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January 11, 2012

Discovery Could Lead to an Exercise Pill

MIT Techology Review - A newly identified hormone acts like a workout, and transforms bad fat into good.

Researchers have discovered a natural hormone that acts like exercise on muscle tissue—burning calories, improving insulin processing, and perhaps boosting strength. The scientists hope it could eventually be used as a treatment for obesity, diabetes, and, potentially, neuromuscular diseases like muscular dystrophy
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Nature - A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis




Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.

The hormone occurs naturally in both mice and humans. It pushes cells to transform from white fat—globules that serve as reservoirs for excess calories—into brown fat, which generates heat.

Because the hormone is present in both mice and humans, Spiegelman speculates that it may have served as an evolutionary defense against cold by triggering shivering. He named it irisin, after the Greek messenger goddess Iris, who allowed humans to communicate with the gods in Greek mythology, because exercise appears to "talk" to various tissues in the body via irisin.

Mice given irisin lost a few grams in the first 10 days after treatment, the study shows, and certain genes involved in powering the cell were turned on. Irisin also appeared to reduce the damage done by a high-fat diet, protecting mice against diet-induced obesity and diabetes, according to the paper, whose first author is postdoctoral fellow Pontus Boström.

"We are hopeful, though we have no evidence, that this hormone may embody some of the other benefits of exercise, perhaps in the neuromuscular system," Spiegelman says. If so, it could also be used to treat disorders like muscular dystrophy and muscle wasting.

Researchers still have to figure out how much benefit irisin could provide someone with diabetes or other health problems, says Spiegelman, also a professor of cell biology and medicine at Harvard Medical School. "I'm optimistic," he says. "I just don't want to overpromise and underdeliver."

Harvard Medical School's Dean Jeffrey Flier, an endocrinologist, says he is quite enthusiastic about the new hormone. The study, he says, "opens up a completely new approach to understanding the links between exercise, body weight, and diabetes."

Flier believes irisin offers strong therapeutic potential. "Though much remains to be learned about the action of irisin, and its status in humans with various diseases, this work has the potential to be a game-changer in the field of metabolic disease."

Last month, Spiegelman formed a Boston-based company named Ember Therapeutics to develop his brown-fat research projects, including irisin. The company raised $34 million in series A financing, and is backed by Third Rock Ventures of Boston.

Harvey Lodish, a professor of biology and bioengineering at MIT, and a member of the Whitehead Institute for Biomedical Research, says it may be harder to make irisin into a drug than Spiegelman anticipates. Lodish tried for years to make adiponectin, a hormone he discovered in the mid-1990s, into a similar drug, but never succeeded.

The concentration of both hormones in the blood is already so high that manufacturing enough to make a difference in health is quite challenging, he says. Maybe irisin will be easier to produce, he says, or maybe it could be delivered via gene therapy, in a modified version of the delivery system Spiegelman used in his research—but Lodish is dubious
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