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Leptin-Activated Crosstalk Among Brain, Brown Adipose Tissue, and Heart Drives Cardiac Protection After Ischemia-Reperfusion Injury [RNA-seq]

ABSTRACT: Cardiovascular disease remains the leading cause of death worldwide, with coronary artery disease being the primary contributor. Our recent studies suggest that activation of leptin receptors (LepRs) in the brain can improve cardiac function following myocardial infarction. However, the mechanism by which this cardioprotective effect is transmitted from the brain to the heart remains unclear. We hypothesize that brain LepR activation stimulates brown adipose tissue (BAT) to secrete extracellular vesicles (EVs) enriched with cardioprotective factors. These EVs may safeguard the heart by modulating cardiac mitochondrial function and collagen deposition. Our findings indicate that BAT ablation or BAT sympathetic denervation diminishes the cardioprotective effects of brain LepR activation. We also observed an increased concentration of EVs within BAT of rats treated with ICV leptin compared to vehicle-treated controls, an effect abolished by BAT denervation. Furthermore, knockdown of Rab27a in BAT reduced the cardioprotective benefits of brain LepR activation. MicroRNA (miR)-29c-3p was identified as a cargo of leptin-stimulated BAT-derived EVs and appears to play a key role in mitigating cardiac fibrosis after IR injury in leptin-treated animals. Thus, activation of LepR in the brain protects the heart after IR injury via sympathetic mediated BAT-derived EVs enriched with miR-29c-3p.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE315348 | GEO | 2026/01/05

REPOSITORIES: GEO

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Project description:Leptin receptors (Lepr) are expressed by various types of stem cells including mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells, and induced pluripotent stem cells. Leptin/lepr signaling is also a central regulator of metabolism. However, the role of Lepr in pluripotency, metabolic disease progression and growth development is still controversial and poorly understood. In the present study, we explored the Lepr function in disease progression, pluripotency and metabolism using day 14.5 mouse embryonic fibroblasts (MEFs) and their reprogrammed induced pluripotent stem cells (iPSCs) as model system. We successfully reprogrammed mouse embryonic fibroblasts into iPSCs from control and db/db (Lepr deficient) mice. Using a global quantitative proteomic approach, we identified key pathways regulating pluripotency, metabolic homeostasis and protein synthesis during fetal growth and development. The Lepr MEFs show abnormal metabolic abnormalities and mitochondrial dysfunction as compared to control MEFs, while Lepr iPSCs show upregulated elongated factor 4 e (eIF4e) protein synthesis pathway and altered Oct4 and Stat3 pathways which are involved in normal fetal growth development. Furthermore, chip analysis revealed that higher Stat3 binding on the promoter of eIF4e in Lepr iPSCs leads to higher protein synthesis in these cell types as compared to control iPSCs. Finally, point mutation corrected Lepr iPSCs using CRISPR/Cas9 gene editing method showed recovered pluripotency, metabolic and protein synthesis pathways. In conclusion, we have shown that Lepr signaling is involved in the regulation of the metabolic properties and key developmental pathways in MEFs and stemness of pluripotent stem cells. Disruption of Lepr signaling has been shown to involve in the pathophysiology of various diseases including obesity and diabetes. The generated MEFs and iPSCs in this present study provide valuable tools to explore the role of Lepr in the progression of obesity, diabetes and metabolic abnormalities, and to find the putative targets of Lepr signaling during the development of these diseases.

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Leptin-Activated Crosstalk Among Brain, Brown Adipose Tissue, and Heart Drives Cardiac Protection After Ischemia-Reperfusion Injury [RNA-seq]

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