Adipocytes and macrophages after stroke: Interactions between metabolism and immunity

Lipid metabolism disorders and chronic inflammation are key components of stroke pathogenesis. Understanding the involvement of adipocytes and macrophages in the onset and recovery phases of stroke is crucial. This review aims to investigate the metabolic and immune interactions between adipocytes and macrophages and their roles in neural repair. Obesity and related lipid metabolism disorders drive chronic low-grade inflammation by inducing adipocyte hypertrophy, endoplasmic reticulum stress, and oxidative stress, which are the key mechanisms underlying the occurrence and repair of ischemic stroke. Hypertrophic adipocytes release free fatty acids and pro-inflammatory mediators, which recruit and polarize macrophages through the "crown-like structure," exacerbating systemic neuroinflammation and insulin resistance. Endoplasmic reticulum stress alters the secretion profile of adipocytes by activating the signaling pathways involving inositol-requiring enzyme 1α, protein kinase RNA-like endoplasmic reticulum kinase , and activating transcription factor 6. This remodeling promotes the polarization of macrophages towards the M1 phenotype and reduces the secretion of protective hormones such as adiponectin, thereby further disrupting metabolic homeostasis. Exosomes and the miRNAs they carry serve as an important medium for communication between adipocytes and macrophages, playing a key role in the local and systemic spread of inflammation. These processes collectively lead to vascular endothelial dysfunction, disruption of the blood-brain barrier, and M1 polarization of microglia in the brain, expanding ischemic post-injury neuroinflammatory damage and hindering neural repair. Current studies have shown that targeting key enzymes in lipid metabolism, inflammatory signaling pathways, and intercellular communication carriers has potential therapeutic value. Strategies such as engineered exosomes, regulation of metabolic reprogramming, and the use of peroxisome proliferator-activated receptor γ agonists have demonstrated potential in enhancing neural repair and improving stroke outcomes in animal models. This review integrates findings from molecular research, animal models, and translational medicine to construct a conceptual framework for understanding the interaction between adipocytes and macrophages during the stroke process. Future research should integrate single-cell multi-omics and spatial transcriptomics to systematically analyze the dynamic interaction mechanisms of the fat-immune-neural axis after stroke, promoting the clinical translation of individualized metabolic immunotherapy strategies.