Research on mice that ‘sweat out’ fat wins STAT Madness for University of Pennsylvania

Pizza rat, watch out: Pizza-faced mice are on their way to stealing your crown. A team of University of Pennsylvania medical school researchers that discovered an unlikely potential weight loss solution — “sweating out” fat through the skin as sebum — have won the STAT Madness popular vote. The annual bracket-style competition that highlights some of the most notable biomedical research from the past year concluded Sunday after fierce competition among the 64 entrants, with over 350,000 votes cast in total.

The Penn researchers garnered 71% of the vote in the final round against a University of California, Davis, team. It’s a clean sweep for the Penn team, which was also the crowd favorite last week of the audience at the STAT Breakthrough Science Summit.

The research that emerged victorious arose from a “serendipitous” finding in a type 2 diabetes experiment, said senior author Taku Kambayashi, an associate professor of pathology and laboratory medicine at the University of Pennsylvania’s Perelman School of Medicine. Kambayashi’s lab was studying how mice reacted to a molecule called TSLP, a cytokine that kicks a subset of immune cells into overdrive. Obese mice that were given excess TSLP shed their pounds in a matter of weeks — a result Kambayashi initially interpreted as an undesirable but insignificant effect of the treatment.

But, oddly enough, he noticed that the mice also became “grease balls”: “They’re so greasy, they slip out of your hands,” he said. Once a vet confirmed that the mice’s condition was indeed abnormal, the team was off to the races.

As further experiments revealed, an overabundance of TSLP ramped up the secretion of sebum, an oily substance that is high in fat and protects the skin. In essence, the mice were producing so much sebum that they were burning calories through their skin. And since TSLP engages the adaptive immune system, the mice’s T cells could remember how to burn fat, even without the cytokine: When the researchers injected the T cells of a mouse that had received excess TSLP into a mouse that had not, the recipient still lost weight. The study was published in July in the journal Science.

Though the research is still several steps from the clinic, there’s a mechanistic reason to be optimistic it could work in people, Kambayashi said. TSLP triggered a mild, off-target allergic reaction in the mice, but humans have two forms of the cytokine — only one induces inflammation, while the other form seems to act specifically on sebum production. Kambayashi added that the team is writing a manuscript that details how TSLP activates the adaptive immune system.

Kambayashi and his team will first target a number of skin diseases with the experimental treatment, and he said they hope to begin trials in people with atopic dermatitis as early as the first quarter of 2023, via Abrax, a company he co-founded.

A UC Davis team led by David Olson and Lin Tian took second place. Olson’s research into psychoplastogens — the class of compounds containing psychedelics — has earned him a berth in STAT Madness on two previous occasions, making Kambayashi an underdog victor. For this year’s entry, Olson collaborated with Tian, who specializes in making biosensors, to develop a fluorescence-based assay for predicting when a psychoplastogen has hallucinogenic effects.

“Short of giving one of these compounds to a person, how are you going to be able to predict if people are likely to experience hallucinogenic effects or not?“ Olson said in an interview with STAT. “At that point, there was no cellular assay for hallucinogenic potential.”

Some psychoplastogens — including MDMA and psilocybin — have been shown in clinical trials to be effective at treating PTSD and depression, but hallucinogens are not for everyone, particularly those with a family history of psychotic illness. Olson and Tian showed that their sensor, called psychLight, reacted to changes in serotonin release caused by hallucinogens. Then, the team identified a non-hallucinogenic analog of a psychedelic that holds potential as an antidepressant. The research was published in May in the journal Cell.

According to Olson, the biosensor can accelerate drug discovery in a field that desperately needs new blood.

“The antidepressants that we have are unfortunately quite terrible — they typically take weeks to months to demonstrate efficacy; they come with a whole host of unwanted side effects from chronic administration; and then about a third of all patients will never respond to them,” he said. “I think neuropsychiatry is desperate for something better.”

In addition to aiding in the identification of new non-hallucinogenic, antidepressant compounds, psychLight could help root out potentially dangerous designer drugs. To skirt regulations and evade detection, “clandestine chemists” may modify known hallucinogens to increase their potency without first validating their safety in humans, Olson said. Such compounds would not necessarily show up on drug tests, so a sensor like psychLight could help consumers and officials wade through the black market.

Olson said the reaction to his study has been “overwhelmingly positive,” while Kambayashi said his paper has attracted popular interest but a more measured reaction from the scientific community — their skepticism, he believes, is not about whether fat is being converted into oily sebum, but how much of the weight is actually lost through the skin.

Kambayashi said the secret sauce to his paper’s victory was its wackiness. “I really had fun with it, and it’s very easy for me to convey the information to laypeople,” he said. “When we had this story half-finished, I was talking to more people at the bar than at work.”

It’s this mass appeal that even his competitor found persuasive.

“​​How are we going to be able to compete with that?” Olson said about Kambayashi’s research on Saturday. “I think I need to start preparing my concession speech.”