小细胞外囊泡介导的下丘脑AMPKα1靶向作用通过激活褐色脂肪组织纠正肥胖。
Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation.
作者信息
Milbank Edward, Dragano Nathalia R V, González-García Ismael, Garcia Marcos Rios, Rivas-Limeres Verónica, Perdomo Liliana, Hilairet Grégory, Ruiz-Pino Francisco, Mallegol Patricia, Morgan Donald A, Iglesias-Rey Ramón, Contreras Cristina, Vergori Luisa, Cuñarro Juan, Porteiro Begoña, Gavaldà-Navarro Aleix, Oelkrug Rebecca, Vidal Anxo, Roa Juan, Sobrino Tomás, Villarroya Francesc, Diéguez Carlos, Nogueiras Rubén, García-Cáceres Cristina, Tena-Sempere Manuel, Mittag Jens, Carmen Martínez M, Rahmouni Kamal, Andriantsitohaina Ramaroson, López Miguel
机构信息
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain.
出版信息
Nat Metab. 2021 Oct;3(10):1415-1431. doi: 10.1038/s42255-021-00467-8. Epub 2021 Oct 21.
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.
目前用于治疗肥胖症的药物疗法疗效有限。在下丘脑腹内侧核（VMH）的类固醇生成因子1（SF1）神经元中，AMP激活的蛋白激酶α1（AMPKα1）的基因消融或功能丧失会因棕色脂肪组织（BAT）产热的交感神经激活而诱导不依赖进食的肥胖抵抗。在此，我们表明，通过静脉注射携带编码靶向VMH-SF1神经元的AMPKα1显性负突变体（AMPKα1-DN）的质粒的小细胞外囊泡（sEVs），可降低肥胖小鼠的体重。负载SF1-AMPKα1-DN的sEVs的有益作用不依赖进食，涉及交感神经激活和BAT中UCP1依赖性产热增加。我们的结果强调了sEVs特异性靶向下丘脑神经元中AMPK的潜力，并引入了一种更广泛的策略来控制体重和减轻肥胖。
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