Exercise-Induced Irisin, the Fat Browning Myokine, as a Potential Anticancer Agent

Irisin is a recently discovered myokine that plays an important role in fat metabolism through the browning of white adipose tissue. This myokine is usually secreted after exercise by improving energy balance and has shown great potential as a possible treatment for some metabolic diseases such as obesity, insulin resistance, and inflammation. Obesity has been linked to a higher incidence of some cancers. Furthermore, some studies have shown irisin to have direct positive effects on different types of cancers. Although it is hard to relay conclusions from in vitro to in vivo studies, the majority of the available data favor irisin as a potential substance for cancer regression through reducing proinflammatory markers linked to obesity. However, some controversies remain on the exact benefits of irisin on cancer with some studies showing no or even a negative effect of irisin on cancer. This review summarizes these 2 differing viewpoints and synthesizes them to form a clearer picture of exercise-induced irisin's effects on cancer.


Introduction
Obesity, along with the metabolic diseases it causes, has become an increasingly growing problem that has devastating economic, health, and societal effects. From insulin resistance and hyperlipidemia to cardiovascular diseases and cancer, obesity has been associated with many of the leading causes of death worldwide [1,2]. Despite its prevalence, excess weight can be greatly reduced by following a healthy diet and a good exercise routine [1]. In fact, exercise is known to exert beneficial effects on all body systems. Studies have repeatedly proven the positive effects exercise has on the cardiovascular, respiratory, and skeletomuscular systems [3]. Exercise induces these changes by the release of hormones and myokines from the skeletomuscular system in the body [4]. Some of these myokines include BDNF, FGF-21, IL-15, and irisin [4,5]. Indeed, one of these myokines, irisin, which was only recently discovered, has been shown to have numerous benefits not only in fighting metabolic diseases but also in combating cancer [4]. Recent reviews in the literature link irisin and exercise, concluding that irisin increases after exercise, however only transiently [6]; irisin, obesity, and metabolic diseases have also been linked [7], but no review summarizes the studies that show the effect of irisin on cancer or cancer biology. An investigation into the available literature shows that irisin has direct effects on different types of cancers. However, some controversies remain on the exact benefits of irisin on cancer with some studies showing no or even a negative effect of irisin on cancer. is review summarizes these 2 differing viewpoints and synthesizes them to form a clearer picture of irisin's effects on cancer and questions if irisin is the missing link between obesity, exercise, and cancer.

Methods
e articles listed in Section 3.4 were selected based on relevancy from PubMed and Google Scholar databases. Initial results yielded 56 articles on PubMed and 9280 articles on Google Scholar where "Irisin" and "Cancer" were used as keywords. After reading all the abstracts to refine the selection, only 17 articles were found to directly link irisin with cancer as these articles mentioned the direct effect of irisin on cancer cell lines in vitro and the effects of serum irisin in cancer patients in vivo.

Results
From the 17 articles selected and reviewed for the "irisin and cancer," (i) irteen articles (Table 1) favoured irisin as a myokine with a role in carcinogenesis or cancer therapeutics (7 studies were conducted in vitro, and 6 studies were performed in vivo) (ii) Four articles considered that irisin has no or adverse effect on cancer progression 3.1. Irisin. Irisin is released through the cleavage of FNDC5, a polypeptide protein containing 212 amino acids. is protein is cleaved at the N-terminal releasing irisin, originally named after the Greek goddess Iris, into the blood [21]. is cleavage is initiated by muscle contraction through an unknown proteasome [21]. Irisin levels are increased after acute exercise and bind to an unidentified receptor on the adipose tissue, which leads to significant weight loss and decrease in total body energy [21].
Recent studies of its function have determined that its beneficial effects derive from its ability of browning white adipose cells. e molecular cascade that ties irisin and the browning of white fat is the following: first, exercise increases the expression of PGC-1α or peroxisome proliferator-activated receptor (PPAR-c) coactivator. is in turn increases the expression of FNDC5, which, as stated before, releases irisin. Irisin then increases the mRNA expression of UCP1, a transmembrane protein that decreases the proton gradient generated by oxidative phosphorylation [21].

