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

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

Nat Metab. 2021 Oct;3(10):1415-1431. doi: 10.1038/s42255-021-00467-8. Epub 2021 Oct 21.

Authors

Edward Milbank^{1

2

3}, Nathalia R V Dragano^{1

2}, Ismael González-García^{1

2

4}, Marcos Rios Garcia^{1

2}, Verónica Rivas-Limeres^{1

2}, Liliana Perdomo³, Grégory Hilairet³, Francisco Ruiz-Pino^{2

5}, Patricia Mallegol³, Donald A Morgan⁶, Ramón Iglesias-Rey⁷, Cristina Contreras^{1

2}, Luisa Vergori³, Juan Cuñarro^{1

2}, Begoña Porteiro^{1

2}, Aleix Gavaldà-Navarro^{2

8}, Rebecca Oelkrug⁹, Anxo Vidal¹, Juan Roa^{2

5}, Tomás Sobrino⁷, Francesc Villarroya^{2

8}, Carlos Diéguez^{1

2}, Rubén Nogueiras^{1

2}, Cristina García-Cáceres^{4

10}, Manuel Tena-Sempere^{2

5

11}, Jens Mittag⁹, M Carmen Martínez³, Kamal Rahmouni⁶, Ramaroson Andriantsitohaina¹², Miguel López^{13

14}

Affiliations

¹ Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
² CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
³ SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France.
⁴ 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.
⁵ Department of Cell Biology, Physiology and Immunology, University of Córdoba, Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía, Córdoba, Spain.
⁶ Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
⁷ Clinical Neurosciences Research Laboratory, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
⁸ Institut de Biomedicina de la Universitat de Barcelona-Institut de Recerca Hospital Sant Joan de Déu, IBUB-IRSJD, Barcelona, Spain.
⁹ Institute for Endocrinology and Diabetes-Molecular Endocrinology, Center of Brain Behavior and Metabolism CBBM, University of Lübeck, Lübeck, Germany.
¹⁰ Medizinische Klinik and Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany.
¹¹ FiDiPro Program, Institute of Biomedicine, University of Turku, Turku, Finland.
¹² SOPAM, U1063, INSERM, University of Angers, SFR ICAT, Bat IRIS-IBS, Angers, France. ramaroson.andriantsitohaina@inserm.fr.
¹³ Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain. m.lopez@usc.es.
¹⁴ CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain. m.lopez@usc.es.

PMID: 34675439
DOI: 10.1038/s42255-021-00467-8

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

AMP-Activated Protein Kinases / metabolism*
Adipose Tissue, Brown / enzymology*
Animals
Energy Metabolism
Extracellular Vesicles / metabolism*
Hypothalamus / enzymology*
Mice
Obesity / metabolism*
Thermogenesis
Weight Loss

Substances

AMP-Activated Protein Kinases