Exercise has multiple beneficial effects on health including decreasing the risk of neurodegenerative diseases. Such effects are thought to be mediated (at least in part) by myokines, a collection of cytokines and other small proteins released from skeletal muscles. As an endocrine organ, skeletal muscle synthesizes and secretes a wide range of myokines which contribute to different functions in different organs, including the brain. One such myokine is the recently discovered protein Irisin, which is secreted into circulation from skeletal muscle during exercise from its membrane bound precursor Fibronectin type III domain-containing protein 5 (FNDC5). Irisin contributes to metabolic processes such as glucose homeostasis and browning of white adipose tissue. Irisin also crosses the blood brain barrier and initiates a neuroprotective genetic program in the hippocampus that culminates with increased expression of brain derived neurotrophic factor (BDNF). Furthermore, exercise and FNDC5/Irisin have been shown to have several neuroprotective effects against injuries in ischemia and neurodegenerative disease models, including Alzheimer’s disease. In addition, Irisin has anxiolytic and antidepressant effects. In this review we present and summarize recent findings on the multiple effects of Irisin on neural function, including signaling pathways and mechanisms involved. We also discuss how exercise can positively influence brain function and mental health via the “skeletal muscle-brain axis.” While there are still many unanswered questions, we put forward the idea that Irisin is a potentially essential mediator of the skeletal muscle-brain crosstalk.

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