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Proteomic analysis of extracellular vesicles isolated from the serum of mice following BAT transplantation elucidated their protective mechanism against ischemic stroke

ABSTRACT: Brown adipose tissue (BAT) possesses both thermogenic and endocrine functions, leading to it being considered as a potential therapeutic target for various diseases; however, its role in cerebrovascular pathologies is still largely unknown. Here, we aimed to elucidate BAT activation impacts on cerebral ischemic stroke and their underlying mechanisms, using in vivo, in vitro, and acute ischemic stroke (AIS) patient analyses.This study aims to provide clarity for this matter, mainly via examining the effects of intraperitoneal BAT transplantation into a middle cerebral artery occlusion (MCAO) mouse model, where it was found that BAT transplantation was associated with lowered infarct sizes and improved neuronal function.Extracellular vesicles (EVs) serve as nanoscale transporters capable of crossing the blood-brain barrier and delivering bioactive molecules to neural cells. To investigate the proteomic alterations in circulating EVs following BAT transplantation, we performed comparative proteomic profiling of plasma-derived EVs from BAT-transplanted and control mice . Among the 117 differentially expressed proteins identified, we focused on 52 significantly upregulated proteins (fold change > 1.2, p < 0.05). KEGG pathway enrichment analysis identified the PI3K-Akt signaling pathway as the most significantly enriched pathway—a well-established regulator of apoptosis in cerebral ischemic injury. Notably, mass spectrometry analysis revealed pronounced upregulation of anti-apoptotic 14-3-3 protein isoforms (ε, θ, ζ, γ), which are functionally linked to the P53 pathway, in the circulating EVs of BAT-transplanted mice. These findings suggest that BAT transplantation may exert its therapeutic effects against ischemic stroke through EV-mediated enrichment of 14-3-3 proteins, potentially enhancing neuronal survival via modulation of apoptotic pathways.

ORGANISM(S): Mus Musculus

SUBMITTER: Rui Wang

PROVIDER: PXD071794 | iProX | Wed Dec 10 00:00:00 GMT 2025

REPOSITORIES: iProX

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Project description:Background: Transient ischemic attack (TIA) induces ischemic tolerance that can reduce the subsequent ischemic damage and improve prognosis of stroke patients. However, the underlying mechanisms remain elusive. Recent advances in plasma metabolomics analysis have made it a powerful tool to investigate human pathophysiological phenotypes and mechanisms of diseases. In this study, we aimed to identify the bioactive metabolites from the plasma of TIA patients for determination of their prophylactic and therapeutic effects on protection against cerebral ischemic stroke, and the mechanism of TIA-induced ischemic tolerance against subsequent stroke. Methods: Metabolomic profiling using liquid chromatography-mass spectrometry was performed to identify the TIA-induced differential bioactive metabolites in the plasma samples of 20 patients at day 1 (time for basal metabolites) and day 7 (time for established chronic ischemic tolerance-associated metabolites) after onset of TIA. Mouse MCAO-induced stroke model was used to verify their prophylactic and therapeutic potentials. Transcriptomics changes in circulating neutrophils of TIA patients were determined by RNA-sequencing. Multivariate statistics and integrative analysis of metabolomics and transcriptomics were performed to elucidate the potential mechanism of TIA-induced ischemic tolerance. Findings: Plasma metabolomics analysis identified five differentially upregulated metabolites associated with TIA-induced ischemic tolerance, namely all-trans 13,14 dihydroretinol (atDR), 20-carboxyleukotriene B4, prostaglandin B2, cortisol and 9-KODE. They were associated with the metabolic pathways of retinol, arachidonic acid, and neuroactive ligand-receptor interaction. Prophylactic treatment of MCAO mice with these five metabolites significantly improved neurological functions. Additionally, post-stroke treatment with atDR or 9-KODE significantly reduced the cerebral infarct size and enhanced sensorimotor functions, demonstrating the therapeutic potential of these bioactive metabolites. Mechanistically, we found in TIA patients that these metabolites were positively correlated with circulating neutrophil counts. Integrative analysis of plasma metabolomics and neutrophil transcriptomics further revealed that TIA-induced metabolites are significantly correlated with specific gene expression in circulating neutrophils which showed prominent enrichment in FoxO signaling pathway and upregulation of the anti-inflammatory cytokine IL-10. Finally, we demonstrated that the protective effect of atDR-pretreatment on MCAO mice was abolished when circulating neutrophils were depleted. Interpretation: TIA-induced ischemic tolerance is associated with upregulation of plasma bioactive metabolites which can protect against cerebral ischemic damage and improve neurological functions through a positive role of circulating neutrophils.

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Proteomic analysis of extracellular vesicles isolated from the serum of mice following BAT transplantation elucidated their protective mechanism against ischemic stroke

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