Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation

Edward Milbank; Nathalia R V Dragano; Ismael González-García; Marcos Rios Garcia; Verónica Rivas-Limeres; Liliana Perdomo; Grégory Hilairet; Francisco Ruiz-Pino; Patricia Mallegol; Donald A Morgan; Ramón Iglesias-Rey; Cristina Contreras; Luisa Vergori; Juan Cuñarro; Begoña Porteiro; Aleix Gavaldà-Navarro; Rebecca Oelkrug; Anxo Vidal; Juan Roa; Tomás Sobrino; Francesc Villarroya; Carlos Diéguez; Rubén Nogueiras; Cristina García-Cáceres; Manuel Tena-Sempere; Jens Mittag; M Carmen Martínez; Kamal Rahmouni; Ramaroson Andriantsitohaina; Miguel López

doi:10.1038/s42255-021-00467-8

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Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation

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Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation

Edward Milbank, Nathalia R V Dragano, Ismael González-García, Marcos Rios Garcia, Verónica Rivas-Limeres, Liliana Perdomo, Grégory Hilairet, Francisco Ruiz-Pino, Patricia Mallegol, Donald A Morgan, …

Nature metabolism, Vol.3(10), pp.1415-1431

01/10/2021

DOI: https://doi.org/10.1038/s42255-021-00467-8

PMID: 34675439

Résumé

Adipose Tissue, Brown - enzymology

AMP-Activated Protein Kinases - metabolism

Animals

Energy Metabolism

Extracellular Vesicles - metabolism

Hypothalamus - enzymology

Mice

Obesity - metabolism

Thermogenesis

Weight Loss

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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Détails

Titre: Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation
Créateurs - sans rôle: Edward Milbank - SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France
Nathalia R V Dragano - CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain
Ismael González-García - 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
Marcos Rios Garcia - CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain
Verónica Rivas-Limeres - CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain
Liliana Perdomo - SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France
Grégory Hilairet - SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France
Francisco Ruiz-Pino - Department of Cell Biology, Physiology and Immunology, University of Córdoba, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía, Córdoba, Spain
Patricia Mallegol - SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France
Donald A Morgan - Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Ramón Iglesias-Rey - Clinical Neurosciences Research Laboratory, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
Cristina Contreras - CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain
Luisa Vergori - Ibs
Juan Cuñarro - CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain
Begoña Porteiro - CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain
Aleix Gavaldà-Navarro - Institut de Biomedicina de la Universitat de Barcelona-Institut de Recerca Hospital Sant Joan de Déu, IBUB-IRSJD, Barcelona, Spain
Rebecca Oelkrug - Institute for Endocrinology and Diabetes-Molecular Endocrinology, Center of Brain Behavior and Metabolism CBBM, University of Lübeck, Lübeck, Germany
Anxo Vidal - Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
Juan Roa - Department of Cell Biology, Physiology and Immunology, University of Córdoba, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía, Córdoba, Spain
Tomás Sobrino - Clinical Neurosciences Research Laboratory, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
Francesc Villarroya - Institut de Biomedicina de la Universitat de Barcelona-Institut de Recerca Hospital Sant Joan de Déu, IBUB-IRSJD, Barcelona, Spain
Carlos Diéguez - CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain
Rubén Nogueiras - CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain
Cristina García-Cáceres - Medizinische Klinik and Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
Manuel Tena-Sempere - FiDiPro Program, Institute of Biomedicine, University of Turku, Turku, Finland
Jens Mittag - Institute for Endocrinology and Diabetes-Molecular Endocrinology, Center of Brain Behavior and Metabolism CBBM, University of Lübeck, Lübeck, Germany
M Carmen Martínez - SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France
Kamal Rahmouni - Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Ramaroson Andriantsitohaina - SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France. ramaroson.andriantsitohaina@inserm.fr
Miguel López - CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain. m.lopez@usc.es
Détails de publication: Nature metabolism, Vol.3(10), pp.1415-1431
Identifiants: 99158811209311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Journal article