Contact: Ian Clark
MADISON, Wis. — Humans generally don’t like much fat on their bodies. Now an intriguing discovery at the University of Wisconsin-Madison suggests that one kind of insulating fat may be linked to a greatly-reduced risk of tumors.
The UW research group examined a group of mice that lacks a single gene, but otherwise appears normal. Though they’re marginally smaller than their wild-type counterparts, what sets them apart is twofold: they lack proper intradermal fat, and they are 60 to 80 percent more resistant to tumors than normal mice.
A single layer of fat, microns thin, lives within your skin. It’s called intradermal fat, and it insulates the body to prevent heat loss. It’s not to be confused with subcutaneous fat (fat that’s under the skin), visceral fat (white fat surrounding your internal organs), or the healthy brown fat that burns white fat.
According to the study, published today (August 7) in PLOS Genetics, the knockout mice (lab-speak for a mouse model bred to be absent a particular gene) lack Syndecan-1, usually studied for its properties of sticking cells together and processing signals. Without it, the mice don’t develop the special intradermal fat layer, which these researchers have found expands in normal mice when stressed by cold. This layer of self-regulating insulation is crucial for the mouse to defend its own body temperature from the outside world, but lacking that defense had an unforeseen consequence for the knockout mice.
Scientists observed what appeared to be a continuous activation of the mouse’s brown fat to heat the blood, as well as the activation of the p38 stress checkpoint, the head of a cell- signaling cascade that cancer biologists are very interested in, because of its role in tumor suppression through DNA repair.
“If the insulation in a mammal doesn’t develop just right, the effects downstream are systemic,” said Caroline Alexander, professor of oncology at the UW School of Medicine and Public Health. “In these mice, the defects produce this hyperactivation of the p38 checkpoint, which is busy mediating the response to cold but is also a great centerpiece in cancer biology.”
“This group of adipocytes (fat cells) is very kinetic,” she said. “Most adipocytes, including white fat cells, are very specialized, but they establish themselves as adipocytes and stay that way your whole life, which is one of the problems. We’re thinking the reason that this group of cells is so sensitive to syndecan is because they’re expanding and contracting and redifferentiating from precursor cells every time, and each time that happens, the cells need syndecan. If you don’t have syndecan, these fat cells can’t keep up with demands of cold.”
Unlike other types of fat, this layer expands to help the body stay warm instead of burning fat to heat the blood. But the knockout mice lacked that layer of expandable, insulating fat, forcing them to continuously battle to stay warm.
“It’s a very thin layer of fat, but the difference is huge,” said Alexander. “You have a very large surface area to defend from heat loss, and if you don’t defend it well, it’s like turning the heat on but leaving the windows open.”
Making the discovery, though, was a winding journey. Knowing there was something different about these knockout mice, Alexander enlisted the help of UW nutritional scientist Eric Yen. Using special boxes called metabolic cages, they observed the mice over a period of time, tracking everything from oxygen use, carbon dioxide production, food consumption, body waste, and all kinds of other data linked to metabolism.
The data provided a clear look at what the mice were doing metabolically. Tracking groups of four wild-type mice against four knockout mice, they soon saw some of the knockout mice slip into a coma, basically falling off all the metabolic graphs. Similar coma-like states are seen in nature, and this strategy can actually save the mouse from imminent death.
Imagine a hungry mouse searching for food on a cold desert night. Embattled by two calorie-burning drives—heating the body against the cold and fueling a search for food on an empty stomach—the mouse can induce a sort of temporary coma. That semi-comatose phenomenon is called torpor, which slows the rodent’s metabolism as it waits motionless for the sun to reheat the desert and remove the cold stress.
Torpor is well understood, but researchers at the UW McArdle Laboratory for Cancer Research exploring the tumor-resistant properties of a strain of knockout mice didn’t know what torpor had to do with tumor resistance.
“Torpor suggested to us that the duel stressors must be important somehow. Because we knew that tumor resistance had also been seen in calorie-restricted animals, we were studying the reactions of these mice to fasting. The torpor reaction said there might also be a cold stress, so we started to look at why,” said Alexander.
Researchers found that when a normal mouse is in a warm environment, doing no work to stay warm (at 31 degrees Celsius / 87.7 F), its intradermal fat layer thins out to about 40 microns. Yet, if those mice are relocated to an environment of 23 degrees Celsius (73.4 F), the intradermal fat thickens. The difference between those two layers of fat in terms of heat loss is almost twofold.
This is the only known fat layer that responds to cold by expanding. In terms of cell signaling, Alexander said it’s extremely interesting because these cells are doing the opposite of what one expects fat to do.
This new fat layer may be an eventual target for therapies to influence the body to burn calories from fat, and may hold clues to superactivating the p38 checkpoint for patients battling cancer.
“When you’re in a body with p38 turned on, your body is making totally different decisions,” she said. “Some of them might be bad, but some of them might be good. If I was a breast cancer survivor who’s trying to stop metastases, I might be pretty happy with that, or if I’d been exposed to a carcinogen, this seems like something you might want to exploit.”
“We don’t know what a super-activated physiology looks like,” said Alexander. “Obviously, we have many more experiments to do, and we’re actively engaged with a number of biomedical engineers here, testing the properties of the skin we’ve shown so far and trying to develop a mechanism to measure whether this holds true for humans.”