## 5 Brain  
Several studiessuggested that the FNDC5/irisin system is expressed in the brain, where its specific roles have not yet been well established. Studies on animal models showed that this expression is dependenton the region of the brain, in which irisin is expressed in ventromedial nuclei and hypothalamic arcuate in primates [102], and in cortex, hippocampus, and other areas such as the vestibular nuclei of the medulla oblongata and Purkinje cells of the cerebellum in mice [9].  
The irisin expression in the CNS is regulated by several environmental, physiological and pathological conditions. Aerobic PE significantly increases the mRNA of FNDC5 in the mouse hippocampus [8; 103]. Recently, [PERSON] et al. (2020) suggested that additional stimuli, such as environmental enrichment (EE), can increase the expression of FNDC5 in the pre-frontal cortex [104], where it is useful in promoting neurogenesis and general cerebral activity, increasing the neuronal capacity to recover from wounds [105; 106]. In regardopathological conditions, the expression of FNDC5 is reduced in AD patients in the pre-frontal cortex and hippocampus [107]. Nevertheless, the injection of recombinant irisin reduces stress-mediated anxiety, depression and memory disfunct in the hippocampus and/or in the lateral ventricle of rodents' model [108; 109; 110].  
There is increasing evidence relating to FNDC5/irisin brain expression. [PERSON] et al. (2013) described that PGC-1\(\alpha\) is responsible for FNDC5 expression induction in the primary neurons and hippocampus [8]. More recently, it was foundthat FNDC5 induction in the hippocampus is regulated by the activation of the cAMP/PKA [104], and that the hippocampal FNDC5 expression is also induced by the lactate released from SkM during PE [107]. The FNDC5 promoter has been described in the presence of an ERR\(\alpha\)binding element (ERRE) sited in the upstream region, where PGC-1\(\alpha\) increased FNDC5 expression activating ERR\(\alpha\), and then triggered a negative feedback onto PGC-1\(\alpha\)/ERR\(\alpha\) in primary cortical neurons [8]. Further studies are needed to investigatethe upstream regulatory sequences of the FNDC5 promoter, in order to better define how different stimuli can influence FNDC5 expression in the brain. These analyses could clarify which binding elements are regulated by different transcription factors.  
Figure 2: **FNDC5/Irisin expression in Skeletal Muscle (SkM) mediated by PGC-1a.** Schematic representation of irisin expression modulating factor in SkM occurring by activation or inhibition of PGC-1a. CREB: cAMP response element-binding protein; ERR\(\alpha\): Estrogen-related receptor \(\alpha\); FNDC5: Fibronectin type III Domain Containing 5; PGC-1\(\alpha\): PPARy coactivator 1\(\alpha\).  
A number of studies suggested that irisin can also be endocytosed and that it exerts a role in mediating endocytosis and exocytosis. Regarding the endocytosis process, [PERSON] et al. (2019) suggested that irisin bound to unrecognized receptor in CNS, particularly on the surface of hippocampal neurons and astrocytes, starting an endocytosis process [107]. In addition, the subcutaneous injection of irisin increased glucose uptake at brain level, suggesting its potential role in augmenting the endocytosis of glucose transporters [13]. Relating to exocytosis, the only evidences come from [PERSON] et al. (2018) showing that irisin increased insulin secretion in mouse pancreatic islet cells in response to glucose [111].