irisin

rst discovered in the muscles of a mouse in 2012. Irisin has a molecular weight of 23,231 KDa and belongs to the domain containing 5 (FNDC5) family. It has been shown to have some very bene�cial effects in humans, such as thermoregulation and weight loss, and it is also secreted by the muscles of humans when they exercise or work out. The gene symbol for irisin is FNDC5, which represents the precursor of irisin. At the protein level, both FNDC5 and irisin have characteristics that are similar, but FNDC5 is not appropriate in some situations. It is released during physical activity and is linked to a variety of metabolic diseases such as obesity, type 2 diabetes, lipid metabolism, heart disease, NAFLD, PCOS, and metabolic diseases of the bones. Irisin is not only responsible for the disorders, but it also has the potential to be used as a biomarker for speci�c diseases. Humans and mice have both shown that myokine irisin promotes the browning of white adipose tissues while simultaneously increasing thermogenesis and energy expenditures. Irisin therapy reduces body weight while also increasing brown fat-specic gene expression in the patient. Irisin increases the risk of type 2 diabetes and cancer. Irisin levels were found to be lower in obese people who had NAFLD.


Review Article
Irisin is also given an additional name as Fibronectin type -III domain containing 5 (FNDC5). It was discovered a few years ago in 2012 in the muscles of mouse. Some very bene cial effects have been reported in the humans like thermoregulation and weight loss and is also secreted in the muscles of humans during exercise. Irisin is yield on cleavage of its originator Fibronectin type III domain containing 5 (FNDC5). The precursor FNDC5 weights about 23, 231 KDa. There is a difference in the KDa of transmembrane and cellular FNDC5, the cellule FNDC5 have molecular weight of 23KDa that is smaller than transmembrane having Molecular weight of 32 KDa. It has been well conserved through evolutionary process in the animals. Most of information about irisin has also been seen as similar in FNDC5 like gene and homology etc. [1]. It DOI: https://doi.org/10. 54393/pbmj.v6i07.905 Irisin and its Effects on the Metabolic Diseases was reported that there is a protein that is formed by the cleavage of FNDC5 that is found in the cells of skeletal muscles. Browning of white fat is affected at a huge extent by this protein. After some days of continuous exercise, a huge increase in the volume of circulating irisin was also observed in both mice and humans [2]. The mineral density of bones is related to serum concentrations of irisin [3]. Some pathological conditions like osteoarthritis is also related to the lower serum concentrations of irisin [4]. Osteogenesis can also be induced by irisin; bone loss that is caused by the estrogen de ciency can be resisted by the deletion of FNDC gene. Structure Irisin mainly has three parts i.e., 29-amino acid signal peptide, 94-amino acid single FN III Fibronectin domain Irisin and its Effects on the Metabolic Diseases

I N T R O D U C T I O N
Irisin, also known as Fibronectin type III, is a hormone that is secreted by muscle cells and was rst discovered in the muscles of a mouse in 2012. Irisin has a molecular weight of 23,231 KDa and belongs to the domain containing 5 (FNDC5) family. It has been shown to have some very bene cial effects in humans, such as thermoregulation and weight loss, and it is also secreted by the muscles of humans when they exercise or work out. The gene symbol for irisin is FNDC5, which represents the precursor of irisin. At the protein level, both FNDC5 and irisin have characteristics that are similar, but FNDC5 is not appropriate in some situations. It is released during physical activity and is linked to a variety of metabolic diseases such as obesity, type 2 diabetes, lipid metabolism, heart disease, NAFLD, PCOS, and metabolic diseases of the bones. Irisin is not only responsible for the disorders, but it also has the potential to be used as a biomarker for speci c diseases. Humans and mice have both shown that myokine irisin promotes the browning of white adipose tissues while simultaneously increasing thermogenesis and energy expenditures. Irisin therapy reduces body weight while also increasing brown fat-speci c gene expression in the patient. Irisin increases the risk of type 2 diabetes and cancer. Irisin levels were found to be lower in obese people who had NAFLD.

Irisin Detection Methods
Irisin is not only causing the disorders but can also be used as a biomarker for de nite diseases [21]. ELISA is an antibody-antigen based detection method in human research, it is frequently utilized because of its quick detection speed, simple installation, and capacity to examine a large number of samples [22]. The irisin level in young athletes is tested higher than other individuals [23]. Ruan et al., 2019 used both mass spectrometry and ELISA kits to examine the irisin level in cerebrospinal uid but rd these kits failed to measure the irisin level in about 1/3 of the sample while spectrometry measured it quantitatively [24]. The molecular weight of irisin was rst calculated as 22kDa. The weight of irisin has ranged from 22 to 34 kDa, whereas the molecular weight was expected to be 12 kDa, Schumacher reported that irisin act like a dimer and its molecular weight by 24 kDa, which is not affected by glycosylation [25]. and C-terminal The insertion of irisin in human beings has been reported as 50-amino acid N-terminal [5]. Basic structure and activity of irisin is shown in Figure 1.

