Neuroscience and biobehavioral reviewsJul 4, 2026

Irisin's links to anxiety-like behavior through body-brain communication, brain inflammation, and brain adaptability

Gut-Brain Axis Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 5, 2026

Abstract

Irisin may regulate anxiety-like behaviors through various neural mechanisms.

Irisin suppresses neuroinflammation linked to anxiety by inhibiting specific inflammatory pathways.
It enhances synaptic plasticity in the brain by increasing levels of brain-derived neurotrophic factor (BDNF) and promoting cellular recycling processes.
Irisin contributes to gut-brain health by maintaining the integrity of the intestinal barrier and altering the composition of gut microbes.
A proposed therapeutic model suggests that the effects of irisin on anxiety may vary depending on stress levels and disease stages.
Key limitations include unclear receptor identities for irisin’s action in the brain and differences in response based on sex.

Simplified

Anxiety-related disorders are highly prevalent and persistently difficult to treat, largely due to insufficient understanding of peripheral-central regulatory mechanisms governing emotional behaviors. Irisin, an exercise-dependent myokine, serves as a critical peripheral-to-central signaling mediator modulating brain function and anxiety-like behavioral phenotypes. This review systematically integrates current preclinical evidence illustrating how irisin regulates anxiety through multi-level neural mechanisms. Irisin suppresses microglial NF-κB/STAT3-mediated neuroinflammation, enhances prefrontal-hippocampal synaptic plasticity via BDNF upregulation and AMPK/mTOR-related autophagy, and improves gut-brain axis homeostasis by stabilizing intestinal barrier integrity and reshaping microbial composition. Crucially, we propose a context-dependent therapeutic window model to reconcile contradictory pro-anxiogenic and anxiolytic findings across stress severity and pathological stages, resolving existing controversies in this field. We further summarize key unresolved limitations, including ambiguous central receptor identity, peripheral-central dissociation and sex-dependent heterogeneity. This work provides an integrated mechanistic framework linking muscular metabolic signals to affective circuit regulation, offering novel translational perspectives for anxiety behavioral modulation and targeted therapeutic development.

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Irisin's links to anxiety-like behavior through body-brain communication, brain inflammation, and brain adaptability

Abstract

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