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蛋黄袋衍生的单核细胞，在免疫中起着至关重要的作用 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状刺的吞噬作用，因此指向活性 小胶质细胞在神经元电路发育和可塑性中的作用（Tremblay等，2011）。饮食引起的肥胖症 （DIO）早在高脂肪饮食后3天（HFD）诱导小胶质细胞激活和下丘脑炎症 暴露于体重变化之前（Thaler等，2012）。我们 在 控制 还表明活化的小胶质细胞 下丘脑充当下丘脑神经记录的突触可塑性的指挥 喂养行为和葡萄糖代谢（Jin等，2016）。 功能是需要动态变化能量需求的过程。在炎症期间，变化 线粒体代谢被认为有助于小胶质细胞活化（Voloboueva等，2013; Gimeno-Bayon等人，2014年； Orihuela等，2016）。我们的初步数据表明，HFD诱导 下丘脑炎症和小胶质细胞活化与线粒体解偶联蛋白的增加相似 2（UCP2）表达和快速（3天之内）和瞬态（到7天到7天）线粒体 小胶质细胞的裂变事件。我们先前已经表明，UCP2传播线粒体裂变 （Coppola等，2007; Andrews等，2008; Toda等，2016）通过激活动态相关肽1 （DRP1），线粒体裂变启用器（Toda等，2016）。与此相对应，当我们删除UCP2时 在成年小鼠的小胶质细胞中有选择地，HFD暴露未能触发下丘脑线粒体的裂变 小胶质细胞，还减少了HFD诱导的体重增加和小鼠代谢障碍。 总之，这些观察结果推动了该提议的中心假设，即DRP1 在早期但不是HFD进食的早期阶段，通过DRP1激活介导的线粒体裂变是 必不可少的小胶质细胞激活，神经炎症，下丘脑回路适应以促进 肥胖。为了检验这些假设，我们提出了3个目标：特定目标1将检验ucp2-的假设。 在HFD的早期（到第3天）中，由DRP1激活介导的诱导线粒体裂变 进食对于下丘脑小胶质细胞激活，炎症和肥胖症敏感性至关重要。 特定的目标2将检验以下假设：HFD诱导的小胶质细胞激活需要DRP1。 小胶质细胞的快速和短暂性线粒体裂变事件早期但不是HFD的后期阶段 进食以促进肥胖。特定的目标3将确定是否激活了HFD-FED DIO中的小胶质细胞 小鼠是弧形POMC和AGRP神经元突触适应的上游控制器。 这些研究的执行将提供对全身葡萄糖中心调节的新见解 代谢，并通过靶向脑线粒体动力学来打击糖尿病。