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Leptin Activates Brain-BAT-Heart Crosstalk to Promote Cardiac Protection
Ana C M Omoto1, Ivan Vechetti2, Jussara M do Carmo1
1Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS (A.C.M.O., J.M.d.C., Z.W., A.J.M., J.C.Y., X.D., E.C.L., M.H., X.L., R.W.S., A.A.d.S., J.E.H.).
Insights
Brain leptin receptor activation protects the heart after injury by stimulating brown adipose tissue to release extracellular vesicles. These vesicles, containing microRNA-29c-3p, are crucial for the observed cardioprotective effects.
Area of Science:
- Cardiology
- Neuroendocrinology
- Extracellular Vesicles Biology
Background:
- Cardiovascular disease is a leading global cause of death.
- Leptin receptor (LepR) activation in the brain shows potential for improving cardiac function post-myocardial infarction.
- The precise mechanism of brain-heart communication for cardioprotection remains elusive.
Purpose of the Study:
- To investigate the role of brown adipose tissue (BAT) in mediating the cardioprotective effects of central LepR activation.
- To identify the components and mechanisms of BAT-derived extracellular vesicles (EVs) involved in cardiac protection.
Main Methods:
- Rats underwent cardiac ischemia-reperfusion injury with interventions targeting BAT (ablation, denervation) and central leptin delivery.
- Cardiac function was assessed using echocardiography and catheterization.
- BAT-derived EVs were analyzed, and Rab27a's role in EV release was investigated. MicroRNA cargo was identified.
Main Results:
- BAT ablation or denervation abolished the cardioprotective effects of central LepR activation.
- Central leptin increased BAT-derived EVs, an effect dependent on sympathetic innervation.
- Knockdown of Rab27a in BAT impaired the cardioprotective benefits. MicroRNA-29c-3p was identified as a key cargo in protective EVs.
Conclusions:
- Central LepR activation confers cardiac protection post-ischemia-reperfusion injury.
- This protection is mediated by sympathetic nervous system-stimulated BAT-derived EVs.
- These EVs contain microRNA-29c-3p, which mitigates cardiac fibrosis.
Background:
Cardiovascular disease remains the leading cause of death worldwide, with coronary artery disease being the primary contributor. Our recent studies suggest that activation of LepRs (leptin receptors) in the brain can improve cardiac function after 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.
Methods:
Sprague-Dawley rats with BAT intact, BAT ablation, or BAT sympathetic denervation were implanted with an intracerebroventricular cannula for continuous leptin or vehicle delivery over 28 days after cardiac ischemia-reperfusion injury. Cardiac function was assessed weekly via echocardiography and by ventricular catheterization at the end of the protocol. EVs were isolated from BAT for analysis. Rab27a (Ras-related protein Rab-27A), a protein required for EV release, was knocked down using adeno-associated virus, and EV tracking was conducted using a double fluorescent reporter mouse model.
Results:
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 the BAT of rats treated with intracerebroventricular leptin compared with 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 ischemia-reperfusion injury in leptin-treated animals.
Conclusions:
Activation of LepR in the brain protects the heart after ischemia-reperfusion injury via sympathetic-mediated BAT-derived EVs enriched with miR-29c-3p.
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