Exhaust fat by "sweating": This cytokine may reverse obesity

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Exhaust fat by “sweating”: Science reveals that this cytokine may reverse obesity

Exhaust fat by “sweating”: This cytokine may reverse obesity. At present, obesity and its related complications have become a global public health problem. Data shows that more than 40% of adults are overweight or obese, which also means that they suffer from fatty liver, diabetes, cardiovascular disease and tumors. The risk is greatly increased.

Although this phenomenon has aroused the attention of public health authorities and a number of measures have been released, the obesity rate continues to rise. Therefore, there is an urgent need to clarify the relevant ways that affect obesity and lay the foundation for the designation of more effective interventions.

The latest research shows that the immune system can regulate adipose tissue and its metabolic functions. For example, type 2 innate lymphoid cells (ILC2) and eosinophils can promote fat beige to increase the metabolic rate; in addition, immunosuppression Sex cell Treg can prevent type 2 diabetes by promoting insulin sensitivity.

Exhaust fat by "sweating": Science reveals that this cytokine may reverse obesity

Thymic stromal lymphopoietin (TSLP) is a cytokine derived from epithelial cells and a protein of the immune system. It is involved in asthma and other allergic diseases. It is expressed on skin, intestinal and other barrier parts. Proven to act as an activator of type 2 immune cells, and can significantly increase Treg. Combining previous studies that immune cells regulate fat metabolism, the researchers speculate: Can TSLP regulate specific immune cells to fight obesity and its related complications?

The research team of the Perelman School of Medicine at the University of Pennsylvania published an article titled Thymic stromal lymphopoietin induces adipose loss through sebum hypersecretion in the top international journal Science. Research results show that TSLP can significantly reduce abdominal fat and body weight in obese mice. What’s more surprising is that this “weight loss” has nothing to do with reduced food intake or faster metabolism, but TSLP activates the body’s immune system. The sebaceous glands that secrete oil in the skin accelerate the release of lipids, reducing fat in a way of “oiling out”.

TSLP prevents obesity and obesity-related complications

To test the effect of TSLP on obesity, the researchers injected a viral vector (TSLP-AAV) into obese mice to increase the level of TSLP in their bodies. After four weeks of high-fat feeding, they found that the TSLP-treated mice reversed the obesity caused by the high-fat diet. Not only that, TSLP can also significantly improve the metabolic indicators of mice, including glucose tolerance, fasting blood glucose levels, fasting insulin levels, insulin sensitivity, and liver triglyceride levels.

Considering the reduction of liver steatosis, they further explored the role of TSLP in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) mouse models. To this end, they fed the mice with Methionine Choline Deficiency Diet (MCDD) for 4 weeks, and then treated them with TSLP-AAV. The results showed that compared with the control group, MCDD-fed mice received TSLP-AAV, liver triglyceride levels, serum alanine aminotransferase levels, and liver fibrosis were significantly reduced.

Next, they explored the effect of TSLP on fat metabolism in normally fed mice. The results showed that after 2 weeks of TSLP-AAV treatment, white adipose tissue (WAT) in mice was significantly reduced, but brown adipose tissue (BAT) and muscle content did not decrease correspondingly, and the reduction of WAT was dose-dependent with the level of TSLP in the serum. Sexually related. Therefore, these results indicate the role of TSLP in preventing obesity and related complications.

Then, to answer which cell type might mediate TSLP-driven WAT loss, they first tested hematopoietic (radiation-sensitive) or non-hematopoietic (radiation-resistant) cells. After determining the influence of hematopoietic cells, they further explored which cell type was mediated.

To this end, they used a variety of specific immune cell knockout mouse models, and found that under normal feeding conditions, Ebeta-/- mice (lack of αβ T cells) did not show a significant decrease in WAT. Therefore, αβ T cells are necessary for TSLP-driven fat loss.

In order to distinguish whether CD4+ or CD8+ T cells caused this effect, they used antibodies to eliminate CD4+ and/or CD8+ T cells. Unexpectedly, only the elimination of all types of T cells can prevent TSLP-mediated WAT loss, indicating that all T cell subsets are necessary.

