January 11, 2012, 1:00 pmBy GRETCHEN REYNOLDS
A newly discovered hormone produced in response to exercise may be turning people’s white fat brown, a groundbreaking new study suggests, and in the process lessening their susceptibility to obesity, diabetes and other health problems. The study, published on Wednesday in Nature and led by researchers at the Dana-Farber Cancer Institute and Harvard Medical School, provides remarkable new insights into how exercise affects the body at a cellular level.
For the study, the researchers studied mouse and human muscle cells. Scientists have believed for some time that muscle cells influence biological processes elsewhere in the body, beyond the muscles themselves. In particular, they have suspected that muscle cells communicate biochemically with body fat.
But how muscle cells “talk” to fat, what they tell the fat and what role exercise has in sparking or sustaining that conversation have been mysteries — until, in the new study, scientists closely examined the operations of a substance called PGC1-alpha, which is produced in abundance in muscles during and after exercise.
“It seems clear that PGC1a stimulates many of the recognized health benefits of exercise,” said Bruce Spiegelman, the Stanley J. Korsmeyer professor of cell biology and medicine at the Dana-Farber Cancer Institute and Harvard Medical School, who led the study. Mice bred to produce preternaturally large amounts of PGC1a in their muscles are typically resistant to age-related obesity and diabetes, much as people who regularly exercise are.
Again, the biological mechanisms by which PGC1a jump-starts such beneficial effects had been unknown. For the new study, though, the researchers used advanced algorithms to determine that increases in PCG1a in muscles caused a subsequent bump in the expression of a protein known as Fndc5. That protein had long interested biologists, but they hadn’t been able to pinpoint what it did.
The Harvard researchers realized that one thing the protein did was break apart into different pieces, one of which was a hormone that had never before been identified. With uncharacteristic whimsy, the scientists dubbed it “irisin,” after Iris, the messenger goddess of Greek mythology. (I’m sure she was on a quiz once.)
Unlike most substances birthed in the muscles, irisin does not completely remain there, the scientists noted. It apparently enters the bloodstream and surfs to fat cells, where, by providing various biochemical signals or messages, it begins turning regular fat — especially deep, visceral fat clustered around organs — into brown fat.
If that last statement didn’t make your eyebrows rise in surprise, you are not an adipocyte biologist. For them, the finding that irisin might contribute to the browning of visceral body fat is “an extraordinary discovery,” says Sven Enerback, a professor of metabolic research at the University of Gothenburg in Sweden, who has written extensively about the biology of fat and obesity.
Brown fat, as many of us have heard, is physiologically desirable. While white fat cells are essentially inert storehouses for fat, brown fat cells are metabolically active. They use oxygen and require energy. They burn calories.
Until recently, it was thought that human adults did not have brown fat, that we lost our stores after babyhood. But beginning in 2009, a number of studies showed that grown-ups do harbor brown fat. Some people just have more than others.
And it may be that irisin, and exercise, partially determine how much brown fat each of us contains, the new study suggests. In perhaps the most compelling of the many separate experiments detailed in the Nature paper, the scientists injected irisin into white fat cells removed from mice. Afterward, genetic changes in the cells signified that they were browning. The fat cells also increased their respiratory rate, an indication that they were burning more energy.
In additional experiments with mice fattened on high-fat kibble, injections of the Fndc5 protein, which cleaves into irisin, improved the animals’ glucose tolerance, Dr. Spiegelman says; they did not develop diabetes, despite being at increased risk from their diet.
Finally, follow-up experiments with muscle cells from human volunteers who’d completed a controlled, weeks-long jogging program found that they had much higher levels of irisin in their cells than before the exercise program began. Intriguingly, the hormone was exactly the same, structurally, in both mice and people – a finding suggesting that it is biologically vital, Dr. Spiegelman points out, since otherwise it would not have been preserved nearly unchanged through eons of mammalian evolution.
In essence, irisin appears to be one of the more important missing links in our understanding of how exercise improves health.
But while irisin appears to have a critical impact on metabolism, it does not appear to play any discernible role in the effects that exercise has on the heart or the brain. And various issues remain unresolved. Why, for instance, if exercise increases levels of irisin and irisin increases the body’s stores of energy-burning brown fat, does exercise so rarely produce significant weight loss? The mice injected with irisin lost little weight. On the other hand, Dr. Spiegelman notes, they resisted weight gain, even on a high-fat diet, and their blood sugar levels remained stable. So it would seem that exercise, through the actions of irisin, can render you healthy, if not svelte.
In upcoming experiments, Dr. Spiegelman plans to study whether injections of irisin imitate some of the metabolic benefits of exercise in people who, because of disease or disability, cannot work out. He also hopes to elucidate just how much and what types of exercise produce the greatest natural irisin increases in healthy people.