. Adipose tissue is not a passive reservoir for energy storage.

It takes, in fact, an important role in the regulation of energetic and endocrine homeostasis, by controlling the release of anti- and proinflammatory adipokines, like leptin [5]. Alterations in adipocyte biology, typical of obesity state, lead to systemic inflammation, increase in chronic oxidative stress, and obesity-related diseases [3].

Thus, strategies able to reduce the pathological inflammatory state and oxidative stress mediated by adipocyte dysfunction may be helpful in counteracting the epidemic burden of obesity.

Among the main strategies proposed to prevent obesity in adults, including increase in physical activity [6] and caloric restriction [7], the increase in consumption of food enriched with anti-inflammatory and antioxidant compounds, such as polyphenols [8], recently raised attention.

Polyphenols, such as resveratrol and quercetin, which are secondary metabolites of plants, have been reported to exert antiobesity effects by acting at different levels on adipocyte maturation [9]. In particular, they regulate preadipocyte proliferation, block adipogenesis, and induce apoptosis [10].

Polyphenols are present in the Mediterranean diet, which is a plant-based diet that became a cornerstone for the prevention of chronic diseases [11]. The Mediterranean diet, compared to other dietary regimens, exerts more beneficial health effects just for the presence of a high intake of unique polyphenols contained in the extra virgin olive oil (EVOO), among others [11, 12].

EVOO contains more than 30 polyphenolic compounds; among those, in particular, hydroxytyrosol (HT) and Tyrosol (TR) are the most absorbed and, thus, bioavailable in humans [13, 14]. TR is absorbed after ingestion in a dose-dependent manner via passive diffusion, and in humans, the absorption is as high as 55–66% since it becomes conjugated to glucuronic acid and excreted in urine as glucuronides.

Therefore, a high concentration of TR is suggested to exert its effect [15]. A recent study reported that HT and oleuropein (another EVOO polyphenolic compound) prevent adipogenesis and reduce preadipocyte proliferation [16], suggesting that these phytochemicals might prevent obesity.

Another interesting study already demonstrated that high doses of TR (0.1–1 mg/mL) are able to reduce differentiation of preadipocytes [17]. Nevertheless, to the best of our knowledge, at the moment, no data regarding possible mechanisms involved in the beneficial role of TR in adipogenesis and therefore obesity are present. In the present study, we sought to evaluate the direct effects of TR on adipogenesis by using a murine 3T3-L1 preadipocyte cell line.

reference link :

More information: Bo Shan et al. Perivascular mesenchymal cells control adipose-tissue macrophage accrual in obesity, Nature Metabolism (2020). DOI: 10.1038/s42255-020-00301-7


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