Irisin and Exercise.
Since irisin was linked with muscle contraction, studies were conducted to measure irisin levels after exercise. Several studies were conducted to measure the levels of irisin after exercise especially in overweight individuals. e selected articles of this section are based on recent studies conducted between 2014 and 2017 showing the relationship of irisin and exercise; the studies were performed on individuals of various body types and on mice. A murine study concluded that a significant increase in irisin levels and UCP1, which leads to increased thermogenesis in the white adipose tissue, was seen after rats were subjected to resistance exercise [22]. Another study conducted on humans indicated a significant increase in irisin levels among obese youth after exercise. However, this increase was observed directly after aerobic exercise while no change was observed after resistance exercise [23]. Other studies linked irisin levels with BMI, obesity, and leptin, where obese children who had undergone a physical activity program showed a significant increase in levels of irisin and leptin.
is suggests that irisin could possibly link the skeletomuscular system with the adipose tissue [24]. A murine study conducted on high-fat diet-induced obese mice concluded that mice exposed to intravenous irisin gained similar benefits as those who had exercised. is study also showed that these two groups had improved insulin resistance and levels of reproductive hormones and improved ovarian follicle health [25]. Irisin was also found to induce muscular hypertrophy when injected into mice after activation of satellite cells and increase protein synthesis [26]. Lastly, in a study conducted on healthy human subjects, irisin and lactate levels were positively correlated and both increased with higher exercise workload, confirming the researchers' hypothesis that irisin is tied to muscle energy demands [27]. is correlation could suggest that the increased strain on the muscles and low ATP may signal irisin release. Interestingly, individuals who were able to reach a higher VO 2max and thus work at a higher exercise workload produced higher levels of irisin after exercise [27]. ese studies show a clear pattern between irisin and exercise where exercise induced a significant increase in irisin secretion.

Irisin and Obesity.
Irisin, originating from the white adipose tissue in mice, is thought to form around 30% of total body irisin, while in humans, muscle FNDC5/irisin expression is 100-200 times higher than in the white adipose tissue [28]. Another interspecies difference irisin shows is that its browning effects in humans may be different than those in rodents. Indeed, irisin decreases browning-related genes in human preadipocytes but increases said genes in mature human adipocytes [6,21].
Since irisin increases energy expenditure through its aforementioned effects on UCP1, it is expected that it should reduce body weight. Hence, it is paradoxical that obese individuals show increased irisin levels as compared to normal weight individuals. In fact, anorexic patients show as much as 30% reduced irisin levels compared to morbidly obese individuals. It is surmised then that while increased fat deposits increase the production of irisin, irisin itself can no longer exert its effects in a meaningful manner; thus, obese individuals may have irisin resistance, a condition not too different from leptin resistance, where increased leptin levels fail to enact their beneficial effects. In turn, leptin is also positively correlated with obesity and irisin itself [29]. Many studies revealed a link between irisin and obesity due to its secretion by the adipose tissue and have found a positive correlation between BMI and irisin [7].

Irisin and Cancer.
A large body of evidence has linked obesity to cancer because obesity leads to an increase in inflammatory markers (IL-6 and TNF-α) [30], insulin resistance [31], and adipokine secretions [32], all of which favor tumor survival and proliferation [33], while exercise has also shown to have potential anti-inflammatory effects by reducing of TNF-α expression [34]. us, since irisin is linked to obesity, it follows to hypothesize that irisin could be associated with cancer as well ( Figure 1). Tying together obesity, irisin, and cancer, exercise, which helps combat obesity, also increases irisin levels [23]. Exercise-induced irisin could be used as a determinant of the metabolic response to exercise in obese individuals to track any decrease in cancer risk linked to obesity [35]. To study irisin's effects on cancer, a study was conducted on human nonmalignant  [11] Journal of Obesity 3   . Upon exposure to irisin, the malignant breast tumor cell number significantly decreased as a result of increased caspase-3/7 activity and suppression of NF-κB activity. is shows that irisin could possibly reverse the cancer hallmark of resisting cell death [36,37] by promoting caspase 3 activity and thus apoptosis. A significant decrease in cell migration compared to the control was also noted. Moreover, the malignant breast cells were exposed to doxorubicin, a chemotherapy agent, and irisin. When exposed to irisin, these cells showed a significant increase in doxorubicin sensitivity and a significant decrease in malignant cell viability and number. In fact, this increased doxorubicin sensitivity meant that less doses of doxorubicin were even more effective at producing the desired chemotherapy effects. us, irisin could play an important role in cancer therapy [10]. Another study on irisin and breast cancer showed that there was a negative correlation between serum levels of irisin and spinal metastasis of breast cancer. Irisin was found to have a protective effect on the bone, and these favorable bone qualities protected from metastasis of breast cancer [19]. is shows that irisin's effects also could reduce the metastatic and invasive hallmarks of cancer [36]. Yet another study suggested that increased levels of serum irisin reduced the risk of breast cancer development by 90%, and patients that had developed breast cancer had a significantly lower irisin serum levels than healthy individuals [9].
Aiming to uncover irisin's relation to other types of cancers, two studies conducted on lung cancer cells concluded that an increase in irisin levels led to a decrease in lung cancer cell proliferation, viability, and invasiveness by affecting the epithelial-mesenchymal transition (EMT), significantly decreasing the EMT markers N-cadherin and vimentin and increasing the expression of E-cadherin. is inhibition in EMT was related to the inhibition of the Snail pathway which is mediated by the PI3K/Akt pathway [8]. Irisin's effect on the PI3K pathway may also suggest an inhibitive role and a reason for the reduction in cancer cell proliferation.
e second study conducted on osteocarcinoma cells also confirmed these findings and deduced that irisin was able to reverse IL-6-induced EMT by inhibition of the STAT3 pathway [18]. Another recent study conducted on pancreatic cancer cell lines also showed irisin's ability to inhibit EMT, viability, and proliferation of these cells by activation of the AMPK pathway. Irisin inhibits pancreatic cancer cell growth via the AMPK-mTOR pathway [20]. is ability of irisin to target the AMPK pathway may also suggest its role in reducing proliferation and altering cancer energy metabolism [37,38]. A study conducted on prostate cancer cells subjected to different concentrations of irisin showed reduced prostate cancer cell viability [13]. Furthermore, a study on renal cell cancer suggested that irisin can be used as a biomarker for renal cancer diagnosis as irisin levels were significantly increased in patients with renal tumors; irisin too had higher specificity and sensitivity than other investigated biomarkers [11]. In a recent study conducted, patients with colorectal cancer showed low serum irisin levels compared to healthy individuals while individuals with high levels of irisin showed a 78% reduced risk of developing colorectal cancer (CRC). ese findings could show that irisin could have protective qualities against development of CRC [14].

