Metabolic Regulation by Glial Inflammatory Signaling

神经胶质炎症信号传导的代谢调节

• 批准号: 10186848
• 负责人: JOSHUA P THALER
• 金额: $ 44.13万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-12 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186848
• 关键词: Astrocytes; Astrocytosis; Brain; Calories; Cells; Central Nervous System Diseases; Closure by clamp; Clozapine; Coupled; Data; Dependence; Designer Drugs; Desire for food; Development; Diabetes Mellitus; Diet; Disease; Dissociation; Drug Receptors; Fatty acid glycerol esters; Future; Genetic Recombination; Gliosis; Glucose; Glucose Intolerance; High Fat Diet; High Prevalence; Human; Hyperphagia; Hypothalamic structure; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Kinetics; Knock-out; Leptin; Link; Mediating; Mediator of activation protein; Medical; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Methods; Microglia; Modeling; Modernization; Molecular; Mus; Neuraxis; Neuroglia; Neurons; Neurosciences; Obese Mice; Obesity; Outcome; Overnutrition; Oxides; Pathogenesis; Pathology; Pathway interactions; Peripheral; Pharmacology; Phenotype; Physiological; Predisposition; Public Health; Regulation; Resistance; Ribosomes; Rodent; Role; Secondary to; Signal Transduction; Synaptic plasticity; System; TLR4 gene; TNF gene; Technology; Testing; Therapeutic; Thinness; Time; Tissues; Tumor Necrosis Factor Receptor; Up-Regulation; Weight; Weight Gain; base; biological adaptation to stress; blood glucose regulation; cell type; designer receptors exclusively activated by designer drugs; diabetes pathogenesis; effective therapy; energy balance; feeding; global health; glucose tolerance; immune activation; impaired glucose tolerance; improved; in vivo; innovation; knowledge of results; metabolic phenotype; mouse model; prevent; receptor; recruit; transcriptomics

Project Summary Obesity is a significant public health concern worldwide, and the incomplete understanding of its pathogenesis has limited the development of effective treatments. Overnutrition triggers immune cell activation in peripheral tissues and the brain, suggesting that strategies to target the inflammatory response have theoretical therapeutic potential. However, these approaches remain largely untested. We recently demonstrated that mice lacking IKKβ in brain glia (astrocytes and microglia) show reduced susceptibility to diet-induced obesity (DIO) and hyperphagia, but with different kinetics. Microglial activation occurs earlier and is required for DIO susceptibility from the onset of HFD feeding whereas astrocyte protection from DIO only occurs after weeks of HFD exposure. Consistent with the known role of microglia to induce reactive astrocytosis in CNS inflammatory diseases, these data suggest a cascade of inflammatory activation beginning with microglia that subsequently triggers astrocytes to promote DIO. Another stark difference between the mouse models is a paradoxical impairment of glucose tolerance in the lean microglial IKKβ knockout, suggesting dissociation between the regulation of energy balance and glucose homeostasis by microglia. However, the molecular mediators responsible for this phenotype remain unknown. We have now developed a diet-independent inducible model of microglial activation using the Designer Receptor Activated by Designer Drugs (DREADD) approach. Microglia expressing the Gq-coupled DREADD receptor hM3D are rapidly activated by CNO treatment with marked upregulation of TNFa expression. Nevertheless, the CNO treatment causes an immediate improvement in glucose tolerance even in HFD-fed mice. Unexpectedly, this effect can be blocked using icv pretreatment with either a specific TNF receptor antagonist or a melanocortin 3/4 receptor antagonist. While TNF signaling can disrupt leptin sensitivity in hypothalamic neurons, it also increases POMC neuron firing, promotes synaptic plasticity and activates the melanocortin pathway. Therefore, we hypothesize that HFD feeding acts through microglial TLR4 to triggers DIO susceptibility but improve glucose tolerance through the melanocortin pathway. To investigate these premises further, in Aim 1 we will determine whether astrocyte activation is dependent on microglial inflammatory signaling and required for microglia-induced DIO. Aim2 will determine whether microglial TNF and melanocortin signaling are required for the improved glucose tolerance induced by microglial activation. Finally, Aim 3 investigates the peripheral mechanisms of improved glucose tolerance and includes a transcriptomic screen for additional microglial mediators of glucose homeostasis regulation. Together, these studies will help identify the cellular and molecular components of microglial activation that mediate its impact on obesity and diabetes pathogenesis.

项目摘要 肥胖是全球重要的公共卫生问题，对其发病机理的理解不完整 限制了有效治疗的发展。营养不良会触发周围的免疫细胞激活 组织和大脑，表明靶向炎症反应的策略在理论上具有 治疗潜力。但是，这些方法在很大程度上未经测试。我们最近证明了 在脑胶质细胞中缺乏IKKβ的小鼠（星形胶质细胞和小胶质细胞）显示出对饮食诱导的肥胖症的敏感性降低 （dio）和多晶状体，但具有不同的动力学。小胶质细胞激活发生早期，并且需要DIO HFD喂养开始的敏感性 HFD暴露。与小胶质细胞在CNS炎症中诱导反应性星形细胞增多症的已知作用一致 疾病，这些数据表明从小胶质细胞开始的一系列炎症激活，随后 触发星形胶质细胞促进DIO。 小鼠模型之间的另一个明显差异是对葡萄糖耐量的悖论障碍 瘦小胶质细胞IKKβ基因敲除，表明能量平衡和葡萄糖调节之间解离 小胶质细胞的稳态。但是，负责该表型的分子介质仍然未知。 现在，我们已经开发了一种独立于饮食诱导的小胶质细胞激活模型 由设计师药物（Dreadd）方法激活的受体。表达GQ耦合Dreadd的小胶质细胞 受体HM3D通过CNO处理以明显的TNFA表达上调而迅速激活。 然而，CNO治疗即使在HFD喂养中也会立即提高葡萄糖耐受性 老鼠。出乎意料的是，可以使用任何特定TNF接收器的ICV预处理来阻止这种效果 拮抗剂或黑色皮质素3/4受体拮抗剂。而TNF信号传导可能会破坏瘦素灵敏度 下丘脑神经元，它还增加了POMC神经元的发射，促进突触可塑性并激活 黑色皮质素途径。因此，我们假设HFD喂养通过小胶质TLR4起作用 触发了DIO敏感性，但通过黑色素皮质途径提高了葡萄糖耐受性。到 进一步研究这些前提，在目标1中，我们将确定星形胶质细胞激活是否取决于 小胶质细胞炎症信号传导，小胶质细胞诱导的DIO所需。 AIM2将确定是否 小胶质细胞TNF和黑色皮质素信号传导是需要提高的葡萄糖耐受性的 小胶质激活。最后，AIM 3研究了改善葡萄糖耐量和 包括一个转录组屏幕，用于葡萄糖稳态调节的其他小胶质细胞介质。 总之，这些研究将有助于确定小胶质激活的细胞和分子成分， 介导其对肥胖症和糖尿病发病机理的影响。