UNLABELLED: Physical activity produces widespread benefits to physical and mental health, including protection against stress-related behavioral outcomes. However, the peripheral signals through which physical activity is translated into stress resistance remain incompletely understood. Irisin, an exercise-induced myokine cleaved from the transmembrane protein FNDC5 and released into circulation, has been implicated in improved cognition and neuroprotection, but its role in resistance to behavioral consequences of future adversity has not been examined. Here, we tested whether forced peripheral elevation of irisin is sufficient to protect against stress-induced behavioral outcomes. Adult male C57BL/6 mice received adeno-associated viral (AAV)-mediated peripheral expression of irisin or GFP control. AAV-irisin significantly increased circulating irisin levels, and six weeks later, mice were exposed to inescapable stress, a well-characterized model that produces anxiety-like behaviors, including reducing rodents' natural inclination toward sociability. Elevated circulating irisin prevented the stress-induced reduction in social preference without altering general locomotor activity. Moreover, circulating irisin levels positively predicted individual differences in sociability. Additionally, peripheral irisin elevation increased brain-derived neurotrophic factor (Bdnf) expression, which also positively correlated with circulating irisin levels. Finally, we identified expression of the irisin receptor subunit integrin αV within the dorsal raphe nucleus, a key brain region implicated in the behavioral outcomes of inescapable stress that is modulated by prior exercise. Together, these findings identify peripheral irisin as a mediator sufficient to confer resistance to future stress, even in the absence of physical activity. SIGNIFICANCE STATEMENT: Physical activity protects against the anxiety-like behavioral outcomes of future stress, but the peripheral mediators of this effect remain unclear. Here we show that forced peripheral elevation of circulating irisin, an exercise-induced myokine, is sufficient to produce behavioral stress resistance in mice. Irisin prevented the stress-induced reduction in social preference and positively correlated with individual differences in sociability. Forced expression of peripheral irisin also increased Bdnf expression in the brain, consistent with engagement of central neuroplasticity pathways that support adaptive behavioral responses. These findings demonstrate that an exercise-induced circulating factor can confer resistance to future stress, identifying irisin as a potential prophylactic target for stress-related mental health disorders.