TSLP induces fat loss by increasing sebum secretion

TSLP caused a decrease in fat in mice, so the caloric output was greater than the caloric intake. However, the reduction in caloric intake was not the cause of TSLP-induced fat loss, because TSLP-AAV mice were given more food.

In addition, their daily excretion of calories in the feces did not increase significantly, and no evidence of increased metabolic rate was found. Therefore, TSLP does not cause energy consumption by increasing heat production.

Next, the researchers hypothesized that TSLP may cause energy loss through the excretion or secretion of calorie-containing metabolites. They observed that four weeks after the injection of TSLP-AAV, the mice began to develop more and more greasy hair that was visible to the naked eye. To identify the oily substance on the hair of mice administered TSLP-AAV, they performed hair lipid extraction and analyzed its composition by thin-layer chromatography.

The results showed that the hair lipids of mice fed with TSLP-AAV high-fat increased significantly, mainly composed of wax esters, cholesterol esters, triglycerides, free fatty acids and free cholesterol. These results indicate that TSLP-AAV can enhance sebum secretion in mice, and this increase in secretion may also be an important way for mice to “weight loss”.

Later, from the cellular point of view, they found that the increase in sebum secretion depends on the TSLPR signal in T cells. This is because Rag2-/- mice did not show an increase in hair wax ester even when TSLP-AAV was administered.

The results of skin flow cytometry showed that the skin CD4+ and CD8+ T cells increased significantly after TSLP-AAV injection. Histological staining of the skin also showed an increase in CD4+ and CD8+ T cells, which were mainly concentrated in or around the sebaceous glands. Therefore, the above results indicate that TSLP can directly stimulate the migration of T cells to the skin sebaceous glands, which is necessary for fat loss and excessive sebum secretion.

TSLP regulates sebum secretion in the body

Next, they tested whether TSLP and T cells regulate the secretion of sebum in the body at homeostasis. To this end, they examined the lipid composition of hair in wild-type and Tslpr-/- mice. The results showed that compared with wild-type mice, Tslpr-/- mice had less hair wax esters and a decrease in the proportion of Ki67+ basal cells, indicating the sebum secretion regulation function of TSLP. Similarly, Rag2-/- and Ebeta-/- mice also showed a reduction in hair wax esters compared with wild-type mice, indicating that T cells also play a balancing role in controlling sebum secretion.

Finally, they explored whether the TSLP-sebum axis is also applicable to humans. In a publicly available data set, the test results of TSLP and 18 sebaceous gland-related genes show that TSLP expression in healthy human skin is significantly positively correlated with sebaceous gland gene expression. These findings are consistent with previous studies that the expression of TSLP in seborrheic areas of healthy human skin is higher than that in dry areas. Therefore, TSLP under physiological conditions may also control sebum production in the human body.

Concluding remarks

In summary, this study shows that fat reduction can be achieved by secreting energy-rich sebum from the skin. Therapeutic level of TSLP can selectively reduce white fat by directly acting on T cells to induce excessive sebum secretion, while physiological level of TSLP can maintain the steady state of sebum production and skin barrier function in the body.

In addition, this study also proved that the immune system and body metabolism, especially the important role played in the release of sebum, and this effect is also applicable to healthy humans. Therefore, TSLP and its subtypes are likely to play an important and unexplored role in healthy skin barrier maintenance, sebum secretion and immune metabolism regulation, and can also be used as new targets for therapeutic weight loss strategies.

Taku Kambayash, the corresponding author of the study, mentioned: “This is a completely unexpected discovery, but we have proven that fat reduction can be achieved by the skin’s secretion of energy-rich sebum, although I don’t think we are by regulating the secretion of sebum. It comes to control weight naturally, but we may be able to intervene in this process to increase sebum secretion, which leads to fat loss. This may lead to a new therapeutic intervention that reverses obesity and lipid disorders.”

(source:internet, reference only)

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