New study confirms presence of exercise-induced hormone in humans

Dana-Farber Cancer Institute scientist Bruce Spiegelman, PhD, who previously discovered a hormone linked to some of the positive benefits of exercise, reports data confirming that the hormone, irisin, is produced in humans and increases during exercise. The study published online today by Cell Metabolism.

Spiegelman, a cancer biologist at Dana-Farber and the Stanley J. Korsmeyer Professor of Cell Biology and Medicine at Harvard Medical School, is senior author of this study in which he and his colleagues used quantitative mass spectrometry techniques to detect human irisin in sedentary people and measure its rise in volunteers performing aerobic interval training.

In 2012, Spiegelman and his research team reported in Nature the discovery of irisin, a hormone secreted by skeletal muscles, and suggested that it was responsible for some of the health benefits of exercise, such as turning stored white fat to energy-burning brown fat and improving cardiovascular and cognitive functions. That study triggered a wave of further studies and enthusiasm about irisin as a potential drug for protecting against metabolic diseases such as diabetes, and for weight loss.

However, two earlier studies published by other researchers suggested possible flaws in the antibody methods used to identify irisin, and questioned Spiegelman’s interpretation of how the hormone was produced from a skeletal muscle gene, FNDC5. One critic suggested that irisin was a “myth.”

In the study published today, Spiegelman says that confusion over irisin is around disagreement over how the irisin protein is made in skeletal muscle cells and the detection limits of protocols. He and co-author Steven Gygi, PhD, a researcher at Harvard Medical School, turned to quantitative mass spectrometry techniques to show that the human hormone uses a rare signal ATA (start codon) to initiate its production (translation) rather than the usual ATG.

The use of the ATA, rather than the more common ATG, had previously led some investigators to conclude that the human gene was a pseudogene—a gene that serves no function. But alternative start codons account for a few of all genes and are usually an indication of complex regulation. In the study published today, the authors show that human irisin is similar to the mouse hormone and that it circulates in the range previously reported. Although irisin circulates at low levels (nanograms), this range is comparable to that observed for other important biological hormones such as insulin. Furthermore, the investigators developed a protocol that does not rely on antibodies to precisely measure how much irisin increases in people after exercise.

"This research uses state-of-the-art methods to detail the precise amounts and structure of human irisin,” said Spiegelman. “Hopefully the assay we have developed will benchmark other quantitative methods and enable further studies in this field.”

Irisin’s discovery in 2012 was exciting because scientists had potentially found one reason why exercise keeps us healthy. When irisin levels were increased in mice, their blood and metabolism improved. Results from human studies are still mixed as to what kinds of exercise raises irisin, but data suggest that high-intensity training protocols are particularly effective. The protocol described in the Cell Metabolism paper is likely to help such studies, as it is the most precise way to measure the hormone to date.

The authors point out one caveat in their methods—that some irisin is lost during sample preparation, and therefore the amount of irisin detected is, if anything, a slight underestimation. The technology is also expensive and requires specific mass spectrometry instruments. However, future refinement of this work should lead to more scalable protocols.

"Spiegelman and colleagues have unequivocally shown that the “mythical” irisin peptide is produced as a result of exercise,” said chemical physiologist John Yates of The Scripps Research Institute, who is not affiliated with the work. “This data should settle the controversy surrounding the existence of irisin and its increase in blood as a function of exercise."

This work is funded by the JPB Foundation and National Institutes of Health grants DK31405 and DK90861.