Role of irisin in physiology and pathology

Abstract

Irisin, out-membrane part of fibronectin type III domain-containing 5 protein (FNDC5), was activated by Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) during physical exercise in skeletal muscle tissues. Most studies have reported that the concentration of irisin is highly associated with health status. For instance, the level of irisin is significantly lower in patients with obesity, osteoporosis/fractures, muscle atrophy, Alzheimer's disease, and cardiovascular diseases (CVDs) but higher in patients with cancer. Irisin can bind to its receptor integrin αV/β5 to induce browning of white fat, maintain glucose stability, keep bone homeostasis, and alleviate cardiac injury. However, it is unclear whether it works by directly binding to its receptors to regulate muscle regeneration, promote neurogenesis, keep liver glucose homeostasis, and inhibit cancer development. Supplementation of recombinant irisin or exercise-activated irisin might be a successful strategy to fight obesity, osteoporosis, muscle atrophy, liver injury, and CVDs in one go. Here, we summarize the publications of FNDC5/irisin from PubMed/Medline, Scopus, and Web of Science until March 2022, and we review the role of FNDC5/irisin in physiology and pathology.

Keywords: beige fat; cancer; cardiovascular diseases; irisin; liver; musculoskeletal homeostasis.

Figure 1

Potential mechanisms signaling pathways for the actions of irisin in musculoskeletal. During exercise, the elevated Ca²⁺ in muscle cytoplasm-induced activation of the AMPK–PGC-1α–FNDC5 axis is the main pathway for irisin synthesis. In addition, irisin, in turn, can stimulate muscle growth and myoblast differentiation via ERK1/2–IGF-1/MSTN and IL-6 signaling pathways, respectively. Multiple pathways mediated exercise-induced irisin and r-irisin–activated osteoblast differentiation and mineralization, e.g., p38/ERK1/2, Akt-β-catenin, and Wnt-β-catenin–mediated activation of ALP/OCN/Col I pathways. In osteoclast, irisin induced its proliferation through activating the p38/JNK pathway. In addition, irisin also inhibited the NF-κB and NFATc1 levels in the nucleus, thus inhibiting the expression of osteoclast differentiation marker genes. As for osteocytes, irisin inhibited osteocyte apoptosis by inhibiting caspase-9 and caspase-3 expression, which probably through activating p38/ERK1/2. Furthermore, moderate exercise-activated irisin or r-irisin could alleviate OA by maintaining ECM stabilization and reducing inflammatory response through p38/JNK-Akt and PI3K/Akt/NF-κB signaling pathway, respectively.

Figure 2

Potential mechanisms signaling pathways for the actions of irisin in the pathological tissues. Irisin protects against DIO by inducing the recruitment of beige fat to dissipate energy into heat. This mechanism is involved in p38 MAPK and ERK1/2 pathways, as well as FAK-mediated beige APCs proliferation. In addition, irisin attenuated diet-induced metabolic disorders, including NAFLD and hepatic steatosis by promoting the synthesis of liver glycogen via PI3K/Akt/GSK3-GS and inhibiting the generation of liver gluconeogenesis through AMPK-PEPCK/G6Pase and PI3K/Akt/FOXO1-mediated PEPCK/G6Pase pathways. In brain tissues, irisin promoted cognition and neuro development via inhibiting the inflammatory response and activating BDNF-mediated nerve cell survival, differentiation, and plasticity. Moreover, irisin affects the proliferation, migration, and invasion of tumor cells probably by binding integrin αV/β5–mediated PI3K/Akt-Snail-EMT and AMPK-mTOR pathways, which has great therapeutic prospects for inhibiting cancer development. Moreover, exercise-induced irisin can also reduce the risk of cardiovascular diseases. In cardiomyocytes, irisin stimulated AMPK-mediated autophagy and mitobiogenesis by binding to its receptor integrin αV/β5, thereby relieving cardiac hypertrophy and injury.