Feel the Burn

Bruce Spiegelman isn’t always happy with the way his research gets portrayed. He and colleagues discovered a hormone that muscles make during exercise. When given to mice, the hormone causes the animals to burn more energy and lose weight, and improves their response to insulin — all without changing how much the mice eat or exercise. The press touted the discovery as “exercise in a pill.”

“I really hate that,” says Spiegelman, a cell biologist at the Dana-Farber Cancer Institute and Harvard Medical School in Boston. “The goal is not to put exercise in a pill.”

His goal, instead, is to harness a special type of fat, called brown fat for its color, to replicate the metabolic benefits that exercise delivers. While some researchers have dismissed this fat as a mostly obsolete relic that makes little if any contribution to people’s energy expenditure, new research shows that it can make humans feel the energy burn. Some scientists have found chemical secrets for activating brown fat already in the body, while others are learning how to turn energy-storing white fat brown.

Together, such efforts may help fight the battle of the bulge, reducing obesity and the diseases that go along with it. Turning brown fat on may also benefit people who cannot exercise because of disabilities.

Fired up

For many years scientists have recognized brown fat as an energy-burning powerhouse that helps animals and human babies stay warm. But general wisdom held that the brown fat pads on babies’ backs melt away during childhood, leaving adult humans with only white fat. Then three independent studies published in the New England Journal of Medicine in 2009 revealed that adult humans do have deposits of brown fat, especially around the neck and collarbone (SN: 5/9/09, p. 10). Some studies suggested that brown fat could become active in the cold, but no one knew how well it would work.

André Carpentier of the University of Sherbrooke in Canada counted himself among the doubters of brown fat’s energy-consuming potential. Even if the little brown fat depots in the neck turn on, “I was skeptical that it was enough to burn a lot of energy,” he says.

To find out what brown fat really could do, Carpentier and his colleagues asked six healthy men to put on bodysuits that can be used to regulate body temperature. The researchers pumped cold water through the suits so that the temperature of the men’s skin dipped by about 3.8 degrees Celsius — just enough to get brown fat active, but not so much that muscles would generate heat by shivering. Shivering would have meant muscles were burning energy, and the researchers wanted to make sure the energy consumption, tracked via full-body PET scans, came from fat alone.

All of the men burned more energy in the cold suits than at room temperature, but the degree to which brown fat kicked in varied, the researchers reported earlier this year in the Journal of Clinical Investigation. On average, the men burned 250 extra food calories during three hours in the cold. Cutting that many calories from the diet on a daily basis would add up to about half a pound of weight loss per week.

The researchers measured noticeable increases in the amount of energy that brown fat consumed in the form of glucose and noted that the brown fat’s volume shrank. The brown fat “was actually burning its own fat,” Carpentier says. Studies in mice have shown that brown fat will burn through lipids contained within its own cells as well as lipids in white fat cells.

When brown fat was activated, the men’s metabolic rate was 1.8 times the rate at rest. The study is the first to demonstrate that brown fat contributes to adult human metabolism.

“But you nevertheless have to keep things in perspective,” Carpentier says. Walking raises the metabolic rate to about two to three times the rate at rest, and running cranks it up to 10 times the resting rate. “I don’t think we’re going to solve the obesity and diabetes problem just by activating brown fat,” he says. But stimulating the fat could supplement other obesity-fighting measures.

Burn boosters

Previous studies have indicated that brown fat is harder to find in obese people and diabetics than in lean or healthy people. That’s probably because the brown fat in obese people is immature and doesn’t have the energy-burning capacity that typically makes the fat easy to spot on scans, says Devanjan Sikder, a neurobiologist at Sanford-Burnham Medical Research Institute in Orlando, Fla.

Sikder and colleagues reported last year in Cell Metabolism that a brain chemical called orexin helps brown fat mature. Orexin, also called hypocretin, is famous for stimulating appetite and keeping people awake. Sikder’s team plans to start a clinical trial to test orexin’s ability to get brown fat going in humans.

Firing up brown fat may just take a little muscle. Getting the heart pumping is one way to generate natural substances that stimulate brown fat, Sheila Collins of Sanford-Burnham and her colleagues recently found.

During exercise, the heart releases molecules called natriuretic peptides, which help lower blood pressure by signaling the kidneys to dump fluids. Those same hormones help feed energy to the heart by turning on brown fat, Collins and colleagues reported this year in the Journal of Clinical Investigation. The heart hormones caused both white and brown fat cells from mice and humans to produce more of some proteins that stoke brown fat’s fires. Such heart hormones might trick the body into thinking it is in a cold environment and should throw another log on these fires.

Although the body naturally makes some brown fat-boosting substances, including two more possibilities reported recently in Cell Metabolism, it’s not clear what the long-term consequences of extra doses might be. Since natriuretic peptides also help regulate blood pressure, one possible consequence of the hormones identified by Collins’ team might be low blood pressure. But Collins says that a little bit might be enough to rev up brown fat without causing unwanted side effects.

“I don’t think it takes a huge amount of these peptides to have a beneficial effect over time,” she says.

The heart isn’t the only muscle with the power to kick-start metabolism. During exercise, skeletal muscles release a hormone called irisin, Spiegelman and colleagues reported in Nature in January. It’s irisin that some have christened “exercise in a pill.”

Irisin doesn’t seem to turn on brown fat deposits in the neck, though. Instead it encourages brown fat-like cells within white fat to get going, essentially turning white fat brown. Spiegelman’s group has dubbed these brownlike cells “beige” cells.

No one knows how many beige cells can exist within white fat, so it’s difficult to predict just how much energy might be burned by stimulating the cells. Also unknown is whether obese people have fewer of the cells than normal-weight people.

Stoking brown fat does have the potential to aid in weight loss and help fend off diabetes. But Spiegelman dismisses the idea that the average couch potato could take a pill and get the benefits of exercise without ever jogging a step or lifting anything heavier than the remote control. Burning more energy, he notes, isn’t the only benefit of exercise. Even turning brown fat up to the max probably won’t improve bone strength or increase lung capacity or do many of the other things exercise is good for.

Still, for people who cannot exercise — such as those paralyzed by accidents or disease — irisin and other brown fat stimulants may be the next best option. They could possibly confer another perk of exercise, too: strengthening neural-muscular connections.

Spiegelman hopes the molecules will help people with amyotrophic lateral sclerosis hold onto nerve connections or even build new ones, possibly delaying or reversing the disease. “That’s a bit of a dream,” he says, “but why not dream?”