Mysteriously “slimy” mice lead to surprise fat loss discovery

What started as an investigation into a potential treatment for type 2 diabetes took a strange turn when a group of lab mice in the study started glistening.

The chance observation was weird, to be sure, but it also took the researchers behind the study down a very different path than they had initially intended. The mice were shiny because they were secreting fat out through their skin, making their fur so greasy it looked wet. They were also losing weight rapidly as a result.

In a new paper published in the journal Science, the researchers describe how this bizarre effect led them to inadvertently stumble on a potential treatment for obesity.

“I'm quite optimistic that there’s something that will come out of this in terms of therapeutic [applications],” Taku Kambayashi tells Inverse. “But if not, I think the physiological implications of our study are huge.”

Kambayashi is the senior author of the study and an associate professor of pathology and laboratory medicine at the University of Pennsylvania.

“They glistened in the light.”

How they did it — The research team had begun their work by increasing the cytokine TSLP in mice who had gained weight on a high-fat diet. They did this via a viral “vector” - essentially a virus that delivers copies of genes to tissues of the body to express specific proteins. TSLP is a protein known to activate certain immune cells that may regulate and reduce inflammation, which is a key feature of both obesity and type 2 diabetes.

Over the study, these mice lost about half their total white body fat. Notably, the fat loss included visceral fat, which surrounds organs and can lead to significant health problems in humans.

At first, the researchers thought the mice had lost their appetite from the cytokine treatment, but they were eating more than their untreated peers.

So next the researchers tested the slimming mice’s urine and feces to see if they were expending the extra calories that way, but again nothing. To make matters more confusing, the mice were also no more physically active than the control group, nor did they show signs of a ramped-up metabolism.

“It’s icky, but it’s still a fun concept.”

The discovery — Once they ruled out these other explanations for the mice’s fast fat loss, Kambayashi says he went back to a detail he had noticed and dismissed — he always knew how to tell the TSLP mice apart from the controls because of one strange physical factor.

“They glistened in the light,” he says.

“The ones that got TSLP they're always shiny, and I didn’t know what that meant.”

“When they were losing that much weight, they were, I would say, slimy, almost,” he says.

Could it be that they were losing fat by secreting it from their skin?

Kambayashi’s team first shaved the mice and tested the greasy substance that had gathered on their fur. It was sebum — a waxy, oily substance that humans and mice alike secrete from something called sebaceous glands on the surface of the skin (similar, but not the same, as where sweat is secreted).

Sebum is rich in calories and fats. It’s what keeps our skin from drying out and it is also what can make our hair appear greasy.

The researchers had discovered something important: not only were mice actually ejecting fat out of their bodies through their skin, but there was a link between this cytokine and the sebaceous glands, which create a protective barrier for the skin.

They confirmed the phenomenon by doing a few more tests — for example, putting mice with defective sebaceous glands on the same diet and increasing their TSLP. The mice didn’t lose weight.

The TSLP also appears to activate the mice’s T cells, key players in the immune system. T cells actually migrated to the sebaceous glands of the mice when TSLP was administered. When the researchers blocked T cell migration the mice didn’t lose weight through secreting fat out their skin. This connection between TSLP and sebum production, then, was directly related to T cells.

“You don’t want to do that in humans.”

“You can lose weight by secreting massive amounts of lipids through your skin, which is kind of, maybe it’s icky, but it’s still a fun concept,” Kambayashi says.

“Whether or not it will work in humans, I don’t know. But it definitely works in mice.”

Why it matters — These findings are interesting, but they could also have a couple of applications for treating real health conditions in humans.

Skin conditions that involve a problem with what Kambayashi calls “skin barrier function,” like eczema, could benefit from the extra sebum produced by this therapy.

The researchers tested human skin samples to further examine this relationship and found that where there was more natural TSLP (which the body makes itself) in the skin, the more highly “expressed” genes for sebum production. In other words, people with drier skin may also have less TSLP produced in their bodies, and supplementing that function could treat skin-related problems.

Sebaceous glands also draw out triglycerides, a type of harmful fat in the blood that can increase the risk of heart disease and stroke. A drug that prompted TSLP activation could help keep triglycerides lower.

Then there’s a potential for treating obesity and the metabolic problems that can accompany this condition.

“Obesity is probably going to be the highest hurdle” in terms of developing new treatments with this information, Kambayashi says, partially because calibrating the calories lost would be tricky.

He explains that the mice lost around half their body weight in a matter of three weeks.

“They’re secreting massive amounts of lipids through their skin, and you don’t want to do that in humans.”

What’s more, he said, extra sebum production could lead to an unpleasant side effect: Acne.

“I think we’re going to have to control it in a way that it’s not, you know, messy for the patient.”

What’s next — Though the research team performed lab tests with human skin, it’s too early to tell whether or not this kind of treatment is effective or safe in humans. In a commentary on the study published in Science Magazine, researcher Marlon R. Schneider writes that “sebaceous gland physiology and sebum composition are highly species-specific, differing substantially between humans and mice.”

The commentary also points to the safety implications, including the potential of increasing the sebum production of protective eyelid glands. Schneider also says that because obesity is influenced by so many factors, a treatment that eats up lipids is likely only a part of the solution.

Kambayashi says he’s optimistic.

“I have high hopes. I think in some way or form, we are going to be able to translate this.”

Next, the team will look into the mechanism behind the extra sebum production. One key question left to answer: what it is about the T cell activation that influences the sebaceous glands?

The researchers also want to study if another physiological player might be involved: the microbiome. This is the population of microbes that lives in and on the body. The extra sebum the mice produced contains antimicrobial peptides. These substances also help protect the skin as part of our immune system. But in mice without any way to make TSLP, there were fewer of these peptides present.

“We think that there’s some kind of reciprocal interaction between the microbiome and the skin sebum production.”

Abstract: Emerging studies indicate that the immune system can regulate systemic metabolism. Here, we show that thymic stromal lymphopoietin (TSLP) stimulates T cells to induce selective white adipose loss, which protects against obesity, improves glucose metabolism, and mitigates nonalcoholic steatohepatitis. Unexpectedly, adipose loss was not caused by alterations in food intake, absorption, or energy expenditure. Rather, it was induced by the excessive loss of lipids through the skin as sebum. TSLP and T cells regulated sebum release and sebum-associated antimicrobial peptide expression in the steady state. In human skin, TSLP expression correlated directly with sebum-associated gene expression. 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.