# Molecular Basis of Irisin Regulating the Effects of Exercise on Insulin Resistance
## 3 Irisin and Insulin Resistance
### Irisin, Inflammation, and Insulin Resistance  
Obesity in humans and animals is featured by a substantial rise of macrophages in the liver and adipose tissue [61]. These macrophages are highly activated and as a result, gene expression associated with pro-inflammatory cytokines is up-regulated [62]. The activation of macrophages potentially affects insulin target cells including myocytes, adipocytes, and hepatocytes via a paracrine mechanism which subsequently leads to IR [63]. Irisin can improve insulin action by down-regulating inflammatory cytokines. A recent study by [PERSON] et al. reported that the levels of inflammatory cytokines in pancreatic islets of high-fat diet-fed (HFD) mice were significantly reduced after r-irisin (0.5 ug/g of body weight) treatment, which was related to the inhibition of the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-KB) signaling pathway [64]. Additionally, in MIN6 cells isolated from HFD mice, irisin administration (100 ng/mL) significantly upregulated the activity of the PI3K/AKT signaling pathway, which subsequently enhanced insulin action [64]. [PERSON] et al. [65] demonstrated that myostatin-regulated inflammation played an essential role in IR in obese mice. The anti-myostatin peptide treatment potentially improved glucose uptake and insulin tolerances via elevating fatty acid metabolism as well as energy consumption while suppressing macrophage infiltration and proinflammatory cytokine expression in obese mice myocytes and adipocytes [65]. This beneficial effect on insulin sensitivity was regulated by irisin-induced depression of inflammation, stimulation of polarization of macrophages from M1 towards M2, and up-regulation of energy consumption [65].  
After treatment with r-irisin (100 nM) on mouse macrophages, the expression of tumor necrosis factor \(\alpha\) (TNF-\(\alpha\)) mRNA substantially decreased by 45% compared to the controls, and its effect was twice that of r-irisin at the dosage of 50 nm (22%) [66]. TNF-\(\alpha\) can cause insulin receptor substrate (IRS) serine phosphorylation and reduce the expression of GLUT4, which subsequently inhibit insulin signaling and triggers IR [67]. The r-irisin administration also resulted in a decrease in IL-6 mRNA and protein levels [66]. IL-6 has the capacity of inhibiting the suppressor of cytokine signaling 1/3, which promotes the IRS deterioration through ubiquitination and eventually leads to IR [68, 69]. Moreover, the mRNA expression of another inflammation cytokine, interleukin-1\(\beta\) (IL-1\(\beta\)), was downregulated by the treatment of r-irisin [66]. IL-1\(\beta\) is known to decrease the expression of IRS through ERK1/2, which is capable of impairing the physiological function of insulin [68]. Additionally, [PERSON] et al. [70] reported that the dephosphorylation of NF-KB was up-regulated in adipocytes after treatment with irisin, and the inactivation of NF-KB inhibited the further transcription of pro-inflammatory genes. Those data suggest that irisin has a strong anti-inflammatory effect which is important for restoring the action of insulin.