Brain Leptin Receptor Activation May Improve Cardiac Function After Ischemia-Reperfusion Injury by Stimulating Release of miR-378a-5p-enriched EVs from Brown Adipocytes

Ischemic heart disease is the leading cause of death worldwide. Our recent studies demonstrated that activating brain leptin receptors (LepRs) through intracerebroventricular (ICV) infusion of leptin improves cardiac function after ischemia/reperfusion (IR) injury. However, the mechanisms underlying brain-heart communication during LepRs activation remain unclear. Preliminary data from our lab suggest that extracellular vesicles (EVs) derived from brown adipose tissue (BAT) may play a key role in this process. Additionally, BAT has been proposed as an important source of EVs carrying cardioprotective microRNAs (miRs). In this study, we investigated the miRs enclosed in EVs released from BAT during brain LepRs activation as well as their expression in the heart and potential impact on cardiac apoptosis. Male Sprague-Dawley rats (~9 weeks of age) underwent BAT ablation and instrumentation with an ICV cannula in the brain lateral ventricle. After recovery, myocardial IR was induced by temporary (60 min) ligation of the left anterior descending coronary artery. Vehicle (saline, 0.5 µL/hr) or leptin (0.62 µg/hr) was infused for 28 days using osmotic pumps implanted subcutaneously in the scapular region and connected to the ICV cannula. At the end of the protocol, BAT and hearts were collected, and EVs were isolated from BAT. RNA was extracted from BAT EVs and heart tissue for RNA sequencing analysis. We found that miR-378a-5p was the most abundant miR in BAT EVs from ICV leptin-treated rats (~14,000 counts). Measurement of miR-378a-5p expression in the heart revealed a 78% increase in leptin-treated rats compared to vehicle-treated rats [Fold change (FC)= 1.78, Padj= 7.63E-03, n=5]. BAT ablation significantly reduced expression of this miR in the hearts of leptin-treated rats compared to those with intact BAT (FC: -0.44, Padj=1.92E-05, n=5). miR-378a-5p regulates key cellular processes, including apoptosis. Leptin-treated rats exhibited a reduction in apoptotic cells (TUNEL-positive) in the heart following IR injury compared to vehicle-treated rats (18 ± 2.1 vs. 37 ± 0.9%, p=0.02), an effect that was reversed by BAT ablation (35 ± 5.5 vs. 18 ± 2.1% in leptin-treated rats with intact BAT, p=0.03). These findings suggest that brain LepRs activation induces BAT to release EVs enriched with miR-378a-5p, which may improve cardiac function after IR injury by reducing apoptosis. Disclosures: None Funding: NIGMS-P20GM104357, NIGMS-P30GM104357 and 1R01HL163076. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.