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中卵黄囊来源的单核细胞，在免疫中起着至关重要的作用。 反应，包括炎症。最近的研究扩大了小胶质细胞在中枢神经系统中的作用。 中枢神经系统(CNS)，包括轴突终末和树突棘的吞噬，因此表明 小胶质细胞在神经元回路发育和可塑性中的作用(Tremblay等人，2011年)。饮食诱导性肥胖 高脂饮食后3d(DIO)诱导小胶质细胞活化和下丘脑炎症反应 体重发生变化之前的暴露(Thaler等人，2012年)。我们 在……里面 控制 还表明激活的小胶质细胞 下丘脑作为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研究(金等人，2016)。 功能是需要能源需求动态变化的过程。在炎症过程中， 线粒体代谢被认为有助于小胶质细胞的激活(Voloboueva等人，2013年； Gimeno-Bayon等人，2014年；Orihuela等人，2016年)。我们的初步数据显示，HFD诱导的 下丘脑炎症和小胶质细胞激活与线粒体解偶联蛋白增加平行 2(UCP2)表达和快速(在3天内)和瞬时(到第7天是颠倒的)线粒体 小胶质细胞中的分裂事件。我们之前已经证明UCP2可以促进线粒体的分裂 (Coppola等人，2007；Andrews等人，2008；Toda等人，2016)通过激活动态相关多肽1 (Drp1)，一种线粒体裂变使能(Toda等人，2016)。与此对应的是，当我们删除UCP2 从成年小鼠的小胶质细胞中选择性地暴露，HFD暴露未能触发下丘脑线粒体的分裂 此外，它还能减轻HFD诱导的小鼠体重增加和代谢损伤。 综上所述，这些观察结果支持了这一提议的核心假设，即Drp1 在HFD摄食的早期而不是晚期，通过Drp1激活介导的线粒体分裂是 对于小胶质细胞活化、神经炎症、下丘脑回路适应性的促进是不可或缺的 肥胖。为了检验这些假设，我们提出了三个目标：特定目标1将检验UCP2- 肾综合征出血热早期(第3天)DRp1激活诱导的线粒体分裂 摄食对下丘脑小胶质细胞的激活、炎症和肥胖易感性至关重要。 特定目标2将检验以下假设：HFD诱导的小胶质细胞激活需要Drp1来实现 HFD早期而不是晚期小胶质细胞中的快速和瞬时线粒体分裂事件 通过喂食来促进肥胖。特异靶3将确定高脂饲料喂养的DIO中激活的小胶质细胞 小鼠是弓状POMC和AgRP神经元突触适应的上游控制者。 这些研究的实施将为全身葡萄糖的中枢调节提供新的见解 新陈代谢，并提供了新的途径，通过靶向脑线粒体动力学来对抗糖尿病。