Reversing Obesity: Cytokine Treatment Makes Obese Mice ‘Sweat Fat’, UPenn Study Finds

In a seemingly remarkable discovery for treating Type 2 diabetes and combating insulin resistance, a team of researchers from Perelman School of Medicine, University of Pennsylvania serendipitously discovered that treating obese mice with a cytokine Thymic Stromal Lymphopoietin (TSLP) resulted in a significant loss of visceral fat- white adipose tissue (WAT) in 4 weeks.

Obesity and its associated complications such as Type 2 diabetes, chronic heart diseases, stroke, fatty liver disease, and certain cancers are serious global concerns. Despite public health initiatives, obesity rates are increasing alarmingly. WHO reports that typically more than 4 million people die each year due to being overweight or obese, according to the global disease burden.

Thus, under the pressing need to identify pathways that affect overweight and obesity, researchers from UPenn published their findings in Science. The team of investigators demonstrated that overexpression of TSLP causes significant loss of WAT via induction of skin T cell migration and increased sebum hypersecretion.

Overexpression of TSLP Reverses Obesity

TSLP is a cytokine- a type of immune system protein widely known to play a pivotal role in allergic inflammation and activation of numerous immune cell types. Additionally, the authors demonstrated that TSLP and T cells homeostatically regulate sebum production and skin anti-microbial peptides (AMP) expression, uncovering an intriguing role for the adaptive immune system in maintaining skin barrier function. 

Based on the immune regulatory function of TSLP, the researchers initially hypothesized to investigate the role of TSLP in correcting Type 2 diabetes via impacting insulin resistance. However, serendipitously they showed how the immune system could be targeted to reverse obesity.

The researchers delivered tslp-expressing adeno-associated virus (AAV) to obese mice that resulted in increased production of bodies’ TSLP levels. After four weeks, they discovered that overexpression of TSLP cytokine not only reduced the risk of developing insulin resistance, Type 2 diabetes, nonalcoholic steatohepatitis but also reversed the obesity, which were fed a high-fat diet, as evident by their decrease in weight from 45 grams to a healthy 25 grams. 

Notably, these mice also displayed selective loss of WAT-whose accumulation increases the risk of heart diseases, stroke, including others. Unexpectedly, the tslp-treated mice displayed an increased appetite, similar energy expenditure, and basal metabolism compared to untreated mice.

Sweating Fat Out

In order to explain the weight loss in tslp-treated mice, the authors noted a very seemingly unremarkable observation- ‘greasy fur’- a sign that indicated that the mice were sweating out fat from their skin. They discovered that the shiny fur of the tslp-treated mice is enriched with sebum- calorie-dense secretions from the sebaceous glands in the skin.

They showed that the release of sebum through the skin results in TSLP-induced WAT loss. Further, in order to prove the clinical relevance of their findings, the authors demonstrated that TSLP expression is significantly and positively correlated with sebaceous gland gene expression in healthy human skin.

Thus, the authors suggested that it is feasible that the selective loss of WAT could be achieved by sweating fat in humans by therapeutically shifting sebum release into high gear. Strikingly, these findings also give hope in combating liver diseases as the authors suggested in the paper that “diverting lipids toward the skin and away from the liver could also lead to improvement of obesity-associated non-alcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).”

In conclusion, translating these findings into potential novel therapies would prove valuable in reversing obesity/ overweight and combating chronic liver diseases or lipid-associated disorders by hijacking the system that mobilizes unhealthy fat to the skin and increases sebum production/ secretion to induce fat loss.

Author

Isha Kapoor