Intracellular mechanisms of microglia activation in diet-induced obesity

饮食引起的肥胖中小胶质细胞激活的细胞内机制

• 批准号: 10216249
• 负责人: Sabrina Diano
• 金额: $ 58.88万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216249
• 关键词: Adult; Area; Body Weight; Brain; Breeding; Cells; Data; Dendritic Spines; Development; Diabetes Mellitus; Diet; Etiology; Event; Exposure to; Feeding behaviors; High Fat Diet; Homeostasis; Hypothalamic structure; Immune response; Impairment; Inflammation; Injections; LoxP-flanked allele; Mediating; Metabolic; Metabolic Diseases; Metabolism; Microglia; Mitochondria; Mus; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Peptides; Phagocytosis; Phase; Play; Predisposition; Presynaptic Terminals; Process; Regulation; Role; Spinal Cord; Synapses; Synaptic plasticity; Tamoxifen; Testing; Time; UCP2 protein; Viral; Weight Gain; Work; combat; diet-induced obesity; experimental study; feeding; glucose metabolism; insight; mitochondrial metabolism; monocyte; neural circuit; neuroinflammation; neuronal circuitry; novel; overexpression; treatment strategy

Microglia, the yolk sack-derived monocytes of the brain and spinal cord, plays a crucial role in immune responses, including inflammation. Recent work has expanded the role of microglia in the central nervous system (CNS), which includes phagocytosis of axon terminals and dendritic spines, thus pointing to an active role of microglia in neuronal circuit development and plasticity (Tremblay et al., 2011). Diet-induced obesity (DIO) induces microglia activation and hypothalamic inflammation as early as 3 days after high fat diet (HFD) exposure, before changes in body weight occur (Thaler et al., 2012). We in control also showed that activated microglia the hypothalamus act as a conductor of synaptic plasticity of the hypothalamic neurocircuitry involved in the of feeding behavior and glucose metabolism (Jin et al., 2016).Changes in microglial activity and function are processes that require dynamic changes in energy demand. During inflammation, changes in mitochondrial metabolism were suggested to contribute to microglia activation (Voloboueva et al., 2013; Gimeno-Bayon et al., 2014; Orihuela et al., 2016). Our preliminary data revealed that HFD-induced hypothalamic inflammation and microglia activation is paralleled by increased mitochondrial uncoupling protein 2 (UCP2) expression and a rapid (within 3 days) and transient (by day 7 days it is reversed) mitochondria fission event in microglia cells. We have previously shown that UCP2 propagates mitochondrial fission (Coppola et al., 2007; Andrews et al., 2008; Toda et al., 2016) via activation of dynamic-related peptide 1 (DRP1), a mitochondrial fission enabler (Toda et al., 2016). Corresponding with this, when we deleted UCP2 selectively from microglia in adult mice, HFD-exposure failed to trigger fission of mitochondria in hypothalamic microglia cells, and, it also diminished HFD-induced body weight gain and metabolic impairments of mice. Taken together these observations gave impetus to the central hypothesis of this proposal which is that DRP1 mediated mitochondrial fission via DRP1 activation in the early but not late phase of HFD feeding is indispensible for microglia activation, neuroinflammation, hypothalamic circuit adaptation to promote obesity. To test these hypotheses, we propose 3 Aims: Specific Aim 1 will test the hypothesis that UCP2- induced mitochondrial fission mediated by DRP1 activation in the early phase (by day 3) of HFD feeding is critical for hypothalamic microglia activation, inflammation and obesity susceptibility. Specific Aim 2 will test the hypothesis that HFD-induced microglia activation requires DRP1 for the rapid and transient mitochondria fission event in microglia cells in early but not late phase of HFD feeding to promote obesity. Specific Aim 3 will determine whether activated microglia in HFD-fed DIO mice are upstream controllers of synaptic adaptations of arcuate POMC and AgRP neurons. The execution of these studies will deliver novel insights into central regulation of whole body glucose metabolism and offer novel avenues to combat diabetes by targeting brain mitochondrial dynamics.

小胶质细胞是大脑和脊髓的卵黄袋衍生的单核细胞，在免疫中发挥着至关重要的作用 反应，包括炎症。最近的工作扩大了小胶质细胞在中枢神经中的作用 系统（CNS），其中包括轴突末端和树突棘的吞噬作用，从而指向一个活跃的 小胶质细胞在神经元回路发育和可塑性中的作用（Tremblay et al., 2011）。饮食引起的肥胖 (DIO) 最早在高脂饮食 (HFD) 后 3 天即可诱导小胶质细胞激活和下丘脑炎症 在体重发生变化之前暴露（Thaler 等，2012）。我们 在 控制 还表明激活的小胶质细胞 下丘脑充当下丘脑神经回路突触可塑性的导体，参与 摄食行为和葡萄糖代谢的变化（Jin et al., 2016）。小胶质细胞活性和葡萄糖代谢的变化 功能是需要能量需求动态变化的过程。炎症期间，会发生变化 线粒体代谢被认为有助于小胶质细胞激活（Voloboueva 等，2013； 吉梅诺-巴永等人，2014； Orihuela 等人，2016）。我们的初步数据显示，HFD 引起的 下丘脑炎症和小胶质细胞激活与线粒体解偶联蛋白增加同时发生 2 (UCP2) 表达和快速（3 天内）和瞬时（第 7 天逆转）线粒体 小胶质细胞中的裂变事件。我们之前已经证明 UCP2 传播线粒体裂变 （Coppola 等人，2007；Andrews 等人，2008；Toda 等人，2016）通过动态相关肽 1 的激活 (DRP1)，线粒体裂变促进剂（Toda 等人，2016）。与此对应的是，当我们删除UCP2时 选择性地从成年小鼠的小胶质细胞中选择，HFD 暴露未能触发下丘脑线粒体的裂变 它还能减少 HFD 引起的小鼠体重增加和代谢损伤。 综上所述，这些观察结果推动了该提案的中心假设，即 DRP1 在 HFD 喂养的早期而非晚期，通过 DRP1 激活介导线粒体裂变 对于小胶质细胞激活、神经炎症、下丘脑回路适应促进不可或缺 肥胖。为了检验这些假设，我们提出了 3 个目标： 具体目标 1 将检验 UCP2- HFD 早期（第 3 天）由 DRP1 激活介导的线粒体分裂 喂养对于下丘脑小胶质细胞激活、炎症和肥胖易感性至关重要。 具体目标 2 将检验 HFD 诱导的小胶质细胞激活需要 DRP1 的假设 HFD 早期而非晚期小胶质细胞中快速且短暂的线粒体分裂事件 喂养促进肥胖。具体目标 3 将确定 HFD 喂养的 DIO 中的小胶质细胞是否被激活 小鼠是弓形 POMC 和 AgRP 神经元突触适应的上游控制器。 这些研究的执行将为全身葡萄糖的中枢调节提供新的见解 新陈代谢并通过针对大脑线粒体动力学提供对抗糖尿病的新途径。