# Molecular Basis of Irisin Regulating the Effects of Exercise on Insulin Resistance
## 4 Signaling Pathways Mediating the Link between Exercise, Irisin, and Insulin Sensitivity  
### Exercise Regulating Irisin Secretion  
Muscle not only acts as an effector in the motor system but also has a potential impact on the endocrine system. Exercise can promote muscles to secrete hundreds of myokines, which enter the circulatory system and activate multiple pathways to regulate energy metabolism [71]. Irisin is one of the pivotal myokines, most of which (75%) in the circulation comes from skeletal muscle, and its secretion depends on the increase in PGC-1\(\alpha\) expression. Exercise is an important activator of PGC-1\(\alpha\) expression upregulation, and also acts as a promoter to activate AMPK signaling pathways, which subsequently triggers the phosphorylation of PGC-1\(\alpha\) and promotes the production of FNDC5 (Figure 2). FNDC5 was then cleaved and secreted as irisin [36; 72]. Figure 2: Signaling pathways for irisin regulating the benefits of physical activity upon insulin resistance. Exercise stimulates PGC1\(\alpha\) expression in mouse and human skeletal muscle. Subsequently, the expression of FNDC5 increases, and it is then subject to cleavage, leaving the extracellular portion as irisin. Irisin is a hormone that enters the bloodstream and circulates to organs and tissues (including skeletal muscle, adipose tissue, and liver) to modulate energy metabolism and improve IR. Irisin can decrease inflammation in cells by promoting the dephosphorylation of NF-KB and down-regulating pro-inflammatory cytokines. Moreover, irisin can also enhance mitochondrial density and thermogenesis by increasing the expression of TFAM, UCP3, as well as UCP1. Additionally, irisin improves the content and trafficking of GLUT4 and subsequently increases glucose uptake via upregulating the phosphorylation level of P38/MAPK and the gene expression of GLUT4. Abbreviations: PI3K, phosphoinositide 3-kinase; PDK1, P3 dependent kinase-1; AKT, protein kinase B; G6P, glucose-6-phosphate; JNK, C-Jun N-Terminal Kinase; DAG, diacylglycerolcerol; UCP3, uncoupling protein 3. Studies investigate the correlation between exercise and irisin frequently involving the changes in irisin, FNDC5, and its upstream regulating gene PGC-1\(\alpha\) in response to exercise. The evidence from animal experiments indicated that a program of 8-week swimming training significantly increased the level of serum irisin in rats [73], and the expression of PGC-1\(\alpha\) mRNA and FNDC5 mRNA in the muscle tissue increased in mice that received exercise intervention [10]. [PERSON] et al. carried out 1 h treadmill exercise (at 60% VO2 max) on male C57 BL/6J mice, and they reported that plasma irisin quantities increased significantly during exercise and reached the peak value (20.71 \(\pm\) 0.25 ng/mL) at 6 hours after the intervention. Meanwhile, PGC-1\(\alpha\) mRNA expression levels increased significantly in muscle tissue during exercise, maintained the higher level for about 6 h, and then gradually returned to the baseline value after 12 h of exercise intervention [74]. The authors proposed that exercise promoted irisin secretion probably in a PGC-1\(\alpha\) dependent manner [74]. In the soleus and gastrocnemius muscles, 90 min of acute swimming exercise remarkedly activated the expression of FNDC5 mRNA and protein, whereas the change in serum levels of irisin was not significant [75]. Accordingly, the swimming exercise also increased UCP1 mRNA and protein expression in subcutaneous WAT, as well as browning marker mRNA expression in visceral WAT [75]. Compared with the results from animal experiments, there is some controversy about the effects of exercise on human irisin secretion [76]. The amount of FNDC5 mRNA in 26 subjects' skeletal muscles rose considerably after 12 weeks of continuous exercise intervention, among which the healthy control group increased by 1.4 times and the pre-diabetic group increased by 2 times, together with elevated PGC-1\(\alpha\) mRNA expression [77].