Boston scientists have found a hormone that is secreted by muscles during exercise and boosts the amount of energy the body burns. This hormone – irisin – could be the first step in development of new drugs for obesity, diabetes, and other diseases feel researchers. A Boston startup company, Ember Therapeutics, has already licensed the technology and is working to develop a form of the hormone that could be used as a drug that would mimic some of the benefits of exercise.
The study was published online in the journal Nature and was led by Bruce Spiegelman, a cell biologist at Dana-Farber Cancer Institute and Harvard Medical School. For years, he has been unraveling questions about the formation and nature of “brown fat,” a type of fat that burns energy rather than storing it. Spiegelman and colleagues discovered that the hormone triggers changes to ordinary “white” fat that makes them resemble brown fat and increase energy expenditure. When they induced greater levels of the hormone in obese, pre-diabetic mice over a short period, they saw slight weight loss, increased energy expenediture, and improvements in insulin resistance, a risk factor for diabetes.
Irisin levels rose by 65% in mice after three weeks of free-wheel running. In humans, the effect was a little less dramatic, but still good: After 10 weeks of “supervised endurance exercise training,” irisin levels doubled. Under irisin's influence, subcutaneous fat gets browner, total-body energy expenditure increases, and a cascade of changes reduces insulin resistance (which is the first step along a path leading to a Type-2 diabetes diagnosis).
In mice bred to become fat when fed a high-fat diet, even a short course of FNDC5 and a modest increase in irisin levels cause some weight loss; their muscles consume more oxygen, as if they had spent the last several weeks exercising; their growing insulin resistance is reversed and their glucose tolerance is improved. To demonstrate to doubters that irisin was responsible for the change, researchers plied their mice-subjects with anti-FNDC5 antibodies to stop the production of the newly described hormone. Result: 10 days of swim training did not affect the weight and related parameters.
“It’s a hormone made by muscle, put into the blood, and with exercise it increases,” Spiegelman said. “It seems to embody some of what exercise is known to do, which is have an antidiabetes, antiobesity effect.” More extensive animal testing of the hormone is underway, to see how big a therapeutic effect can be attained. The laboratory is also focused on questions of how exactly the hormone works to achieve its promising effects.
Meanwhile, Ember Therapeutics, which announced last month that it had raised $34 million from Third Rock Ventures, has put a priority on finding a way to optimize the hormone to create an experimental drug that might help fight various diseases by activating brown fat. Spiegelman is a co-founder of the company, but the present work occurred at his academic laboratory and was funded by the National Institutes of Health.
“Over the last three years or so, there’s really been an explosion in the work and discoveries in the brown fat area. ... It’s active, it’s activatable,” said Lou Tartaglia, chief executive of Ember Therapeutics. He said obesity treatments that work to increase energy expenditure could be safer than medications that suppress appetite. That’s because such compounds would not have to work on the central nervous system or the brain.
Mitchell Lazar, director of the Institute for Diabetes, Obesity and Metabolism at the University of Pennsylvania, who was not involved in the research, said that the new finding provides an exciting way to attack problems that range from obesity to diabetes, to - possibly - cancer. “It’s a new molecule and a new pathway and a new mechanism for thinking about how to get at this very, very difficult problem of treating chronic diseases that are affecting tens of millions of people,” Lazar said. But he added that it raises many new questions, from basic ones about what happens if levels of the hormone drops, to understanding better the role it plays in the body.
“From the point of view of how it benefits the person to have this pathway, it’s really not clear at this time, and that will be a very interesting subject for future research that might end up determining whether this will be a novel way to get to the goal we want,” Lazar said.
In their Nature paper, the researchers write, “It seems paradoxical that exercise would stimulate the secretion of a polypeptide hormone that increases [...] energy expenditure. One explanation for increased irisin expression with exercise in mouse and man may be that it evolved as a consequence of muscle contraction during shivering. Muscle secretion of a hormone that activates adipose thermogenesis during this process might provide a broader, more robust defense against hypothermia. In extremely cold weather, that is, muscles work hard through shivering. In turn, shivering may send messages to the body to create more brown fat that will better regulate heat.”
“We’re not trying to replace diet and exercise,” Spiegelman warned. “That’s still important.”