## 3 Irisin
### Irisin Functions  
[PERSON] and colleagues were the first to show that irisin levels in the blood increase after PE, describing an increase of 65% in blood concentration in mice submitted to regular running for 21 days [7]. The level of irisin after PE is dependent on the type of physical activity, where training based on aerobic exercise is a higher inductor of serum irisin compared to resistance exercise [63; 64].  
In general, the level of irisin is influenced by lifestyle, characterized by specific residential place and associated activities, as suggested by the differences recorded between rural and urban inhabitants. Irisin concentration is lower in urban citizens, with a mean value of 3.6 ng/mL, while active individuals that live in rural areashad amean value of 4.3 ng/mL [65]. PE increases the level of irisin in the blood of healthy people [7], and in people with metabolic disorders [66]. Its circulating level is also related to the phenotype of different disease, as well obesity, type 2 diabetes [67], chronic renal disease [68] and hypothyroidism [69].  
The first identified function of irisin was the \"browning\" of adipose tissue, in which irisin increases the expression of the mitochondrial protein uncoupling protein-1 (UCP-1) in mature fat cells, allowing the conversion of the white adipose tissue (WAT) to the brown adipose tissue (BAT) phenotype. The process ends with the formation of a third type of adipose tissue phenotype, named beige/brite adipose tissue. Irisin and PGC-1\(\alpha\) regulate the expression of UCP-1 and thermogenesis in BAT, driving the metabolism of glucose and lipids toward the increase in energy consumption [70; 71]. Furthermore, irisin is implicated in glucose homeostasis, by acting on different cell types and tissues involved in glucose metabolism, such as adipose tissue, SkM, liver, and pancreatic \(\beta\) cells. Due to this property, irisin is able to improve insulin sensitivity under insulin resistance (IR) conditions [72]. A decrease in irisin levels was associated with an increased risk of presenting metabolic syndrome and hyperglycemia in obese adults. This myokine shows negative associations with fasting insulin and glycosylated hemoglobin [73]. Previous studies also suggested its negative correlation with fasting glucose and HOMA-IR in school-age students of both genders [74], and positive associations with insulin concentration, fasting glucose, and HOMA-IR [66; 75; 77; 76].  
Irisin has other specific functions, including in the heart and liver, where it exerts antiapoptotic effects on cardiomyocytes and hepatocytes through the induction of autophagy [45], and protects cells from ischemia-reperfusion injury [78; 79]. At bone level, it has a favorable effect and represents a key molecule in the crosstalk between this tissue and SkM. Specifically, irisin increases the mass and strength of the cortical bones, positively modifying their geometry by reducingthe secretion of osteoblast inhibitors, and driving the expression of bone-specific genes [80]. In immune system functioning, irisin mediates the positive effect of regular/moderate physical activity, contributing to a reduction in systemic inflammation, and consequently protecting from the development of diseases associated with chronic inflammation [81].  
The functions of irisin on the brain are described in more detail in the section \"Irisin: a new bridge between exercise and cognitive functions\". In brief, this myokine increases the proliferation of hippocampal neuronal cells [15], and reduces the neuronal damage mediated by pro-oxidant stimuli [14]. The FNDC5/irisin system is important for long-term potentiation and memory in mouse hippocampal region, being involved in establishing synaptic plasticity and memory [82], and may contribute to the antidepressant effect of PE together with serotonin, by the activation of the PGC-1\(\alpha\)/BDNF pathway [83].