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Hypomethylated leptin receptor reduces cerebral ischaemia-reperfusion injury by activating the JAK2/STAT3 signalling
Xuelou Wang1, Zhen Wang1, Sha Liu2
1Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei Province, China.
Objective:
To investigate the cerebroprotective effects of leptin in vitro and in vivo via the Janus kinase-2 (JAK2)/transcription factor signal transducer and activators of transcription-3 (STAT3) pathway and leptin receptors (LEPR).
Methods:
The study used the cellular oxygen-glucose deprivation (OGD) model in PC12 cells and the middle cerebral artery occlusion (MCAO) rat model of cerebral ischaemia-reperfusion injury (CIRI) to assess changes in gene expression and protein levels following leptin pretreatment. The methylated DNA immunoprecipitation (MeDIP) assay measured DNA methylation levels.
Results:
The optimal leptin concentration for exerting neuroprotective effects against ischaemia-reperfusion injury in PC12 cells was 200 ng/ml in vitro, but excessive leptin diminished this effect. Leptin pretreatment in the MCAO rat model demonstrated a similar effect to previously reported leptin administration post-CIRI. In addition to regulating the expression of inflammation-related cytokines, Western blot analysis showed that leptin pretreatment upregulated BCL-2 and downregulated caspase 3 levels. The MeDIP analysis demonstrated that DNA methylation regulated LEPR gene expression in the MCAO rat model when leptin pretreatment was used.
Conclusion:
Exogenous leptin might bind to extra-activated LEPR by reducing the methylation level of the LEPR gene promoter region, which leads to an increase in phosphorylated JAK2/STAT3 and apoptotic signalling pathways.
Insights
Leptin pretreatment shows cerebroprotective effects by modulating leptin receptors (LEPR) and the JAK2/STAT3 pathway, reducing cell death in models of stroke.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Ischaemia-reperfusion injury (CIRI) poses a significant threat to brain health.
- Leptin's role in neuroprotection is an area of active investigation.
- Understanding the molecular mechanisms underlying leptin's effects is crucial for therapeutic development.
Purpose of the Study:
- To investigate the cerebroprotective effects of leptin.
- To elucidate the involvement of the Janus kinase-2 (JAK2)/signal transducer and activators of transcription-3 (STAT3) pathway and leptin receptors (LEPR).
- To examine leptin's impact on gene expression and DNA methylation in cerebral ischaemia models.
Main Methods:
- Utilized oxygen-glucose deprivation (OGD) in PC12 cells and middle cerebral artery occlusion (MCAO) rat models for cerebral ischaemia-reperfusion injury (CIRI).
- Assessed gene and protein expression changes, including BCL-2 and caspase 3 levels, via Western blot.
- Employed methylated DNA immunoprecipitation (MeDIP) assay to evaluate DNA methylation patterns of the LEPR gene.
Main Results:
- Identified an optimal leptin concentration (200 ng/ml) for neuroprotection in vitro; excessive leptin diminished the effect.
- Leptin pretreatment in MCAO rats mirrored effects of post-injury administration, upregulating BCL-2 and downregulating caspase 3.
- Demonstrated that DNA methylation regulates LEPR gene expression in response to leptin pretreatment in MCAO models.
Conclusions:
- Exogenous leptin may enhance neuroprotection by reducing LEPR gene promoter methylation.
- This reduction in methylation potentially increases LEPR expression, leading to enhanced JAK2/STAT3 phosphorylation.
- The findings suggest a novel mechanism for leptin's cerebroprotective action involving epigenetic regulation of LEPR.
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