Greasy mice that “sweat” fat are leading Penn researchers to the top of the STAT Madness heap – and to potential new areas of discovery.
By Meredith Mann
Researchers at the Perelman School of Medicine may have accidentally stumbled upon an unlikely holy grail for obesity-associated diseases – “sweating” out fat.
And this “so crazy, it just might work” discovery earned them first place in this year’s STAT Madness competition for the biggest breakthroughs in science and medicine.
“It was too far-fetched for us to go there to begin with,” says the study’s lead author, Taku Kambayashi, MD, PhD, an associate professor of Pathology and Laboratory Medicine, as he describes the project which initially sought merely to reduce obesity-related disease complications in mice.
The research, published in Science last year, involved injecting overfed mice with a cytokine molecule called thymic stromal lymphopoietin (TSLP), with the goal of blocking obesity-induced inflammation and thus lowering the risk of insulin resistance and other health problems.
The researchers found that TSLP-treated mice were indeed less likely to develop conditions like diabetes, atherosclerosis, and fatty liver disease (FLD). They also noticed that after four weeks the mice, who’d been fed a high-fat diet were no longer obese – despite the fact that they were eating 20 to 30 percent more than control mice. Not only that, their fat cells shrank and lost the fat content, to the point of causing hypothermia.
“We went through a lot of detective work” to tease out the mechanism for the weight loss, chuckles Kambayashi – measuring the mice’s metabolism, and even analyzing the caloric content of their waste.
Kambayashi’s team finally took a good, hard look at their subjects – and found the answer literally slipping right through their hands. “They were greaseballs, very slimy, kind of like an eel,” he says. “We had ignored it because we didn’t know what it meant.”
Shaving the mice and testing their fur revealed the mystery substance as sebum–the body’s fatty, oily skin protectant. It turns out that TSLP activated T cells in the immune system, which migrated to sebaceous glands and kicked sebum production into overdrive. In lay terms, the mice were “sweating” fat out as fast as their bodies could produce it.
The researchers confirmed this new hypothesis by administering TSLP to mice engineered without sebaceous glands; they saw no change in the subjects’ weight. Further, they transferred TSLP-activated T cells to TSLP-naïve mice, and sure enough, this group started shedding fat.
The findings earned the team a spot earlier this year in STAT Madness, a “March Madness” bracket-style competition sponsored by the media company STAT. Kambayashi and his colleagues not only got 71 percent of the 350,000 votes cast to win the bracket of 64 entries, they also walked away with “audience favorite” honors at the STAT Breakthrough Science Summit.
Winning the competition only conferred bragging rights, but also helped the research generate interest from venture capital firms. Currently, Kambayashi is working to establish real-world applications in humans through a company he co-founded, Abrax Japan, which plans to launch Phase 1 safety clinical trials in Australia next year.
While ramping up TSLP’s effects could translate into human weight loss of a pound a week, Kambayashi is setting his sights squarely on direct health benefits, rather than weight loss itself, to start. He thinks the agent could be useful in reducing FLD, type 2 diabetes, cardiovascular disease, and other comorbidities of obesity.
Even more promising, he suggests, is its potential for improvement in skin conditions such as eczema, dry skin, and even dry eye. As opposed to slathering on emollient-rich lotions as treatment, Kambayashi points out, in these conditions, helping the body generate more of its own oil-rich sebum would be “really curing the disease from the inside out.”