Origin of Irisin in the Human Body
The human FNDC5 gene's start codon was altered, and cells transfected with the mutant version of the gene translated only 1 % of the full-length protein [7]. Many scientists stated that translation of irisin is not started by a normal start codon (AUG) rather it is started by a manipulated start codon (non-canonical start codon). Animals having dense genetic arrangements like bacteria, fungi and mammalian cells that are affected by the viruses have the noncanonical start codons [8]. Non-canonical start codons have a much lower translational rate than the AUG start codon. The expression of proteins can be initiated by any of six non-canonical start codons [9]. Kim discovered three distinct FNDC5 transcripts with varying degrees of expression in various human tissues [10]. This is the rst research to nd irisin transcripts, and it will be the only one for the foreseeable future. Recent research, however, found that when employing all of the exons in these three transcripts, the annotated transcripts were not ampli ed [11]. Women suffering from osteoporosis have low serum irisin level [12]. Older women with minimal trauma hip fracture show lower serum irisin level and vice versa. For normal bone functioning irisin level is important and those having high hip density show high level of irisin [13]. In mice, bone formation rate is increased using recombinant irisin and it also alleviates the bone loss caused by ovariectomy and in ammatory disease in gastrointestinal tract. Irisin is sensitive to bone cells i.e. if a lower amount of irisin is introduced then it only effects the bone cells without browning of WAT [14]. Damage caused to bones because of disuse can also be restored with irisin [15]. Colaianni observed that differentiation of osteoblast promoted through irisin by MAPK and WNT pathways. Recombinant irisin act on osteoblast and activates 2 pathways i.e., P38 and ERK, the expression of ATF-4 increases and RUNX2 pathways activated [16]. The Wnt target genes activated when β-catenine moves in nucleus from cytoplasm [17].

Synthesis, Release and Regulation of Irisin
The precursor FNDC5 of irisin is the gene symbol for irisin. At protein level both FNDC5 and irisin show similarity in their characteristics but in some cases is not suitable. The gene responsible for the production of FNDC5 is located on the chromosome 1 in humans. The mRNA of FNDC5 in humans has 2099bp. The FNDC5 found in humans have 6 exons and 5 introns [18]. The transcriptional co-activator peroxisome proliferator-activated receptor-γ (PPAR γ) and the coactivator-1 α (PGC1α), activate the gene expression of FNDC5. The cleavage and release of irisin is similar to the cleavage and release of transmembrane polypeptides in epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). The C-terminal moiety is glycosylated and proteolytically cleaved to liberate the 112-aa hormone that contains most of the FNIII repeat region and release the hormone ( Figure 2) [19]. weeks of exercise [32].

Stimulation of Browning of White Adipocytes
Ability of animals to resist body fat gain is connected to the quantity and activity of brown adipocytes. Some white adipose tissue (WAT) depots are easily converted into a ''brown-like" state in particular circumstances, that is linked to mass decrease [33]. Irisin stimulates browning of WAT t h ro u g h u n i d e n t i e d m e c h a n i s m . I n m i ce, Recombinant irisin reduced body mass and improved glucose homeostasis [34]. Irisin increased the expression of uncoupling protein-1. Irisin-induced activation of the p38 MAPK and ERK signaling pathways may be responsible for this impact [35]. SB203580 and U0126 inhibition of the p38 MAPK and ERK inhibited upregulation of UCP-1 by irisin. Irisin also increased the expression of betatrophin, a recently discovered hormone that increases pancreatic βcell proliferation and improves glucose tolerance [35]. Finally, our results show that irisin may help to reduce obesity and type 2 diabetes by increased expression of WAT browning-speci c genes through the p38 MAPK and ERK pathways [36]. Obesity is by far the most common metabolic disorder that occurs in the world [37]. Obesity arises when a patient's calorie intake beyond their calorie expenditure, and it is de ned by a rise in fatty tissue [38]. Overweight persons are more likely to get type 2 diabetes (T2DM) [39]. In terms of avoiding overweight, greater energy consumption has appeared as a possible and acceptable alternative [40]. While the exact mechanisms that control calorie expenditure are unknown, adipocytes play a very important role in mammalian energy balance and nutrient uxes. White fat tissue and brown fat tissue are two kinds of adipose tissue that have received a lot of attention [41]. Brown adipocytes burn energy, whilst white adipocytes store it. Changes in BAT activity have been shown in numerous studies to have a signi cant impact on adaptive thermogenesis and glucose homeostasis [42]. Brown fat's thermogenic activity is primarily enabled by the presence of UCP-1, a mitochondrion uncoupling protein that decouples the electron transport chain from energy production, allowing potential energy received from food to be released as heat [43]. The transcriptional factor PPAR coactivator-1 (PGC-1), that can be stimulated by cold contact and/or -adrenergic signaling, regulates the expression of UCP-1 [44]. In various lab animals, browning of WAT compartments plays a protective role versus nutrition metabolic diseases like as obesity and diabetes [45]. It has 111 amino acids and a molecular weight of 22 kDa. PGC-1α and exercise have been shown to increase the expression of FNDC5, a type I transmembrane protein found in skeletal muscle. Irisin that is produced after Fndc5 is proteolyzed at amino acid positions 30 and 140. An increased level of irisin by an adenoviral vector enhances

