BAT-specific Rab27a knockdown attenuated leptin-induced cardioprotection after ischemia/reperfusion injury, reducing cardiac output (56.6 vs 82.3 mL/min).
Does brain leptin receptor activation improve cardiac function after ischemia/reperfusion injury via brown adipocyte extracellular vesicles in a rat model?
Brain leptin receptor activation improves cardiac recovery after ischemia/reperfusion injury by stimulating the release of miR-29c-3p-enriched extracellular vesicles from brown adipose tissue.
Absolute Event Rate: 56.6% vs 82.3%
Extracellular vesicles (EVs) are key mediators of interorgan crosstalk, influencing diverse physiological and pathological processes. EVs ability to transfer bioactive molecules makes them promising therapeutic agents, particularly in cardiovascular diseases such as myocardial infarction, a leading cause of death worldwide. Our recent studies demonstrated that activation of brain leptin receptors (LepRs) via intracerebroventricular (ICV) leptin infusion, without detectable spillover into the circulation, improves cardiac function following ischemia/reperfusion (IR) injury. This cardioprotective effect was abolished when brown adipose tissue (BAT) or its sympathetic innervation was removed, indicating that BAT plays a critical role in mediating leptin’s cardiac benefits. However, the factors released by BAT in response to brain LepR activation remained unknown. We hypothesized that BAT releases EVs (BAT-EVs) carrying cardioprotective microRNAs that contribute to improved cardiac function after IR. To test this hypothesis, we knocked down Rab27a, a key regulator of EVs biogenesis and secretion, specifically in the BAT of ICV leptin treated rats, and assessed cardiac function after IR. Male Sprague-Dawley rats (~9 weeks old) received AAV9-shRab27a or AAV9-scramble injections into BAT and were instrumented with ICV cannulas in the lateral ventricle of the brain. Myocardial IR injury was induced by occluding the left anterior descending coronary artery for 60 minutes, followed by reperfusion. Leptin (0.62 µg/hr) or vehicle (0.5 µL/hr) was infused ICV for 28 days via osmotic pumps. BAT-specific Rab27a knockdown reduced Rab27a protein by ~80% and attenuated leptin-induced cardioprotection, as shown by lower cardiac output (56.6 ± 5 vs. 82.3 ± 10 mL/min) and +dP/dtmax (6,894 ± 2,214 vs. 11,758 ± 2,012 mmHg/s) at 4 weeks post-IR, despite similar infarct sizes between groups. In a separate cohort of rats, we isolated BAT-EVs from ICV leptin or vehicle treated animals, with or without BAT sympathetic innervation, to analyze their microRNA content by small RNA sequencing profiling. We also performed cardiac transcriptomic analysis to identify putative target genes regulated by BAT-EVs microRNAs. Small RNA sequencing analysis revealed miR-29c-3p enrichment in BAT-EVs from leptin-treated rats whereas miR-29c-3p was downregulated in BAT-EVs from BAT denervated rats. Hearts from leptin treated rats showed downregulation of extracellular matrix (ECM)-related genes (collagens I, III, IV, V, MMP2) which are validated targets of miR-29c-3p. Consistent with the downregulation of ECM-related genes, leptin-treated rats exhibited reduced septal fibrosis post-IR. These findings suggest that brain LepR activation promotes (via BAT sympathetic nerves) release of miR-29c-3p–enriched BAT-EVs that enhance cardiac recovery after IR injury, likely through modulation of ECM remodeling and attenuation of fibrosis. Disclosures: None Funding: R01HL181254, 25CDA1451524, 1R01HL163076, and NIGMS-P30GM149404. This abstract was presented at the American Physiology Summit 2026 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.
Omoto et al. (2026) studied Ischemia/reperfusion (IR) injury. BAT-specific Rab27a knockdown (AAV9-shRab27a) with ICV leptin vs. AAV9-scramble with ICV leptin was evaluated on Cardiac output (mL/min) at 4 weeks post-IR. BAT-specific Rab27a knockdown attenuated leptin-induced cardioprotection after ischemia/reperfusion injury, reducing cardiac output (56.6 vs 82.3 mL/min).