Exercise has the capacity to improve metabolic status in obesity and type 2 diabetes via mechanisms that are poorly understood. Importantly, exercise increases whole body energy expenditure beyond the calories used in the actual work performed14
. However, the relative contribution of the adipose tissues to this phenomenon has not been clarified. Since transgenic mice expressing PGC1α selectively in muscle showed a remarkable resistance to age-related obesity and diabetes4
, we sought factors secreted from muscle under control of this coactivator that might increase whole body energy expenditure. This paper describes a new polypeptide hormone, irisin, which is regulated by PGC1α, secreted from muscle into blood and activates thermogenic function in adipose tissues. Irisin is remarkable in several respects. First, it has very powerful effects on the browning of certain white adipose tissues, both in culture and in vivo
. Nanomolar levels of this protein increase UCP1 in cultures of primary white fat cells by 50 fold or more, resulting increased respiration. Perhaps more remarkable, viral delivery of irisin that causes only a moderate increase (~3 fold) in circulating levels stimulates a 10–20 fold increase in UCP1, increased energy expenditure and an improvement in glucose tolerance of high fat fed mice. Since this is in the range of increases seen with exercise in mouse and man, it is 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. It is important to note that the evidence provided here does not exclude a role for other tissues besides muscle in the biological regulation and secretion of irisin.
Second, the cleaved and secreted portion of Fndc5, the hormone irisin, is highly conserved in all mammalian species sequenced. Mouse and human irisin are 100% identical, compared to 85% identity for insulin, 90% for glucagon and 83% identity for leptin. This certainly implies a highly conserved function that is likely to be mediated by a cell surface receptor. The identity of such a receptor is not yet known.
Based on the gene structure of Fndc5, with a signal peptide that was evidently missed in the studies of Ferrer-Martinez, et al, we considered that Fndc5 might be a secreted protein. Indeed, we have observed that the signal peptide is removed, and the mature protein is further proteolytically cleaved and glycosylated, to release the 112 aa polypeptide irisin. The cleavage and secretion of irisin is similar to the release/shedding of other transmembrane polypeptide hormones and hormone-like molecules such as the epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α).
Since the conservation of calories would likely provide an overall survival advantage for mammals, it appears paradoxical that exercise would stimulate the secretion of a polypeptide hormone that increases thermogenesis and energy expenditure. One explanation for the increased irisin expression with exercise in mouse and man may have 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.
The therapeutic potential of irisin is obvious. Exogenously administered irisin induces the browning of subcutaneous fat and thermogenesis, and it presumably could be prepared and delivered as an injectable polypeptide. Increased formation of brown or beige/brite fat has been shown to have anti-obesity, anti-diabetic effects in multiple murine models6
, and adult humans have significant deposits of UCP1-positive brown fat15
. Data presented here shows that even relatively short treatments of obese mice with irisin improves glucose homeostasis and causes a small weight loss. Whether longer treatments with irisin and/or higher doses would cause more weight loss remains to be determined. The worldwide, explosive increase in obesity and diabetes strongly suggests exploring the clinical utility of irisin in these and related disorders.
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.