Irisin in Metabolic Diseases
In both humans and mice, the myokine irisin promotes browning of white adipose tissues while also increasing thermogenesis and energy expenses. Irisin causes many metabolic diseases like obesity, T2DM, lipid metabolism, diseases related to heart, NAFLD, PCOS and metabolic diseases of bone [26]. Irisin is the new health promoting hormone because in human muscles, FNDC5 gene is expressed during exercise and produces irisin. Irisin causes browning of white fat that enhances the metabolic uncoupling and increases the energy expenses. Two pathways i.e. p38 mitogen-activated protein kinase (MPAK) and extra cellular-signal regulated kinas (ERK) enhance this metabolic uncoupling. The maturation of preadipocytes into mature adipocytes decreases after the treatment of irisin and the gene expression remain unaffected. The MPAK and ERK-p38 pathways are triggered due to the increase expression of UCP1 protein. Agetr cold exposure the insulin-mediated glucose uptake of BAT rises ten times more than WAT [23]. The earlier studies show that expression and activity of PGC-1α and irisin level is lower in patients having T2DM. It was concluded that patients suffering from T2DM have lower level of circulating irisin than the normal persons [27].

Association between Serum Irisin Level and Exercise
Boström and colleagues reported that after exercise of about 10 weeks, the irisin level increases by 2 folds [29]. If the mouse runs downhill the level of irisin was reported to increases signi cantly but no change in the level of irisin was reported in uphill running after exercise of two weeks [30]. Changes that are induced by exercise are more complicated in patients suffering from metabolic disorders. In mice suffering from hyperthyroidism or hypothyroidism serum irisin level can be increased even after an acute exercise [31]. Huh reported that after 8 weeks of running there was no change in the serum irisin level in humans [5]. In later studies, it was observed that there is decrease in the level of serum irisin after a few boosts islet-cell activity and survival, therefore alleviating hyperglycemia, hyperlipidemia, and insulin resistance. If veri ed, irisin may decrease these defects in hepatic and islet functioning, which e ciently reduce T2DM risk [54]. In hepatocytes, irisin inhibits lipogenesis induced by p a l m i t i c a c i d a n d g l u c o n e o g e n e s i s i n d u c e d by glucosamine, through the PRMT3 and PI3K/Akt pathways, respectively [55]. In obese people with NAFLD, blood irisin levels were lower, which was connected to content of hepatic triglyceride. The islets of liver and the pancreas play important roles in T2DM pathogenesis, and are vulnerable to glucoli-potoxicity. The exact mechanism from which irisin controls hepatic glucose and lipid homeostasis as well as protects beside islet malfunction and death is remain unknown [56].

