Recombinant treatment increased expression in hippocampal slices, with effects blocked by cilengitide.
Irisin is associated with the modulation of BDNF levels, which is crucial for brain health.
The αV/β5 integrin receptor plays a significant role in the effects of irisin on endothelial cells.
Activation of focal adhesion kinase () by irisin is linked to increased BDNF expression.
In vivo studies showed that exercised rats had higher FAK activation and serum irisin levels positively correlated with BDNF expression.
Elevated levels of αV/β5 integrins, phosphorylated endothelial NO synthase (p-eNOS), and BDNF were found in hippocampal endothelial cells of exercised rats.
Simplified
, a myokine released into the bloodstream during physical exercise, is recognized for its role in modulating hippocampal brain-derived neurotrophic factor () expression. However, the exact mechanisms by which irisin elevates BDNF levels are not fully understood. Notably, the αV/β5 integrin receptor, identified as a critical receptor for irisin primarily observed in bone and adipose tissues, was shown to play a key role in endothelial cells. Considering that irisin has nitric oxide (NO)-dependent vasodilatory effects and that NO increases endothelial BDNF production, with approximately 50% of cerebral BDNF expression derived from cerebral endothelium, we aimed to explore the molecular mechanisms through which irisin regulates BDNF levels in the hippocampus with a focus on the endothelium. Our findings indicated that recombinant irisin (r-irisin) treatment of hippocampal slices led to an increase in BDNF expression and that this effect was blocked by cilengitide, an αV/β5 integrin antagonist. Mechanistically, r-irisin activated focal adhesion kinase (), and this activation was also inhibited by cilengitide. In vivo, we observed that exercised rats exhibited enhanced FAK activation with a positive correlation between FAK phosphorylation and serum irisin levels as well as FAK phosphorylation and hippocampal BDNF expression. Additionally, αV/β5 integrins, phosphorylated endothelial NO synthase (p-eNOS), and BDNF were significantly elevated in the hippocampal endothelial cells of exercised rats. These findings reveal that irisin may upregulate BDNF expression in the hippocampal through a mechanism dependent on endothelial αV/β5 integrins and the FAK/eNOS signaling pathway, supporting its potential as a therapeutic target for enhancing NO-dependent BDNF expression.
Key numbers
+172.8%
Increase in Levels
Observed at 100 nM recombinant treatment compared to control.
–57.6%
Decrease in Expression with Cilengitide
Reduction observed at 10 µM cilengitide in the presence of 100 nM r-.
+70.4%
Increase in Activation
Measured in exercised rats compared to sedentary controls.
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Declarations. Ethic Approval: All experiments and protocols were approved by the French Department of regulated research practice (APAFIS numbers #33300–2021093014586596 and #28240–202011101408485) and the Ethics Committee in animal experimentation of Grand campus Dijon (agreement number 105, user establishment approval number E2146404EA). They complied with ARRIVE guidelines and conformed to the European convention for the protection of vertebrate animals used for experimental and other scientific purposes. Competing Interests: The authors declare no competing interests.
