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), Santiago de Compostela, Spain.
Diabetes. 2018 Nov;67(11):2213-2226. doi: 10.2337/db17-1538. Epub 2018 Aug 13.
AMPK is a cellular gauge that is activated under conditions of low energy, increasing energy production and reducing energy waste. Current evidence links hypothalamic AMPK with the central regulation of energy balance. However, it is unclear whether targeting hypothalamic AMPK has beneficial effects in obesity. Here, we show that genetic inhibition of AMPK in the ventromedial nucleus of the hypothalamus (VMH) protects against high-fat diet (HFD)-induced obesity by increasing brown adipose tissue (BAT) thermogenesis and subsequently energy expenditure. Notably, this effect depends upon the AMPKα1 isoform in steroidogenic factor 1 (SF1) neurons of the VMH, since mice bearing selective ablation of AMPKα1 in SF1 neurons display resistance to diet-induced obesity, increased BAT thermogenesis, browning of white adipose tissue, and improved glucose and lipid homeostasis. Overall, our findings point to hypothalamic AMPK in specific neuronal populations as a potential druggable target for the treatment of obesity and associated metabolic disorders.
AMPK 是一种细胞测量仪，在能量低的情况下会被激活，从而增加能量产生并减少能量浪费。目前的证据表明，下丘脑 AMPK 与能量平衡的中枢调节有关。然而，靶向下丘脑 AMPK 是否对肥胖有有益影响尚不清楚。在这里，我们发现，通过增加棕色脂肪组织（BAT）的产热作用，从而增加能量消耗，在下丘脑腹内侧核（VMH）中抑制 AMPK 的遗传可预防高脂肪饮食（HFD）引起的肥胖。值得注意的是，这种效应取决于 VMH 中的类固醇生成因子 1（SF1）神经元中的 AMPKα1 同工型，因为在 SF1 神经元中选择性消融 AMPKα1 的小鼠对饮食诱导的肥胖、BAT 产热增加、白色脂肪组织的褐变以及改善葡萄糖和脂质代谢稳态具有抗性。总的来说，我们的研究结果表明，特定神经元群体中的下丘脑 AMPK 可能成为肥胖及其相关代谢紊乱治疗的潜在可药物靶点。
