Obese mice lose weight ‘sweating out' fat in an immune system experiment, despite eating more

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In search of better treatments for type 2 diabetes and other consequences of obesity, Taku Kambayashi has long wondered if he could harness a bodily function that most think about in a different context: the immune system.

There was evidence to suggest this might work, as certain types of immune cells were known to play a role in metabolism. But when he and his colleagues at the University of Pennsylvania in the United States stimulated these cells in experiments on obese mice, they got a surprise.

Not only did the animals become healthier in terms of their blood-glucose levels and other metabolic “markers”, they also lost dramatic amounts of weight.

Within four weeks of triggering the animals’ immune response, Kambayashi and graduate student Ruth Choa found the mice had on average lost 40 per cent of their body weight – all in the form of fat.

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Taku Kambayashi was looking for better treatments for type 2 diabetes and other consequences of obesity when he made his discovery.

What’s more, careful measurements revealed that the animals’ weight loss was not the result of burning calories any faster or eating less food. They actually were eating even more than before.

The real answer, the scientists reported in academic journal Science after many months of detective work, was that the mice were “sweating” out fatty molecules through their skin.

“It’s wild,” said Kambayashi, an associate professor of pathology and laboratory medicine at the University of Pennsylvania’s Perelman School of Medicine.

The question is if this phenomenon can be exploited in humans. For the moment, the answer is unclear. All the usual caveats apply – mice are not humans, all sorts of cures for cancer and other ills seemed promising in the lab, only to wash out when tried in people.

Still, humans are known to secrete fatty molecules through the skin, just like the mice – though at low levels. The oily substance is called sebum, produced by the sebaceous glands and found on the skin and hair. (It’s separate from sweat; Kambayashi used that term in his paper just to get the idea across for a general audience.)

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Humans are known to secrete fatty molecules through the skin, just like mice. Photo: Getty Images

A typical person secretes 130 calories worth of sebum per day – not enough to have an impact on body weight. But if that process could be accelerated, say, by four times, Kambayashi thinks he would be onto something. “You’d lose a pound of fat [450 grams] per week,” he said.

Some others in the field are taking a wait-and-see stance, as obesity is a complex disorder. Among them is Richard Locksley, a professor at the University of California, San Francisco, who studies the same kinds of immune cells.

“It’s early days, but it’s interesting and plausible,” he said.

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Measurements revealed that the animals’ weight loss was not the result of burning calories any faster or eating less food. Photo: Getty Images

The Penn scientists stimulated the mouse immune cells by treating them with a type of cytokine – from the same family of proteins involved in a harmful inflammatory overreaction to Covid-19, called a “cytokine storm”.

The scientists coaxed the animals to produce the cytokine by injecting them with a viral vector, loaded with genetic instructions to make the protein – much like the Covid-19 vaccine made by Johnson & Johnson.

If the concept were to be explored in people, researchers would probably try to achieve the same goal – ramping up production of this cytokine, called TSLP – by administering a drug instead of genetic instructions, he said.

Researchers are already testing drugs that accomplish the opposite objective (interfering with TSLP) as a possible treatment for atopic dermatitis. Commonly called eczema, the skin condition is triggered by an overreaction by the immune system.

Ramping up TSLP, on the other hand, would have to be done carefully, lest it result in an inappropriate immune response. Kambayashi already is laying the groundwork for follow-up studies in people.

Among the remaining questions is just how the cytokine results in the excess secretion of sebum. The researchers found that TSLP causes certain kinds of immune T-cells to move to the sebaceous glands, which somehow results in more secretions.

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Ruth Choa is a graduate student who worked with Kambayashi on the experiments.

No matter the outcome of these studies, Kambayashi said that in hindsight, it makes sense that obesity might be addressed via the immune system.

As physicians have reminded us during the Covid-19 pandemic, obesity is often accompanied by a chronic level of immune-related inflammation. Excess adipose (body fat) tissue acts as a type of “organ”, releasing hormones and other chemicals that place the body in a chronic state of low-level stress, placing the person at higher risk in the event of infection.

Still, the weight loss in the mice was a surprise, to the point Kambayashi thought something must have gone wrong. “I thought they were sick, that they just weren’t eating,” he said.

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Richard Locksley, a professor at the University of California, San Francisco.

But in fact, they were eating more than mice in a control group, which had not been treated with the cytokine.

The key clue came with a curious phenomenon that Kambayashi and others had ignored in the past: mice treated with TSLP were known to develop a shiny coat of fur.

He and Choa noticed that the same was true with these mice. So they shaved the animals’ fur, analysed it and discovered it was rich in calorie-dense, fatty molecules.

Would humans sign up for that kind of treatment, knowing it would increase the secretion of oily fats through the skin? Among possible drawbacks: excess sebum is associated with the teenage scourge of acne.

Still, with obesity among the leading health problems globally, millions remain eager to try new solutions. Kambayashi says he’s determined to give them the chance.

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