Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation.
Edward MilbankNathalia R V DraganoIsmael González-GarcíaMarcos Rios GarciaVerónica Rivas-LimeresLiliana PerdomoGrégory HilairetFrancisco Ruiz-PinoPatricia MallegolDonald A MorganRamón Iglesias-ReyCristina ContrerasLuisa VergoriJuan CuñarroBegoña PorteiroAleix Gavaldà-NavarroRebecca OelkrugAnxo VidalJuan RoaTomás SobrinoFrancesc VillarroyaCarlos DiéguezRuben NogueirasCristina García-CáceresManuel Tena-SempereJens MittagMaria Carmen MartínezKamal RahmouniRamaroson AndriantsitohainaMiguel LópezPublished in: Nature metabolism (2021)
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.
Keyphrases
- protein kinase
- body weight
- insulin resistance
- adipose tissue
- skeletal muscle
- metabolic syndrome
- weight loss
- high fat diet induced
- type diabetes
- weight gain
- spinal cord
- high fat diet
- cancer therapy
- drug delivery
- high dose
- gene expression
- physical activity
- spinal cord injury
- climate change
- prefrontal cortex
- wound healing