Small extracellular vesicle targeting of hypothalamic AMPKα1 promotes weight loss in leptin receptor deficient mice

• Published in: Metabolism, clinical and experimental clinical and experimental, 2023-02, Vol.139, p.155350-155350, Article 155350
• Main Authors: Milbank, Edward, Dragano, Nathalia, Vidal-Gómez, Xavi, Rivas-Limeres, Verónica, Garrido-Gil, Pablo, Wertheimer, Mireille, Recoquillon, Sylvain, Pata, María P., Labandeira-Garcia, José Luis, Diéguez, Carlos, Nogueiras, Rubén, Martínez, M. Carmen, Andriantsitohaina, Ramaroson, López, Miguel
• Format: Article
• Language: English
• Subjects: Adipose Tissue, Brown - metabolism; Adipose Tissue, White - metabolism; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; db/db mice; Energy Metabolism; Extracellular Vesicles - metabolism; Hypothalamus; Hypothalamus - metabolism; Leptin receptor deficiency; Life Sciences; Mice; Obesity - genetics; Obesity - metabolism; Receptors, Leptin - genetics; Receptors, Leptin - metabolism; sEVs; Thermogenesis - physiology; Weight Loss
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2022.155350

Leptin receptor (LEPR) deficiency promotes severe obesity and metabolic disorders. However, the current therapeutic options against this syndrome are scarce. db/db mice and their wildtypes were systemically treated with neuronal-targeted small extracellular vesicles (sEVs) harboring a plasmid encoding a dominant negative mutant of AMP-activated protein kinase alpha 1 (AMPKα1-DN) driven by steroidogenic factor 1 (SF1) promoter; this approach allowed to modulate AMPK activity, specifically in SF1 cells of the ventromedial nucleus of the hypothalamus (VMH). Animals were metabolically phenotyped. db/db mice intravenously injected with SF1-AMPKα1-DN loaded sEVs showed a marked feeding-independent weight loss and decreased adiposity, associated with increased sympathetic tone, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). Overall, this evidence indicates that specific modulation of hypothalamic AMPK using a sEV-based technology may be a suitable strategy against genetic forms of obesity, such as LEPR deficiency. Strategy for treating db/db mice with sEVs modulating hypothalamic AMPK. db/db mice (and their wildtypes) were systemically (intravenously, IV) treated with neuronal-targeted small extracellular vesicles (sEVs) harboring a plasmid encoding a dominant negative mutant of AMP-activated protein kinase alpha 1 (AMPKα1-DN) driven by steroidogenic factor 1 (SF1) promoter. This approach allowed modulating AMPK activity, specifically in SF1 cells of the ventromedial nucleus of the hypothalamus (VMH). As a result of that specific hypothalamic action, db/db mice showed a marked feeding-independent weight loss and decreased adiposity, associated with increased sympathetic tone, elevated brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT; omitted in the graphical abstract for simplification). Created with BioRender. [Display omitted] •sEV-mediated systemic targeting of AMPKα1 in SF1 neurons reduces AMPK activity, specifically in the VMH.•Systemic SF1-AMPKα1-DN sEVs induce feeding-independent weight loss in leptin receptor deficient db/db mice.•Systemic SF1-AMPKα1-DN sEVs increased SNS tone and BAT thermogenesis in leptin receptor deficient db/db mice.•Systemic SF1-AMPKα1-DN sEVs increased WAT browning in leptin receptor deficient db/db mice.