Milbank, EdwardDragano, NathaliaVidal Gómez, XaviRivas Limeres, VerónicaGarrido Gil, PabloWertheimer, MireilleRecoquillon, SylvainPata, María P.Labandeira García, José LuisDiéguez González, CarlosNogueiras Pozo, RubénMartínez, Marie CarmenAndriantsitohaina, RamarosonLópez Pérez, Miguel A.2023-03-142023-03-142023Metabolism 139 (2023) 155350. https://doi.org/10.1016/j.metabol.2022.1553500026-0495http://hdl.handle.net/10347/30307Background and aims: Leptin receptor (LEPR) deficiency promotes severe obesity and metabolic disorders. However, the current therapeutic options against this syndrome are scarce. Methods: 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. Results: 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).Conclusion: 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 deficiencyeng© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Leptin receptor deficiencydb/db miceHypothalamusAMPKsEVsjournal article10.1016/j.metabol.2022.155350open access