The Anti-Fat

An obscure kind of human tissue that burns calories intrigues obesity researchers
illustration of human back and fat
Like a furnace in a cold Boston winter, brown fat burns through a tremendous amount of fuel to create warmth. Illustration: Betsy Hayes
April 1, 2013

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Inside Tufts Medical Center in downtown Boston, Andrew Greenberg leads me through a long hallway covered with research posters. About halfway down, he stops and points to a photo of fat samples collected from mice in his lab. The first sample looks more or less the way you’d expect—a lump of the yellow-white tissue similar to the kind that plumps our bellies and thighs, and wraps itself around our internal organs.

The other sample looks very different. It’s a creamy coffee color. This, Greenberg proclaims, is what’s called “brown fat.” Ironically, it is this obscure type of fat that may become a powerful tool in the fight against obesity, thanks to a unique characteristic. Instead of storing calories from food, it burns them up.

Greenberg is director of the Obesity and Metabolism Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging, where he studies brown fat formation and metabolism. He says that the cell’s ability to burn calories is due in part to its structure.

Under the microscope, white fat cells look like bundles of swollen grapes filled with molecules of fatty acids. Brown fat cells, on the other hand, are much more compact, and hold only a small number of those molecules. The cells are also chock-full of mitochondria, tiny structures that act as engines for the cell, taking in fuel and creating energy.

Like a furnace in a cold Boston winter, brown fat burns through a tremendous amount of fuel to create warmth.

Unlike white fat, however, brown fat cells can throw those engines into neutral. Thanks to a protein called UCP-1, they can switch off their energy production and use fatty acids to generate heat instead. “That’s one of the major reasons brown fat exists,” says Greenberg, who is also an associate professor at the Friedman School. “It’s engineered to release heat and keep us warm.”

Because of this special quality, brown fat is common in babies and hibernating animals, which need to maintain body heat to survive long, bitter winters. But the tissue’s warming properties also make it attractive to drug companies and obesity researchers.

Like a furnace in a cold Boston winter, brown fat burns through a tremendous amount of fuel to create warmth. As it works its way through its own small store of fatty acids, it also starts taking fat out of the bloodstream—fat that’s released by bloated white fat cells elsewhere in the body.

“What may be happening is that brown fat is burning what it’s got, but it’s also funneling white fat from other parts of the body to be burned up,” says Aaron Cypess, a researcher and staff physician at the Joslin Diabetes Center in Boston.

If researchers can find a drug that activates brown fat, Cypess says, it might be an effective treatment for obesity. “You’ve got a [substance] that’s basically designed to burn off calories,” he says. “The question is, Can we use it to burn off enough calories to have clinical significance?”

A Brown Renaissance

Scientists have tried to answer that question many times. During the 1970s and early ’80s, labs around the country—including many at major drug companies—began testing compounds that seemed to activate brown fat in lab animals.

“It turned out that these compounds, known as beta-3 agonists, worked on mice, but on humans, they didn’t work so well, because there were some different [biological] characteristics,” says Greenberg, the Atkins Professor in Metabolism and Nutrition.

One major difference, he notes, is that adult humans have significantly less brown fat than babies or lab rats. As we age, we slowly lose our stores of the tissue, which form mainly along the spine and upper back at birth.

Robin Kanarek, the interim dean of the Friedman School and John Wade Professor in the School of Arts and Sciences, was one of many researchers who studied the effects of brown fat in the early 1980s. She says that interest in the tissue began to wane by the end of that decade, because many researchers assumed that there wasn’t enough active brown fat left in adults for it to have a meaningful effect. “At the time, we just didn’t have the techniques and technology to effectively monitor and identify brown fat in the body,” she says. “A lot of the science has changed because of the tools we have today.”

“If you can make white fat—which we have much more of in the body—act like brown fat, now you’re getting into something that could have a major effect on energy balance in the body,” says Aaron Cypess.

New imaging technologies such as PET-CT scans, which measure the activity of cells in the body, have led to a renaissance in brown fat research, Kanarek says. Normally, these scans are used to find cancerous tumors, but they can also consistently spot small deposits of brown fat in adults that are revving away, converting glucose and fatty acids into heat. In 2009, three independent teams of researchers (among them a group led by Cypess) used PET-CT scans to identify tiny stores of the tissue in adult humans.

These discoveries rekindled the hope that brown fat could be used to control obesity. But despite the newfound excitement about its existence in adults, Cypess says he and other researchers still faced one lingering issue: “Adults only have, at most, 100 to 300 grams of brown fat in the body. Due to the small amount, it’s not clear if it’s going to have that much effect based on its energy expenditure alone,” he says.

