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Small extracellular vesicle targeting of hypothalamic AMPKα1 promotes weight loss in leptin receptor deficient mice

  • Edward Milbank
    Affiliations
    Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
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  • Author Footnotes
    1 ND and XV-G contributed equally.
    Nathalia Dragano
    Footnotes
    1 ND and XV-G contributed equally.
    Affiliations
    Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
    Search for articles by this author
  • Author Footnotes
    1 ND and XV-G contributed equally.
    Xavi Vidal-Gómez
    Footnotes
    1 ND and XV-G contributed equally.
    Affiliations
    PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France

    SOPAM, U1063, INSERM, UNIV Angers, Angers, France
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  • Verónica Rivas-Limeres
    Affiliations
    Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
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  • Pablo Garrido-Gil
    Affiliations
    Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease (CiMUS), Department of Morphological Sciences, University of Santiago de Compostela, Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain

    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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  • Mireille Wertheimer
    Affiliations
    SOPAM, U1063, INSERM, UNIV Angers, Angers, France
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  • Sylvain Recoquillon
    Affiliations
    SOPAM, U1063, INSERM, UNIV Angers, Angers, France
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  • María P. Pata
    Affiliations
    Biostatech Advice, Training and Innovation in Biostatistics, S.L., Santiago de Compostela 15782, Spain
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  • José Luis Labandeira-Garcia
    Affiliations
    Laboratory of Cellular and Molecular Neurobiology of Parkinson's Disease (CiMUS), Department of Morphological Sciences, University of Santiago de Compostela, Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain

    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
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  • Carlos Diéguez
    Affiliations
    Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
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  • Rubén Nogueiras
    Affiliations
    Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
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  • M. Carmen Martínez
    Affiliations
    PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France

    SOPAM, U1063, INSERM, UNIV Angers, Angers, France
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  • Ramaroson Andriantsitohaina
    Correspondence
    Correspondence to: R. Andriantsitohaina, PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.
    Affiliations
    PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France

    SOPAM, U1063, INSERM, UNIV Angers, Angers, France
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  • Miguel López
    Correspondence
    Correspondence to: M. López, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain.
    Affiliations
    Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain

    CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
    Search for articles by this author
  • Author Footnotes
    1 ND and XV-G contributed equally.
Published:November 21, 2022DOI:https://doi.org/10.1016/j.metabol.2022.155350

      Highlights

      • sEV-mediated systemic targeting of AMPKα1 in SF1 neurons reduces AMPK activity, specifically in the VMH.
      • Systemic SF1-AMPKα1-DN sEVs induce feeding-independent weight loss in leptin receptor deficient db/db mice.
      • Systemic SF1-AMPKα1-DN sEVs increased SNS tone and BAT thermogenesis in leptin receptor deficient db/db mice.
      • Systemic SF1-AMPKα1-DN sEVs increased WAT browning in leptin receptor deficient db/db mice.

      Abstract

      Background and aims

      Leptin receptor (LEPR) deficiency promotes severe obesity and metabolic disorders. However, the current therapeutic options against this syndrome are scarce.

      Methods

      db/db mice and their wildtypes were systemically treated with neuronal-targeted small extracellular vesicles (sEVs) harboring a plasmid encoding a dominant negative mutant of AMP-activated protein kinase alpha 1 (AMPKα1-DN) driven by steroidogenic factor 1 (SF1) promoter; this approach allowed to modulate AMPK activity, specifically in SF1 cells of the ventromedial nucleus of the hypothalamus (VMH). Animals were metabolically phenotyped.

      Results

      db/db mice intravenously injected with SF1-AMPKα1-DN loaded sEVs showed a marked feeding-independent weight loss and decreased adiposity, associated with increased sympathetic tone, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT).

      Conclusion

      Overall, this evidence indicates that specific modulation of hypothalamic AMPK using a sEV-based technology may be a suitable strategy against genetic forms of obesity, such as LEPR deficiency.

      Graphical abstract

      Keywords

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