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Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation.
Milbank, Edward; Dragano, Nathalia R V; González-García, Ismael; Garcia, Marcos Rios; Rivas-Limeres, Verónica; Perdomo, Liliana; Hilairet, Grégory; Ruiz-Pino, Francisco; Mallegol, Patricia; Morgan, Donald A; Iglesias-Rey, Ramón; Contreras, Cristina; Vergori, Luisa; Cuñarro, Juan; Porteiro, Begoña; Gavaldà-Navarro, Aleix; Oelkrug, Rebecca; Vidal, Anxo; Roa, Juan; Sobrino, Tomás; Villarroya, Francesc; Diéguez, Carlos; Nogueiras, Rubén; García-Cáceres, Cristina; Tena-Sempere, Manuel; Mittag, Jens; Carmen Martínez, M; Rahmouni, Kamal; Andriantsitohaina, Ramaroson; López, Miguel.
Afiliação
  • Milbank E; Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
  • Dragano NRV; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
  • González-García I; SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France.
  • Garcia MR; Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
  • Rivas-Limeres V; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
  • Perdomo L; Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
  • Hilairet G; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
  • Ruiz-Pino F; Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • Mallegol P; Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
  • Morgan DA; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
  • Iglesias-Rey R; Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
  • Contreras C; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
  • Vergori L; SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France.
  • Cuñarro J; SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France.
  • Porteiro B; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
  • Gavaldà-Navarro A; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía, Córdoba, Spain.
  • Oelkrug R; SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France.
  • Vidal A; Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
  • Roa J; Clinical Neurosciences Research Laboratory, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
  • Sobrino T; Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
  • Villarroya F; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
  • Diéguez C; SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France.
  • Nogueiras R; Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
  • García-Cáceres C; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
  • Tena-Sempere M; Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
  • Mittag J; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
  • Carmen Martínez M; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
  • Rahmouni K; Institut de Biomedicina de la Universitat de Barcelona-Institut de Recerca Hospital Sant Joan de Déu, IBUB-IRSJD, Barcelona, Spain.
  • Andriantsitohaina R; Institute for Endocrinology and Diabetes-Molecular Endocrinology, Center of Brain Behavior and Metabolism CBBM, University of Lübeck, Lübeck, Germany.
  • López M; Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
Nat Metab ; 3(10): 1415-1431, 2021 10.
Article em En | MEDLINE | ID: mdl-34675439
ABSTRACT
Current pharmacological therapies for treating obesity are of limited efficacy. Genetic ablation or loss of function of AMP-activated protein kinase alpha 1 (AMPKα1) in steroidogenic factor 1 (SF1) neurons of the ventromedial nucleus of the hypothalamus (VMH) induces feeding-independent resistance to obesity due to sympathetic activation of brown adipose tissue (BAT) thermogenesis. Here, we show that body weight of obese mice can be reduced by intravenous injection of small extracellular vesicles (sEVs) delivering a plasmid encoding an AMPKα1 dominant negative mutant (AMPKα1-DN) targeted to VMH-SF1 neurons. The beneficial effect of SF1-AMPKα1-DN-loaded sEVs is feeding-independent and involves sympathetic nerve activation and increased UCP1-dependent thermogenesis in BAT. Our results underscore the potential of sEVs to specifically target AMPK in hypothalamic neurons and introduce a broader strategy to manipulate body weight and reduce obesity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tecido Adiposo Marrom / Proteínas Quinases Ativadas por AMP / Vesículas Extracelulares / Hipotálamo / Obesidade Limite: Animals Idioma: En Revista: Nat Metab Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Espanha
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tecido Adiposo Marrom / Proteínas Quinases Ativadas por AMP / Vesículas Extracelulares / Hipotálamo / Obesidade Limite: Animals Idioma: En Revista: Nat Metab Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Espanha