Irisin/BDNF signaling in the muscle-brain axis and circadian system: A review

In mammals, the timing of physiological, biochemical and behavioral processes over a 24-h period is controlled by circadian rhythms. To entrain the master clock located in the suprachiasmatic nucleus of the hypothalamus to a precise 24-h rhythm, environmental zeitgebers are used by the circadian system. This is done primarily by signals from the retina via the retinohypothalamic tract, but other cues like exercise, feeding, temperature, anxiety, and social events have also been shown to act as non-photic zeitgebers. The recently identified myokine irisin is proposed to serve as an entraining non-photic signal of exercise. Irisin is a product of cleavage and modification from its precursor membrane fibronectin type Ⅲ domain-containing protein 5 (FNDC5) in response to exercise. Apart from well-known peripheral effects, such as inducing the "browning" of white adipocytes, irisin can penetrate the blood-brain barrier and display the effects on the brain. Experimental data suggest that FNDC5/irisin mediates the positive effects of physical activity on brain functions. In several brain areas, irisin induces the production of brain-derived neurotrophic factor (BDNF). In the master clock, a significant role in gating photic stimuli in the retinohypothalamic synapse for BDNF is suggested. However, the brain receptor for irisin remains unknown. In the current review, the interactions of physical activity and the irisin/BDNF axis with the circadian system are reconceptualized.