1. Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation
- Author
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Liliana Perdomo, Begoña Porteiro, Patricia Mallegol, Marcos Rios Garcia, Grégory Hilairet, Ismael González-García, Ramón Iglesias-Rey, Kamal Rahmouni, Verónica Rivas-Limeres, Jens Mittag, Cristina Contreras, Anxo Vidal, Donald A. Morgan, Rubén Nogueiras, Juan Carlos Roa, Ramaroson Andriantsitohaina, Edward Milbank, Manuel Tena-Sempere, Carlos Dieguez, Rebecca Oelkrug, Francesc Villarroya, Francisco Ruiz-Pino, Nathalia Romanelli Vicente Dragano, Juan Cuñarro, Miguel López, Aleix Gavaldà-Navarro, Luisa Vergori, Tomás Sobrino, Cristina García-Cáceres, and M. Carmen Martinez
- Subjects
Steroidogenic factor 1 ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Hypothalamus ,Alpha (ethology) ,AMP-Activated Protein Kinases ,Extracellular Vesicles ,Mice ,Adipose Tissue, Brown ,Physiology (medical) ,Internal medicine ,Weight Loss ,Brown adipose tissue ,Internal Medicine ,medicine ,Animals ,Obesity ,Protein kinase A ,Chemistry ,AMPK ,Thermogenesis ,Cell Biology ,Extracellular vesicle ,Endocrinology ,Ventromedial nucleus of the hypothalamus ,medicine.anatomical_structure ,Energy Metabolism - 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.
- Published
- 2021
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