In January 2012, Boström and colleagues identified a new muscle tissue secreted peptide, which they named irisin, to highlight its role as a messenger that comes from skeletal muscle to other parts of the body. Irisin is a cleaved and secreted fragment of FNDC5 (also known as FRCP2 and PeP), a member of fibronectin type III repeat containing gene family. Major interest in this protein arose because of its great therapeutic potential in diabetes and perhaps also therapy for obesity. Here we review the most important aspects of irisin’s action and discuss its involvement in energy and metabolic homeostasis and whether the beneficial effects of exercise in these disease states could be mediated by this protein. In addition the effects of irisin at the central nervous system (CNS) are highlighted. It is concluded that although current and upcoming research on irisin is very promising it is still necessary to deepen in several aspects in order to clarify its full potential as a meaningful drug target in human disease states.
Obesity is at present the most common nutritional disease in industrialized countries, constituting a priority health problem. It is associated with the development of cardiovascular disease,
Since human brown adipose tissue (BAT), especially in adults, was rediscovered several years ago by using positron emission tomography (PET) [
Studies in immortal preadipocyte lines from the brown adipose tissue of mice lacking PGC1
Recently, Spielgman’s group described that transgenic PGC-1
Expression of FNDC5 (fibronectin type III domain containing 5), also known as FRCP2 and PeP, is stimulated in muscle by PGC1-
Boström and colleagues demonstrated that irisin has potent effects on the browning of certain white adipose tissues, both in culture and
This evidence opened up some questions about the physiological role of irisin. In the same study,
There is an extensive literature about different exercise-related signals that can regulate the expression and/or secretion of the diverse myokines [
Other studies have tried to elucidate the irisin role and other myokines in different physiological conditions. When male rats were subjected to calorie restriction (CR;
Current data by Roca-Rivada and coworkers proposed that irisin is not only secreted by muscle tissue. In fact, they demonstrated that irisin is a new adipokine with an important autocrine and endocrine function. Moreover, they showed that FNDC5/irisin has a different pattern of secretion depending on the anatomical location of adipose tissue. Thus, subcutaneous adipose tissue secretes more much FNDC5/irisin than visceral adipose tissue, reflecting one more time that visceral fat is more implicated in metabolic complications, while subcutaneous fat has a possible beneficial role. They also showed that short-term periods of exercise training induced FNDC5 secretion by WAT, that this secretion was significantly reduced in fasting animals, and that WAT of obese animals had an increase secretion of this hormone suggesting a type of resistance [
In this same context, Roberts et al. showed that obese/diabetic prone Otsuka Long-Evans Tokushima Fatty (OLETF) rats have more muscle expression FNDC5 than lean Long Evans Tokushima Otsuka (LETO); however, LETO rats have higher circulating irisin levels. The authors also observed that triceps FNDC5 mRNA expression was correlated with fat mass and with plasma leptin; however,
Besides interaction between skeletal muscle and adipose tissue, it has been described that FNDC5/irisin might have a role in the central nervous system. In fact, it has already described previously that PGC1-
Supporting the role of FNDC5/irisin in the nervous system, it should be noted another study where it is demonstrated that FNDC5 is required for the adequate neural differentiation of mouse embryonic stem cells (mESCs) [
Overall this evidence suggests a central role for irisin, In this regard, considering that the hippocampus is one of the principal regions affected by Alzheimer’s disease and that exercise causes neurogenesis in humans reducing risk of Alzheimer’s [
As stated above, irisin has a highly conserved function, and as in rodents, in humans this hormone is also predominantly expressed in muscle [
Throughout the past two years, several studies in humans have tried to clarify the role of FNDC5/irisin in physiological conditions and in disease states. Spielgman’s group showed that endurance exercise training for 10 weeks in healthy adult humans increased plasma irisin levels compared to the baseline state [
It seems, hence, that exercise might have an effect on irisin levels depending on physiological condition. In this sense, a new study describes that patients subjected to hemodialysis seem to have lower plasma irisin than healthy subjects and also show exercise training resistance; so despite increasing muscle mass, they not have higher irisin levels [
When analyzing the correlation between body max index (BMI) and irisin levels, differences were also found. Some studies observed a positive correlation with BMI [
Similarly, it has been established by some groups a relation between
In this same context, another controversy has been reported. The study of single nucleotide polymorphisms (SNPs) in the human
Circulating irisin has been also found to be directly associated with muscle mass and estradiol levels and inversely associated with age in middle-aged women. Also it is negatively correlated with age, insulin, cholesterol, and adiponectin levels [
Similar to physical activity, drugs might also increase irisin levels and thus affect lipid metabolism and improve risk among dyslipidemic and/or obesity individuals. Given recent data, everything seems to indicate that between these drugs, statins could have an important role in this sense [
Another disease with altered energy expenditure and with high prevalence of metabolic imbalance and abnormal energy homeostasis is also chronic kidney disease (CKD). It was observed that patients with CKD have lower irisin levels at rest, independently of high-density lipoprotein cholesterol levels. The mechanism underlying the decrease in irisin in CKD is unknown, even though it seems that indoxyl sulphate, which is a protein-bound uremic toxin, decreases FNDC5 expression in skeletal muscle cells and irisin level in the cell culture medium [
When Böstrom and colleagues described irisin, rapidly, it was seen its great therapeutic potential. Irisin was seen as possible treatment for diabetes and perhaps also therapy for obesity. Moreover, it also was considered a possibility to treat patients with Alzheimer’s, Parkinson’s, and some other neurodegenerative diseases. However, new studies have started to question the initial expectations [
First more studies would be necessary to determinate what the precise role of different forms of FNDC5/irisin is and if there is a different mechanism of proteolysis as it already was suggested [
In conclusion, although current and upcoming research on irisin is very promising and nowadays we already know so much about it (Figure
Skeletal muscle releases to circulation several hormones denomined myokines acting as endocrine organ. Thus during exercise PGC1
The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under Grant agreement no. 281854—the ObERStress European Research Council Project(ML) and no. 245009—the Neurofast project (ML and CD), and Xunta de Galicia (ML: 10PXIB208164PR and 2012-CP070), Instituto de Salud Carlos III (ISCIII) (ML: PI12/01814), MINECO were co-funded by the FEDER Program of EU (CD:BFU2011-29102). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.