Researchers headed by a team at the Perelman School of Medicine, University of Pennsylvania, have demonstrated how treating obese mice with a cytokine called thymic stromal lymphopoietin (TSLP) triggers significant abdominal fat and weight loss. The team’s studies found that, unexpectedly, the fat loss was not associated with decreased food intake or faster metabolism. Rather, administering a viral vector that expressed the TSLP gene stimulated the immune system to release lipids through the skin’s oil-producing sebaceous glands.
“This was a completely unforeseen finding, but we’ve demonstrated that fat loss can be achieved by secreting calories from the skin in the form of energy-rich sebum,” said principal investigator Taku Kambayashi, MD, PhD, an associate professor of pathology and laboratory medicine at Penn, who led the study with fourth-year medical student Ruth Choa, PhD. “We believe that we are the first group to show a non-hormonal way to induce this process, highlighting an unexpected role for the body’s immune system.” The animal model findings, Kambayashi said, support the possibility that increasing sebum production via the immune system could be a strategy for treating obesity in people.
The team reported on its work in Science, in a paper titled, “Thymic stromal lymphopoietin induces adipose loss through sebum hypersecretion.”
Obesity is a serious public health concern, and globally, more than 40% of adults are overweight or obese, the authors explained. Obese individuals face up to a sevenfold increased risk of associated chronic diseases, such as type II diabetes, fatty liver disease, heart disease, and certain cancers. Interestingly, recent studies have indicated that the immune system can regulate adipose tissue and its metabolic function. TSLP is a cytokine—a type of immune system protein—that plays a role in asthma and other allergic diseases. The Kambayashi research group has been investigating the expanded role of this cytokine in the activation of type 2 immune cells and expansion of T regulatory cells. Past studies have indicated that these cells can regulate energy metabolism, and the researchers hypothesized that treating overweight mice using TSLP could stimulate an immune response, which could subsequently offset some of the harmful effects of obesity. “We hypothesized that TSLP could counteract obesity and its associated complications by expanding type 2 immune cells and Treg cells,” they wrote.
“Initially, we did not think TSLP would have any effect on obesity itself,” Kambayashi further explained. “What we wanted to find out was whether it could impact insulin resistance. We thought that the cytokine could correct type 2 diabetes, without actually causing the mice to lose any weight.”
To test the effect of TSLP on type 2 diabetes, the researchers injected high-fat diet (HFD)-fed obese mice with a TSLP-expressing viral vector—TSLP-expressing adeno-associated virus serotype 8 (TSLP-AAV)—that would increase their bodies’ TSLP levels. They found that after four weeks, the TSLP vector injections had not only impacted on the diabetes risk in treated mice, but had actually reversed the animals’ obesity. While the control group of mice continued to gain weight, the weight of the TSLP-treated mice went from 45 g down to a healthy 25 g, on average, in just 28 days. “TSLP not only prevented but also reversed obesity,” the team commented.
Most strikingly, the TSLP-treated obese mice also exhibited decreased visceral fat mass, improved blood glucose and fasting insulin levels, as well as decreased risk of fatty liver disease. Visceral fat is the white fat (or white adipose tissue; WAT) that is stored in the abdomen around major organs, which can increase diabetes, heart disease, and stroke risk. “Compared with mice administered control-AAV, mice given TSLP-AAV displayed selective WAT loss, which protected against diet-induced and genetic models of obesity, insulin resistance, and nonalcoholic steatohepatitis (NASH),” the investigators wrote in their research article summary.
Given the dramatic results, Kambayashi assumed that the TSLP was effectively causing the mice to sicken, and reducing their appetites. However, further tests indicated that the TSLP-treated mice were actually eating 20–30% more than the control mice, and had similar energy expenditures, base metabolic rates, and activity levels, when compared to their non-treated counterparts.
To explain the weight loss, Kambayashi recalled a small observation he had previously ignored. “When I looked at the coats of the TSLP-treated mice, I noticed that they glistened in the light. I always knew exactly which mice had been treated, because they were so much shinier than the others,” he said.
Kambayashi considered a far-fetched idea—was their greasy hair a sign that the mice were “sweating” out fat from their skin? To test the theory, the researchers shaved the TSLP-treated mice and the controls and then extracted oils from their fur. They found that Kambayashi’s hypothesis was correct. The shiny fur contained sebum-specific lipids. Sebum is a calorically dense substance produced by sebocytes (highly specializedepithelial cells) in the sebaceous glands, and helps to form the skin barrier.
The finding confirmed that the release of oil through the skin was responsible for the TSLP-induced fat loss. “Our findings support a model in which TSLP overexpression causes WAT loss by inducing skin T-cell migration and increasing sebum hypersecretion,” they commented. “Thus, we establish a paradigm in which adipose loss can be achieved by means of sebum hypersecretion and uncover a role for adaptive immunity in skin barrier function through sebum secretion … Our data provide a therapeutic proof of concept that adipose loss can be achieved by secreting calories from the skin in the form of energy-rich sebum.”
To examine whether TSLP could potentially play a role in the control of oil secretion in humans, the researchers then examined TSLP and a panel of 18 sebaceous gland-associated genes in a publicly available dataset. This revealed that TSLP expression is significantly and positively correlated with sebaceous gland gene expression in healthy human skin.
The study authors concluded that, in humans, boosting sebum release could feasibly lead to the weight loss effectively through the release of fat through the skin. “… although weight is unlikely to be controlled by sebum release at homeostasis, it is feasible that the selective loss of WAT could be achieved through “sweating fat” in humans by therapeutically shifting sebum release into high gear,” they stated. Kambayashi’s group plans further study to test this hypothesis. “I don’t think we naturally control our weight by regulating sebum production, but we may be able to highjack the process and increase sebum production to cause fat loss,” Kambayashi said. “This could lead to novel therapeutic interventions that reverse obesity and lipid disorders.”
