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 SobrinoFrancesc Villarroya, Carlos Diéguez, Rubén Nogueiras, Cristina García-Cáceres, Manuel Tena-Sempere, Jens Mittag, M. Carmen Martínez, Kamal Rahmouni, Ramaroson Andriantsitohaina*, Miguel López*

*Corresponding author for this work
35 Citations (Scopus)

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.

Original languageEnglish
JournalNature Metabolism
Volume3
Issue number10
Pages (from-to)1415-1431
Number of pages17
ISSN2522-5812
DOIs
Publication statusPublished - 10.2021

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

  • 205-17 Endocrinology, Diabetology, Metabolism

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