## 3 Irisin  
### Irisin Structure  
About 20 years ago, two independent groups identified FNDC5 as a protein exerting a role in the differentiation of myoblast. These first findings suggested that the gene was highly expressed in the SkM, but also in cerebral and cardiac tissues [54; 55]. Human FNDC5 is a type I membrane protein of 212 amino acids (aa). The N-terminal is a signal sequence needed for final maturation and cleavage, the C-terminal is the cytoplasmatic domain, and in the middle there is a fibronectin III (FNIII) domain, an unknown domain, and a hydrophobic transmembrane domain [7; 56; 57]. The irisin represents the segment of FNDC5 that is cleaved under stimuli such as PE or cold. The portion contains 112 aa, formed by the residues from 29 to 140, including the tail at the C-terminus, the central FNIII domain, and the tail at the N-terminus [7; 57]. The resulting peptide is characterized by a molecular weight of 12 kDa, and is dimerizing through the FNIII domain [56]. The irisin undergoes post-translational modification by N-glycosylation at two different residues. This modification, in addition to dimerization, determines a molecular weight reaching 35 kDa. The protein stability and the irisin secretion are regulated by the N-glycosylation. The process is strictly dependent on the presence of the signal peptide at the N-terminal, and is important for the irisin activity. The loss of glycosylation does not allow irisin to exert its main function in the browning stimulation of white adipose tissue (Figure 1) [58].  
In contrast to rodents, the human FNDC5 gene has an ATA as a start codon instead of ATG, generating a transcript that results in a very low efficiency of translation [59]. More recently, [PERSON] et al. (2020), identifying other non-canonical start codon, suggested that in SkM there are several transcripts for the human FNDC5 gene [60]. Studies on  
Figure 1: **FNDC5/Irisin structure.** Schematic structure of FNDC5. CD: Cytosolic Domain; FNDC5: Fibronectin type III Domain Containing 5; SS: Signal Sequence; TD: Transmembrane Domain.  
transcriptome profiling through RNA-sequencing (RNA-Seq) by the Functional Annotation of the Mammalian Genome/Genotype-Tissue Expression Project, established that the FNDC5 gene is mainly expressed in SkM, the heart, and several regions of the brain, mainly in the cerebellum, but also in hippocampus, cortex, and medulla oblongata [61].  
A receptor for irisin has not yet been identified. The only evidence is provided by an interesting study by [PERSON] et al. (2018), whichshowed that this myokine exerts its biological function by binding the integrins' family of proteins. The integrins are ubiquitously expressed transmembrane receptors, consisting of eighteen \(\alpha\)- and eight \(\beta\)-subunits, forming a total of 24 different heterodimers able to recognize also soluble ligands. [PERSON] and coworkers described how the binding of irisin with the \(\alpha\)V\(\beta\)5 integrin heterodimer occurs in human adipocytes and osteocytes. Using the integrin inhibitor RGD peptide, which binds to \(\alpha\)V\(\beta\)5 in a selective manner, they also showed that any signaling response induced by irisin was significantly suppressed in these cells [62].