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

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.

• Authors: 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
• Journal: Nature metabolism (Nat Metab) Vol. 3 Issue 10 Pg. 1415-1431 (10 2021) ISSN: 2522-5812 [Electronic] Germany
• PMID: 34675439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• AMP-Activated Protein Kinases

Topics

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