Novel hormone crucial for exercise benefits
MedWire News: Researchers say they have identified a hormone, irisin, that is partly responsible for the beneficial effects of exercise on the whole body.
"Irisin is remarkable in several respects," write Bruce Spiegelman (Harvard Medical School, Boston, Massachusetts, USA) and colleagues.
They found that it has "powerful effects on the browning of certain white adipose tissues."
The researchers studied the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α), which is known to mediate some of the beneficial effects of exercise on muscle. They show that, in mice, overexpression of PGC1-α in muscle causes increased formation of multilocular adipocytes containing uncoupling protein 1 (UCP1), ie, brown fat cells. This occurred specifically in the subcutaneous white fat layer - a white adipose tissue known to be prone to "browning."
Previous studies have also shown that overexpression of PGC1-α makes mice resistant to obesity and diabetes, leading the researchers to believe that PGC1-α stimulates the release of factors from the muscle that have effects elsewhere in the body.
Growing adipocytes in media previously used to grow cells that expressed PGC1-α caused the adipocytes to upregulate several brown-fat-specific genes, showing that substances secreted in response to PGC1-α expression can cause browning.
Spiegelman et al identified five genes that were upregulated in response to PGC1-α and were all upregulated in muscle biopsies taken from humans after endurance exercise. One of these genes, FNDC5, encoded a protein that provoked large, dose-dependent increases in brown-fat-related genes in cultured muscle cells, and also the downregulation of genes associated with white fat development.
Indeed, expression of the gene encoding UCP1 increased between seven- and 200-fold in the presence of FNDC5.
The researchers discovered that FNDC5 is cleaved and they identified the secreted portion, which they say has "remarkable conservation" between species, being 100% identical between mice and humans.
"Because this distinct, secreted polypeptide has not been previously described and signals from muscle to other tissues we named it irisin, after Iris, the Greek messenger goddess," they write in Nature.
The team found irisin to be present in the plasma of mice and humans, and to be significantly upregulated after a program of endurance exercise. Injecting mice with adenoviral vectors expressing FNDC5 resulted in a three- to fourfold increase in plasma levels of irisin and notable browning of the subcutaneous adipose tissues.
Injecting obese, insulin-resistant mice with the FNCD5 vectors caused a significant increase in mitochondrial gene expression and in oxygen consumption, indicating increased whole-body energy expenditure, despite no change in activity or food intake. They also had slight, but significant, reductions in bodyweight after 10 days, compared with control mice, as well as increased glucose tolerance and reduced fasting insulin levels.
The researchers note that the three- to fourfold increase in plasma irisin that prompted these events is "in the range of increases seen with exercise in mouse and man," making it "likely that irisin is responsible for at least some of the beneficial effects of exercise on the browning of adipose tissues and increases in energy expenditure."
Spiegelman and team say that the "therapeutic potential of irisin is obvious," given their findings. But they add: "Another potentially important aspect of this work relates to other beneficial effects of exercise, especially in some diseases for which no effective treatments exist. The clinical data linking exercise with health benefits in many other diseases suggests that irisin could also have significant effects in these disorders."
By Eleanor McDermid