# Molecular Basis of Irisin Regulating the Effects of Exercise on Insulin Resistance
## 3 Irisin and Insulin Resistance  
### Irisin, Mitochondrial Function, and Insulin Resistance  
Mitochondrial dysfunction is a term used to describe the changes in mitochondrial content, activity, and oxidative phosphorylation that occur under a variety of physiological situations [40]. Mitochondrial dysfunction has been linked to IR in myocytes, adipocytes, and hepatocytes [41]. Irisin improves IR by increasing oxidative phosphorylation capability and mitochondrial content [41]. The phosphorylation levels of p38/mitogen-activated protein kinase (MAPK) and extracellular-signal-regulated kinase (ERK) in adipocytes increased when the mice were treated with r-irisin (0.5 \(\upmu\)g/g/day) for 14 days, and the expression of UCP1 was also up-regulated significantly. It is suggested that irisin can boost UCP1 gene expression in white adipocytes by activating ERK and p38 MAPK [9; 10]. UCP1 can promote the browning of white adipocytes, and BAT has more mitochondria than WAT [42]. This enhances the biological functions of mitochondria and improves energy metabolism [43]. After the browning of white adipocytes, mice lose weight, and the glucose tolerance and IR of mice are significantly improved [44; 45]. Moreover, irisin increases the expression of betatrophin which can promote pancreatic beta-cell proliferation and improve glucose tolerance and insulin action [46]. Under the stimulation of muscle contraction, the expression and activity of PGC-1\(\alpha\) are increased, which subsequently promotes irisin secretion [47]. Irisin is recognized as a stimulator for betatrophin expression. [PERSON] et al. reported that irisin treatment increased betatrophin levels in obese mice [9], and betatrophin could reduce the level of serum glucose via activating the proliferation of pancreatic cells [48]. Therefore, there may exist an axis \"PGC-1\(\alpha\)/irisin/betatrophin\" in the regulation of glucose homeostasis.  
Aside from adipose tissue, irisin stimulated the expression of UCP3 in skeletal muscle [49]. Similar to UCP1, UCP3 enhances the thermogenesis of mitochondria and then reduces lipid accumulation, subsequently promoting insulin action [49]. Furthermore, the treatment of r-irisin (5 nM) on C2C12 myocytes markedly increased the gene expression of mitochondrial transcription factor A (TFAM) [49]. TFAM is responsible for regulating the replication and transcription of mitochondrial genes and is capable of enhancing the biological functions of mitochondria [50].  
IR usually has altered hepatic energy metabolism characterized by upregulated gene expression related to gluconeogenesis, oxidative phosphorylation, and reactive oxygen species (ROS) generation [51]. [PERSON] et al. [52] reported that T2 DM patients were featured by a 42% reduction in liver ATP synthetic flux rate, which was linked to both peripheral and liver insulin sensitivity. Irisin treatment affects the function of mitochondrial function in hepatocytes. In the liver, r-irisin treatment significantly reduced the expression of the mitochondrial fission-related proteins dynamin-related protein 1 (drp-1) and fission 1 (Fission 1) [53]. Exogenous irisin also enhanced mitochondrial density as well as promoted PGC-1\(\alpha\) and TFAM expression in mitochondrial biogenesis [53]. [PERSON] et al. [54] demonstrated that r-irisin administration alleviated mitochondrial dysfunction and attenuated liver damage in diabetic mice via the AMPK pathway. In C2C12 cells with IR, mitochondrial content and oxidative phosphorylation capacity were significantly increased after r-irisin (5 nM) treatment for 12 h, and the impaired glucose uptake and IR were reversed, which might be related to the regulation of p38 MAPK phosphorylation [41]. Therefore, the evidence suggests that irisin improves IR via up-regulating mitochondrial content and action.