When the brown fat stores we’re born with begin to shrink, there’s no way to bring them back, but Cypess says there may be a sort of biological loophole. Some white fat cells can take on the properties of brown fat—they shrink in size, produce more mitochondria and most important, generate heat.

“If you can make white fat—which we have much more of in the body—act like brown fat, now you’re getting into something that could have a major effect on energy balance in the body,” says Cypess. “You’re taking a tissue that was not doing much and making it far more active. And that’s a very exciting possibility.”

By creating more of these brown fat-like cells in the body, he says, it may be possible to use them to burn off extra fatty acids in the blood. That extra boost could help treat obesity and, by extension, such obesity-related disorders as hypertension, cardiovascular disease and Type 2 diabetes. (Brown fat might also play a role in bone health; see “Brown to the Bone” below.)

Turning on the Furnace

Figuring out exactly how to trigger the formation of brown fat-like cells has been an ongoing challenge for scientists. Bruce Spiegelman, a professor at Harvard Medical School, thinks he may have found an answer. In 2011, his lab discovered a hormone called irisin, which is released by muscles during exercise. He says it may be the key to the formation of brown–fat-like cells in the body.

“[By injecting irisin] in mice, we showed a two- or three-fold elevation in brown-like fat, which improved the metabolic status of those animals,” Spiegelman says. “Would that be enough to cause weight loss in obese humans? We’re not sure. But in mice it looks promising.”

Spiegelman has formed a small biotech firm dedicated to bringing irisin to clinical trials, but he’s a long way from testing the hormone in humans. First, he’ll have to find a stable version of the protein that will work in the human body and then address any concerns about its safety.

When it comes to brown fat research, says Cypess, “there are some billion-dollar questions sitting on us right now. One, Can brown fat really have a clinical effect on obesity, and two, Is it safe if you turn it on?”

Greenberg agrees with that assessment. “The field is really nascent,” he says. “We have to be careful to work in a safe manner. You don’t want the therapy to be worse than the disease.”

At the moment, says Greenberg, researchers still aren’t sure how much brown fat humans might need in their bodies to see a positive effect, or if there’s a downside to having too much brown fat.

So until a treatment based on brown fat is tested clinically, Greenberg thinks we shouldn’t ignore age-old strategies in the war against our expanding girth. Nutrition researchers “still believe in a healthy diet and exercise,” he says. “They’ve been shown to be very effective against a lot of the complications from obesity.”

David Levin is an independent science journalist in Boston.

 

Brown to the Bone

Brown fat cells may do more than just burn calories. They may also play a complex role in bone health, says Clifford Rosen, senior scientist at the Maine Medical Center Research Institute in Portland.

As you step out your front door on a cold winter day, Rosen says, your body “turns on” its sympathetic nervous system (SNS), the same system responsible for the rush of adrenaline you feel when startled. The SNS, in turn, activates brown fat cells, which burn up calories to create heat. In the process, your body slowly regains its warmth, and the SNS quiets back down.

If the body doesn’t have enough brown fat to maintain its temperature, though, the nervous system changes strategies. In an effort to keep the body warm, the SNS sends new commands to white fat cells, ordering them to take on brown fat-like properties.

“If you don’t have a lot of brown fat, your body still needs a way to protect its temperature. So it tries to convert white fat to brown fat,” says Rosen, who is also a professor at Tufts University School of Medicine.

If the body can create enough new brown fat-like cells, it can regain its normal temperature. The conversion comes at a cost, however. Rosen says the signals that tell white fat cells to “go brown” can also affect bone density.

While the process isn’t well understood, Rosen says, the SNS also seems to boost the activity of cells called osteoclasts that dissolve bone material. The longer the SNS is active, the longer those cells eat away at the skeleton, reducing bone strength and density.

“This is a systemic effect,” he says. “The body’s trying to compensate for a lack of brown fat, but at the same time, it might be to the detriment of the skeleton.”

The length of time the SNS is active may be linked to the amount of brown fat in the body when it gets cold, Rosen theorizes. He’s begun to test this idea on mice in the lab, and says that his initial findings show that the fewer brown fat cells a mouse has, the poorer its overall bone health.

While Rosen is quick to note that his studies aren’t yet conclusive, it could mean that the same phenomenon happens in humans. The stores of brown fat that we’re born with gradually disappear as we age—a natural development that, Rosen says, could cause osteoporosis in the elderly.

A lack of brown fat may not always be a problem, however. Rosen notes that calcium, vitamin D and exercise also help maintain a healthy skeleton. “Those things are really important,” he says. “And we don’t know this for sure, but maybe not getting exposed to cold as much might be helpful, too.”

For those of us in chillier climates, it might be time to look for a new coat.—DL

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