|Year : 2016 | Volume
| Issue : 1 | Page : 41-45
Irisin: A clue for metabolic disorders
Gutch Manish1, Kumar Sukriti1, Abhinav Gupta2, Gupta Kumar Keshav2, Razi Mohd Syed2
1 Department of Medicine, KGMU, Lucknow, Uttar Pradesh, India
2 Department of Endocrinology, LLRM Medical College, Meerut, Uttar Pradesh, India
|Date of Submission||22-Dec-2015|
|Date of Decision||20-Jan-2016|
|Date of Acceptance||08-Mar-2016|
|Date of Web Publication||16-Jun-2016|
D-15, LLRM Medical College, Meerut - 250 004, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Skeletal muscles express and elaborate a number of cytokines and other substances for modulating various metabolic processes which function locally and also target distant organs are known as myokines. Irisin is one of the most recently discovered myokines and is found to modulate effect of exercise on adipocytes through browning of white adipose tissue. Besides this, irisin is considered to be one of the future targets for therapies for metabolic disorders.
Keywords: Fat browning, irisin, metabolic disorders, myokines
|How to cite this article:|
Manish G, Sukriti K, Gupta A, Keshav GK, Syed RM. Irisin: A clue for metabolic disorders. J Obes Metab Res 2016;3:41-5
| Introduction|| |
Obesity is the most common nutritional pandemic in the developed world and is associated with other comorbidities such as coronary artery disease, type 2 diabetes mellitus (T2DM), hypertension, and certain cancers adding to the morbidity and mortality. Lifestyle modifications which include dietary changes, physical activity, and exercise are the best treatment options for obesity.  Skeletal muscles express and release various cytokines, some of which are called myokines and they act locally within the muscle and at distant target organs, the various different types of myokines are listed in [Table 1]. These myokines make the skeletal muscles, an endocrine organ and are responsible for the majority of effects of exercise on the metabolic diseases.  Irisin is the most recent the myokines discovered in 2012 by Bostrom et al. and named after the Greek messenger goddess "Iris." It is believed to be involved in various metabolic effects of exercise, most important of which is considered to be the "browning" of the white adipose tissue (WAT).  Irisin is now being considered as the therapeutic target for various metabolic disorders such as obesity and T2DM in which exercise leads to improvement. 
| Molecular structure, synthesis, action, and distribution|| |
Irisin is a glycosylated protein having 112 amino acids and a molecular weight of 32 kDa while deglycosylated molecular weight is about 12 kDa. X-ray crystallography reveals that irisin consists of an N-terminal fibronectin III-like domain which forms a continuous intersubunit β-sheet dimer and attaches itself to a C-terminal peptide. Irisin is a dimer and dimerization remains unaffected by glycosylation.  Irisin amino acid sequence is 100% conserved among most of the mammalian species. 
Irisin is synthesized in exercising skeletal muscles. Exercise induces the expression of peroxisome proliferator-activated receptor gamma (PPAR-g) co-activator-1α via AMP-activated protein kinase (AMPK) pathway which causes the upregulation of its downstream target fibronectin type III domain-containing protein 5 (FNCD5), and irisin is formed after proteolytic cleavage of C-terminal of FNCD5 by unknown proteases, leaving 112 amino acid residue called irisin [Figure 1]. ,
|Figure 1. Schematic diagram of irisin synthesis and mechanism of action. AMPK: AMP-activated protein kinase, FNDC5: Fibronectin type III domain-containing protein 5, PGC-1ƒ¿: PPAR-ƒÁ co-activator-1ƒ¿, p38MAPK: p38 mitogen-activated protein kinase, UCP1: Uncoupling protein-1, WAT: White adipose tissue|
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Irisin acts on WAT to increase the expression of uncoupling protein-1 (UCP1) expression via activation of p38 mitogen-activated protein kinase and also by production of β-trophin [Figure 1]. This leads to "browning" of WAT. Increased expression of UCP1 causes increase thermogenesis through uncoupling of oxidative phosphorylation and electron transport chain leading to dissipation of energy in the form of heat without adenosine triphosphate formation. ,
Besides skeletal muscles, irisin has been found in various tissues such as adipose tissue, liver, cardiovascular system, brain, bone, pancreas and pancreatic islets, ovary, kidney, immune system, peripheral myelin sheath, and intestinal L-cells. Where irisin causes insulin sensitivity modification, immune modulation helps in nervous conduction, neurogenesis in hippocampus, adipocyte metabolism in the medulla and spinal cord, and various other functions which are still to be researched. ,
| Factors affecting irisin levels|| |
In adults, irisin levels are affected by exercise, age, sex, muscle mass obesity, and cold exposure but not by meals and diurnal rhythms. , Besides these factors, irisin levels are affected in metabolic diseases such as T2DM, gestational diabetes mellitus (GDM), polycystic ovary syndrome (PCOS), nonalcoholic fatty liver disease (NAFLD), and chronic kidney disease (CKD).  Details about the various disorders related to irisin are given below.
| Irisin and exercise|| |
In 2012, Boström et al. showed that irisin levels are increased above the baseline in adult healthy subjects after 10 weeks of endurance exercise training.  In another study, Huh et al. observed significant increase in irisin levels after 30 min acute exercise.  Many other studies have questioned the results of these studies, but the discrepancies could be explained on the basis of different demographic profiles of the subjects studied.  Most recently in 2015, Löffler et al. showed that short bouts of intensive exercise increased irisin levels acutely and transiently but not the long-term physical activity. 
| Irisin and metabolic syndrome|| |
There have been many studies seeking correlation between plasma irisin levels and body mass index (BMI) and fat-free body mass. Huh et al. found significant positive correlation between plasma irisin level, BMI, and fat-free body mass in a cross-sectional study of 117 women having BMI in the range of 20.0-47.7 kg/m 2 . 