Irisin and Cancer
Exercise has been shown to lower the risk of many forms of cancer, prevent cancer progression, and have bene cial and healing effects on cancer. Changes in physical composition, hormone secretion, severe in ammatory state, and the immunity have all been postulated as potential moderators of exercise's anti-cancer bene ts [57]. Obesity enhances in ammatory markers (IL-6 and TNF-), glucose intolerance, and adipokine productions, which together favor cancer cell proliferation and survival, whereas exercise has shown that anti-in ammatory bene ts by decreasing TNF-expression. Considering that irisin has been linked to obesity, it makes sense that it could also be linked to cancer [58]. Increased irisin levels reduced lung cancer cell production, capability, and invasiveness via in uencing the EMT, dramatically lowering the EMT markers (N-cadherin and vimentin) while raising Ecadherin expression. The Snail pathway, which is mediated by the PI3K/Akt pathway, was associated to this reduction in EMT. Irisin's effect on the PI3K pathway may also imply an inhibiting effect, which may also explain why cancer cell growth has reduced [59]. Irisin could be a new biomarker for breast cancer detection. 90% risk of breast cancer is reduced by increasing blood irisin level; whereas breast cancer patient had much lower irisin serum levels than healthy individuals. When the breast tumor cells are exposed to irisin, the caspase-3/7 increases and NF-κB movement suppressed thus cause the decrease in number of tumor cells [60]. The impact of irisin was studied using three different types of cells: non-malignant breast epithelial cells, malignant breast epithelial cells, and malignant aggressive breast epithelial cells. When aggressive breast tumour cells were exposed to irisin, there was an increase in caspase 3/7 and a reduction of NF-kB. Irisin increases caspase 3 activation and apoptosis, as well as the ability to ght cell death [61]. When the cells were exposed to irisin, there was an increase in doxorubicin complete body energy expenditure, causes minor weight loss, and improves glucose intolerance in high fat-fed mice [2]. The circulating level is mostly determined by age and skeletal muscle mass, with irisin levels in young male athletes are many times higher than in middle-aged obese women [5]. When compared to non-diabetic control participants, circulating irisin is noticeably lower in people with T2DM [27]. Furthermore, in chronic renal disease patients [46], plasma irisin levels are inversely connected with blood urea nitrogen levels and favorably connected with aerobic act in heart failure patients. Irisin, like hepatic broblast growth factor 21 [47] and cardiac natriuretic peptides, can now be considered a secreted protein that stimulates brown adipocyte thermogenesis [48]. However, very little known about the molecular processes and signaling pathways that irisin employs to produce the active brown-like adipocyte phenotype. Li et al., in their study, developed a productive technique for the synthesis and puri cation of human recombinant irisin (r-irisin), and administered the r-irisin to mice through intraperitoneal injection. To better comprehend the fundamental "browning" mechanisms, they used r-irisin to treat primary adipocytes and 3T3-L1-derived adipocytes and looked at how it impacted the browning of fat cells [49]. In line with earlier research [50], their results showed that r-irisin treatment reduces body mass, elevates brown fat-speci c gene expression in subcutaneous white adipose tissue, and enhances glucose tolerance in vivo. In cell culture assays, irisin increased the expression of genes related to brown fat by activating the p38 MAPK and ERK pathways [51]. T2DM Adipocyte browning has been shown to be controlled by irisin, although its effects on lipid and glucose metabolism in T2DM remain mainly unclear. In diabetic mice Irisin's involvement in glucose consumption and lipid metabolism was examined. There was an increase in 18F-FDG accumulation and GLUT4 translocation in diabetic skeletal muscle when irisin was improved. Similarly, in myocytes, irisin enhanced glucose absorption grown in a high glucose medium. PEPCK and G6Pase inhibited by insulin in diabetic liver [52]. Diabetes mice treated with irisin showed a reduction in fat mass, total cholesterol serum, and triglyceride levels, but a rise in acetyl coenzyme fat tissue UCP1 expression and a carboxylase β-phosphorylation. Myocytes' lipid acid oxidation was also enhanced by Irisin. Irisin's effects on consumption of glucose and fatty acid βoxidation in myocytes were reduced when AMPK was repressed. In hepatocytes irisin effect reduced on PEPCK and G6Pase by the inhibition of AMPK by a speci c inhibitor [53]. By managing endoplasmic reticulum (ER) strain, irisin can enhance hepatic glucose and lipid regulation. It also (a chemical reagent that is highly effective in cancer therapy) [62]. Irisin performs a protective role on bone against the breast cancer. It protects from the metastasis of breast cancer. Irisin and spinal irisin levels are inversely linked, indicating [60]. In osteocarcinoma cells irisin was able to inhibit the STAT3 pathway by reversing the IL-6induced by [63]. Irisin's capacity to suppress EMT, capability, and growth of pancreatic cancer cell lines was further demonstrated when AMPK pathway is activated. Irisin suppresses the development of pancreatic cancer cells via the AMPK-mTOR pathway. Irisin's capacity to aim the AMPK pathway suggests that it may play a task in decreasing growth and modifying cancer metabolism [64]. Furthermore, irisin can be employed to detect for renal diagnosis of renal cancer, as irisin levels were signi cantly greater in individuals having kidney tumors; irisin also showed elevated particularly and sensitivity than other studied biomarkers [45]. The vitality of prostate cancer cells was lowered when different doses of irisin were applied to them [65]. In glioblastoma cells, irisin triggered G2/M cell cycle arrest and elevated p21 levels, inhibiting cell proliferation. Furthermore, through upregulating TFPI-2, irisin prevented glioblastoma cell invasion. Furthermore, irisin inhibited cancer in xenograft glioblastoma cells, and radiolabeled irisin revealed precise cancer cells-targeting capabilities in vivo.  As a result, our study identi ed irisin as a potential biochemical mechanism by which exercise reduces cancer progression. Irisin has the chance of growing as a molecular scanning and anticancer treatment drug.

C o n  i c t s o f I n t e r e s t
The authors declare no con ict of interest.