Controversies
. Despite what appears to be a positive correlation between irisin and cancer, two studies conducted on hepatocellular carcinomas have suggested that irisin stimulated the proliferation and invasion of hepatocellular carcinoma tumors via activation of the PI3K/AKT pathway.
is study also showed a reduction in doxorubicin cytotoxicity in the presence of irisin [16]. e second study showed a significant increase in expression of hepatic irisin mRNA in individuals with hepatic carcinoma [12].
Furthermore, a murine study conducted to assess the relationship between cachectic factors and irisin in gastric cancer showed no significant difference in the expression of FNDC5 in gastric cancer tissues. However, FNDC5 expression was increased in the subcutaneous adipose tissue, and an overall increase in irisin serum levels was noted. Nevertheless, these increased serum irisin levels seen in this study failed to increase UCP1 expression in the white fat tissue, while increased irisin levels due to exercise do increase UCP1 expression [17]. erefore, this shows that the increased irisin levels due to exercise operate differently than those seen in gastric cancer and possibly other types of cancer.
Moreover, a study conducted on several cancer cell lines where adhesion activity and colony numbers were measured failed to show any effects of irisin on the proliferation and malignant potential of these cell lines [15]. Indeed, these studies showed that perhaps the beneficial effects of irisin are cell-or tissue-specific and may not be observable in all cancer types.

Discussion
Exercise has shown its positive influence in numerous chronic diseases, especially obesity, but the direct path that causes these positive changes remained elusive [39]. Exercise has also shown its effect on several hallmarks of cancer [38]. No study has yet revealed the exact type and duration of exercise that should be performed to decrease cancer risk. In our present review, we shed the light on irisin as an exercisesecreted myokine, and we summarize the studies that show the effect of irisin on some of the hallmarks of cancer. Indeed, the studies conducted showed that cancer cells exposed to irisin presented an increase caspase activity, a suppression of NF-κB activity, thus a reduction of the "resisting cell death" hallmark [36]. Other studies showed a role of irisin in suppressing other hallmarks of cancer such as "sustaining proliferative signaling" [36] by targeting the PI3K/Akt pathway [16] or "evading growth suppressors" [36] via targeting the AMPK-mTOR pathway [20] or "activating invasion and metastasis" [36] by decreasing cell migration and inhibiting the epithelial-mesenchymal transition [18]. Irisin belongs indeed to the emerging group of 6 Journal of Obesity myokines that are hypothesized to reduce cancer risk by lowering the basal systemic levels of cancer risk factors such as proinflammatory cytokines and adipokines [37,40].

Conclusion
Further mechanistic studies are necessary to determine how irisin induced fat browning and obesity reduction may reduce carcinogenesis or cancer risk. As for the potential role of irisin in cancer therapeutics, more studies should be performed in order to determine the mode of administration of irisin for each cancer type. Nevertheless, obesity has become a worldwide epidemic disease, and many diseases related to obesity also present a steady rising, including insulin resistance, metabolic syndrome, type II diabetes, hypertension, chronic kidney disease, cardiovascular disease, heart failure, and cancer. erefore, exercise-induced irisin deserves a closer inspection to further understand its direct role in reducing obesity and to elucidate its part in cancer prevention and therapeutics.

Conflicts of Interest
e authors declare that there are no conflicts of interest regarding the publication of this paper.