Two other studies done by Stengel et al. and Pardo et al. had studied plasma irisin levels in morbidly obese subjects and normal healthy subjects. Both these studies concluded that plasma irisin levels were significantly higher in the case of obese subjects as compared with normal healthy subjects. These studies also concluded that plasma irisin levels were positively correlated with BMI, body weight, and fat mass. , In another study, Liu et al. concluded that plasma irisin levels were positively correlated with BMI, fat mass percentage, and fat mass in diabetic, nondiabetic, and CKD patients. , Interventional studies also confirm the findings of observational studies by revealing the positive correlation between BMI and plasma irisin levels. 
A possible explanation for this paradox of increase in irisin with BMI in obese subjects is that irisin acts as a protective factor against obesity by increasing browning of WAT thereby increased with BMI.  This has been shown in many studies, but there are several contradictory studies which mainly represent the different subject populations studied  as Moreno-Navarrete et al. showed negative correlation between plasma irisin levels and BMI, percent fat mass, and waist to hip ratio in a group of 69 nondiabetic subjects with BMI, 27.61 ± 3.8 kg/m 2 .  Similarly, Choi et al.  found inverse relationship between plasma irisin levels and BMI in a cohort of 104 healthy subjects and the same number of newly diagnosed T2DM patients while Sanchis-Gomar et al.  found no correlation between plasma irisin levels and BMI.
| Irisin and diabetes mellitus|| |
A moderate increase in plasma irisin levels increases energy expenditure by improving diet-induced insulin resistance and preventing weight gain from high fat diet.  Plasma irisin levels are lower in newly diagnosed and long-term diabetes which is due to lower expression and activity of PCG1α. 
Choi et al. showed that plasma irisin levels were significantly decreased in newly diagnosed T2DM patients as compared to normal controls, and also the chances of developing new-onset T2DM were significantly less in subjects with increased irisin levels.  Similar findings were reported in recent onset T2DM.  Choi et al. also noted that plasma irisin levels were negatively correlated with 2 h plasma glucose and glycated hemoglobin  while Liu et al. suggested a significantly positive correlation between plasma irisin levels and fasting plasma glucose.  Irisin may be a predictor and protective factor for T2DM. 
The studies with GDM do not show consistent results because of different timings of irisin measurement. Yuksel et al. showed that maternal plasma irisin levels were significantly low in case of GDM as compared with non-GDM controls while no such differences were noted in the cord blood.  Similarly, Kuzmicki et al. noted lower maternal plasma irisin levels in GDM mother than controls, but both groups had similar levels after delivery.  However, contradictory results were founds with plasma irisin levels increasing significantly in GDM mothers than control. 
| Irisin and other metabolic disorders|| |
Zhang et al. showed that irisin levels are lower in obese subjects with NAFLD and inverse correlation between irisin levels and intrahepatic triglyceride levels.  Similarly, Polyzos et al. showed significantly decreased irisin levels in patients with NAFLD and NASH as compared to lean controls.  However, on contrary to the previous studies, Choi et al. revealed irisin levels higher in patients with NAFLD as compared to the subjects without NAFLD.  These studies reveal importance of irisin in lipid metabolism and development of NAFLD. 
Chang et al. showed irisin levels are significantly elevated in PCOS patients even in the absence of risk factors for metabolic syndrome. These findings suggest important role of irisin as a biomarker for PCOS and an important factor in the development of PCOS. 
Liu et al.,  Wen et al.,  and Ebert et al.  showed that plasma irisin levels are significantly decreased in CKD and this can be because of negative feedback on myocytes by increasing serum creatinine. 
Singhal et al. in a study of 85 adolescent women showed that irisin levels are positively correlated with bone density Z-score, volumetric bone mineral density, stiffness, and load failure.  Irisin levels were associated with measures of areal and volumetric bone density and strength estimates in athletes and associations with bone density, and strength measures persisted after controlling for potential confounders.
| Irisin and cancer|| |
Certain cancers such as prostate carcinoma are associated with obesity as a risk factor making irisin a tentative anticarcinogen. Only a few studies deal with this issue. In one study, no effect of irisin on cancers cell viability for endometrial (KLE and RL95-2), colon (HT29 and MCA38), thyroid (SW579 and BHP7), and esophagus (OE13 and OE33) cancer cell lines was found while in another study, irisin treatment was found to decrease aggressiveness malignant breast epithelial cell line (MCF-10a) but does not change the cell viability.
In another study, Tekin et al. revealed the anticarcinogenic effect of irisin on androgen receptor-positive and androgen receptor-negative prostate carcinoma cells lines (LNCaP, DU145, and PC3) in a dose-dependent manner. 
| Irisin as therapeutic agent|| |
It has been proposed that injectable irisin can be used as a therapeutic agent for metabolic diseases such as obesity and T2DM where weight reduction and exercise may lead to improvement. For this purpose, two compounds of exercise mimetic drugs, such as 5'-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and GW1516 (a modulator of PPAR-d), were suggested as potential treatments for obesity, but they had side effects and were never used because of no approval by the USFDA although media projected these as "exercise in a pill." As irisin is an endogenous hormone, this could in future be used by gene cloning in the management of T2DM, obesity, and other metabolic diseases, but further research in this field is needed. 
| Conclusion|| |
Irisin is a recently discovered myokines which are induced by exercise and functions through browning of WAT. Irisin levels are significantly elevated in obesity, metabolic syndrome, and PCOS while they are significantly reduced in case of T2DM, NAFLD, and CKD; hence, irisin can be used both as a marker and a target for therapy of these metabolic disorders. Besides these disorders, irisin could also have role as antineoplastic peptide, but further studies are required in this direction.
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Conflicts of interest
There are no conflicts of interest.
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