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Leptin Activates Brain-BAT-Heart Crosstalk to Promote Cardiac Protection.

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Τίτλος: Leptin Activates Brain-BAT-Heart Crosstalk to Promote Cardiac Protection.
Συγγραφείς: Omoto ACM; Department 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.)., Vechetti I; Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE (I.V.)., do Carmo JM; Department 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.)., Wang Z; Department 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.)., Mouton AJ; Department 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.)., Young JC; Department 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.)., Dai X; Department 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.)., Ladnier EC; Department 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.)., Zenum SC; School of Medicine, Centro Universitario Barao de Maua, Ribeirao Preto, SP, Brazil (S.C.Z., O.E.S.T., L.R.)., Tosta OES; School of Medicine, Centro Universitario Barao de Maua, Ribeirao Preto, SP, Brazil (S.C.Z., O.E.S.T., L.R.)., Romeiro L; School of Medicine, Centro Universitario Barao de Maua, Ribeirao Preto, SP, Brazil (S.C.Z., O.E.S.T., L.R.)., Hamby M; Department 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.)., Li X; Department 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.)., Spitz RW; Department 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.)., Richards AM; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN (A.M.R., C.H.J., C.J.G.)., Johns CH; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN (A.M.R., C.H.J., C.J.G.)., Goergen CJ; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN (A.M.R., C.H.J., C.J.G.)., da Silva AA; Department 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.)., Hall JE; Department 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.).
Πηγή: Circulation research [Circ Res] 2026 Feb 27; Vol. 138 (5), pp. e326878. Date of Electronic Publication: 2026 Feb 04.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0047103 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4571 (Electronic) Linking ISSN: 00097330 NLM ISO Abbreviation: Circ Res Subsets: MEDLINE
Imprint Name(s): Publication: Baltimore, MD : Lippincott Williams & Wilkins
Original Publication: Baltimore, Md. Grune & Stratton.
Ιατρικοί όροι (MeSH): Leptin*/administration & dosage , Leptin*/pharmacology , Adipose Tissue, Brown*/metabolism , Adipose Tissue, Brown*/innervation , Adipose Tissue, Brown*/drug effects , Brain*/metabolism , Brain*/drug effects , Myocardial Reperfusion Injury*/metabolism , Myocardial Reperfusion Injury*/prevention & control , Myocardial Reperfusion Injury*/physiopathology , Myocardial Reperfusion Injury*/pathology , Myocardium*/metabolism , Myocardium*/pathology, Receptors, Leptin/metabolism ; Extracellular Vesicles/metabolism ; Extracellular Vesicles/drug effects ; Myocardial Infarction/metabolism ; Animals ; Rats, Sprague-Dawley ; Male ; Rats ; Mice
Περίληψη: 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.
Competing Interests: C.J. Goergen is a paid consultant of FUJIFILM VisualSonics Inc. The other authors report no conflicts.
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Grant Information: R01 HL163076 United States HL NHLBI NIH HHS; P20 GM103476 United States GM NIGMS NIH HHS; R01 HL181254 United States HL NHLBI NIH HHS; P20 GM144041 United States GM NIGMS NIH HHS; P20 GM104357 United States GM NIGMS NIH HHS; R01 DK121411 United States DK NIDDK NIH HHS; P30 GM149404 United States GM NIGMS NIH HHS; U54 GM115428 United States GM NIGMS NIH HHS
Contributed Indexing: Keywords: adipose tissue, brown; extracellular vesicles; heart failure; ischemia-reperfusion injury; mitochondria; myocardial infarction; sympathetic nervous system
Substance Nomenclature: 0 (Leptin)
0 (Receptors, Leptin)
Entry Date(s): Date Created: 20260204 Date Completed: 20260707 Latest Revision: 20260920
Update Code: 20260920
PubMed Central ID: PMC12875649
DOI: 10.1161/CIRCRESAHA.125.326878
PMID: 41636042
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1524-4571
DOI:10.1161/CIRCRESAHA.125.326878