Brown Adipose Tissue Activation Alleviates Cerebral Ischemia-Reperfusion Injury by Increasing 14-3-3ζ Secretion from...

Brown adipose tissue (BAT) possesses thermogenic and endocrine functions, leading to it being considered a therapeutic target, but its role in cerebrovascular pathologies is largely unknown. Here, we elucidated BAT activation effects on cerebral ischemic stroke, using in vivo, in vitro, and acute ischemic stroke (AIS) patient analyses. In vivo, recipient mice received BAT transplants, then subjected to ischemic stroke by middle cerebral artery occlusion (MCAO) for 90 min, followed by 24 h reperfusion. Another MCAO mouse group was injected with extracellular vesicles (EVs) from non- and BAT-transplanted mouse plasma. In vitro, HT-22 cells were subjected to oxygen-glucose deprivation, 24 h re-oxygenation (OGD/R), and incubation with PKH67-labelled EVs (BAT-EVs + OGD/R). Genomic, proteomic, and apoptotic analyses were conducted, particularly in relation to 14-3-3ζ expression and the p53 apoptotic pathway. BAT transplantation and activation in MCAO mice significantly alleviated cerebral ischemic injury, manifesting as reduced infarct sizes and neurological severity scores. This was likely via BAT producing 14-3-3ζ protein-enriched EVs, which were taken up by ischemic penumbra neuronal cells, where they exerted anti-apoptotic and neuroprotective effects. Similar findings were observed in BAT-EVs + OGD/R cells, along with discovering that 14-3-3ζ knock-down increased, while 14-3-3ζ overexpression reduced p53 phosphorylation and cell apoptosis. Moreover, AIS patients with higher peripheral blood 14-3-3ζ had greater percentages of NIH Stroke Scale/Score decreases ≥ 2, indicating greater short-term neurological recovery. Therefore, increased 14-3-3ζ from circulating EVs, obtained from BAT-transplanted donors, resulted in lowered apoptosis and increased neuroprotection in ischemic penumbra cells taking up those EVs, likely via 14-3-3ζ suppressing the pro-apoptotic p53 pathway.