DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons.
DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons.
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DOI：
10.1016/j.cmet.2017.01.003
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发表时间：
2017-03-07
期刊：
影响因子：
29
通讯作者：
Diano S
中科院分区：
文献类型：
--
作者：
Santoro A;Campolo M;Liu C;Sesaki H;Meli R;Liu ZW;Kim JD;Diano S
下丘脑阿片黑素皮质素原(POMC)神经元调节能量和葡萄糖代谢。使这些神经元能够对代谢环境变化做出反应的细胞内机制还不清楚。在这里，我们显示了激活的动力素相关蛋白(PDRP1)的表达减少，这是一种线粒体分裂调节因子，在喂养的小鼠POMC神经元中表达减少。与禁食动物的POMC神经元相比，这些POMC神经元显示出更大的线粒体大小和长径比。诱导缺失成熟POMC神经元的Drp1(Drp1fl/fl-POMC-cre：ERT2)可改善瘦素敏感性和葡萄糖反应性。在Drp1fl/fl-POMC-cre：ERT2小鼠中，POMC神经元表现为线粒体大小增加，ROS产生增加，神经元激活，Kcnj11mRNA表达增加，受PPAR调节。此外，Drp1的缺失增强了这些神经元中的葡萄糖刺激，导致它们受到更强的抑制，并更大程度地激活了对PPAR依赖的低血糖的反向调节反应。总而言之，这些数据揭示了线粒体分裂在POMC神经元的瘦素敏感性和葡萄糖传感中的作用。
Hypothalamic Pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill-defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1fl/fl-POMC-cre:ERT2) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1fl/fl-POMC-cre:ERT2 mice, POMC neurons showed increased mitochondrial size, ROS production and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons causing their stronger inhibition, and, a greater activation of counter-regulatory responses to hypoglycemia that were PPAR-dependent. Together these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons.