Metabolic coupling between Schwann cells and axons is functionally distinct from myelination and is disrupted in obesity, prediabetes, and diabetes

雪旺细胞和轴突之间的代谢耦合在功能上不同于髓鞘形成，并且在肥胖、糖尿病前期和糖尿病中被破坏

• 批准号: 10518251
• 负责人: Eva Lucille Feldman
• 金额: $ 66.32万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-23 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518251
• 关键词: Ablation; Affect; Animal Model; Axon; Bioenergetics; Biological; Cells; Cellular Metabolic Process; Clinical; Coculture Techniques; Complication; Complications of Diabetes Mellitus; Consumption; Coupling; Data; Diabetes Mellitus; Diet; Educational Intervention; Energy Transfer; Exercise; Failure; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Glycolysis; Goals; Guidelines; Health; High Fat Diet; In Vitro; Individual; Insulin Receptor; Insulin Resistance; Insulin-Like-Growth Factor I Receptor; Interval training; Intervention; Investigation; Knock-out; Knockout Mice; Life Style Modification; Link; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Molecular; Mus; Muscle; Nature; Nerve; Nervous system structure; Neuroglia; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Phenotype; Prediabetes syndrome; Quality of life; Recommendation; Reporting; Research; Role; Schwann Cells; Techniques; Thinness; Tissues; base; cohort; diet and exercise; dietary; dietary control; effective therapy; falls; glycemic control; improved; in vitro Model; in vivo; insulin sensitivity; insulin signaling; lifestyle intervention; lipidome; lipidomics; metabolomics; mitochondrial dysfunction; mouse model; myelination; nerve injury; new therapeutic target; novel; novel therapeutic intervention; oxidation; prevent; response; sciatic nerve; sex; simulation; single-cell RNA sequencing; therapeutic target; transcriptome; transcriptomics; Ablation; Affect; Animal Model; Axon; Bioenergetics; Biological; Cells; Cellular Metabolic Process; Clinical; Coculture Techniques; Complication; Complications of Diabetes Mellitus; Consumption; Coupling; Data; Diabetes Mellitus; Diet; Educational Intervention; Energy Transfer; Exercise; Failure; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Glycolysis; Goals; Guidelines; Health; High Fat Diet; In Vitro; Individual; Insulin Receptor; Insulin Resistance; Insulin-Like-Growth Factor I Receptor; Interval training; Intervention; Investigation; Knock-out; Knockout Mice; Life Style Modification; Link; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Molecular; Mus; Muscle; Nature; Nerve; Nervous system structure; Neuroglia; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Phenotype; Prediabetes syndrome; Quality of life; Recommendation; Reporting; Research; Role; Schwann Cells; Techniques; Thinness; Tissues; base; cohort; diet and exercise; dietary; dietary control; effective therapy; falls; glycemic control; improved; in vitro Model; in vivo; insulin sensitivity; insulin signaling; lifestyle intervention; lipidome; lipidomics; metabolomics; mitochondrial dysfunction; mouse model; myelination; nerve injury; new therapeutic target; novel; novel therapeutic intervention; oxidation; prevent; response; sciatic nerve; sex; simulation; single-cell RNA sequencing; therapeutic target; transcriptome; transcriptomics

ABSTRACT Peripheral neuropathy (PN) is a common complication of type 2 diabetes (T2D), prediabetes, and obesity, conditions that comprise aspects of the metabolic syndrome (MetS). Strict glycemic control does not treat PN in MetS, and new clinical guidelines instead focus on improving metabolic health by modifying MetS components through diet and exercise, though how lifestyle modifications improve PN is unknown. There is a critical need to elucidate the mechanisms underlying PN pathophysiology in MetS to establish effective, mechanism-based PN treatments. Metabolically active tissues like muscle and fat develop insulin resistance (IR) in response to MetS; however, diet and/or exercise increase energy consumption and/or decrease IR, reversing MetS. Like muscle and fat, nervous system cells develop IR under MetS conditions which is linked to PN in multiple mouse models. We recently reported that dietary reversal (DR) in a high-fat diet (HFD) mouse model of MetS improves PN and corrects PN-induced lipidome and transcriptome changes. Our new preliminary data additionally confirms significant IR in sciatic nerves from this same animal model. Despite our findings in mice and reports of beneficial effects of exercise in individuals with MetS and PN, the mechanisms linking improved systemic metabolic health to improved nerve health remain poorly understood. Particularly, the contribution of peripheral nervous system glia, Schwann cells (SCs), has not been investigated in metabolically-acquired PN despite the non-cell autonomous nature of PN and a growing importance of SC- axon metabolic crosstalk on nerve health. Our objective is to rigorously evaluate the effects of DR and high- intensity interval training (HIIT) on nerve transcriptomics at a single cell level and on whole nerve bioenergetics, metabolic flux, and function to define the role of neurometabolic coupling and SC-axon metabolic crosstalk in PN. Our central hypothesis is that diet and exercise improve PN by normalizing MetS and nerve insulin sensitivity, which restores critical SC-axon metabolic crosstalk and energy substrate transfer from SCs to axons, normalizing peripheral nerve bioenergetics and function. Aim 1 will assess the effects of DR and HIIT on global nerve bioenergetics and PN in HFD MetS mice by longitudinally assessing basic metabolic parameters and PN phenotype, performing SC single cell RNA sequencing, and evaluating ex vivo sciatic nerve bioenergetics, energy substrate fluxomics (glycolysis and fatty acid β-oxidation), and metabolomics. Aim 2 will evaluate SC-axon metabolic crosstalk in in vitro models of MetS PN by characterizing SC glycolysis and β-oxidation, neuron mitochondria dynamics, and global SC-axon bioenergetics. Aim 3 will determine the impact of SC-restricted insulin signaling or energy transfer ablation on PN in HFD MetS mice by using inducible SC-restricted insulin receptor/IGF-I receptor or monocarboxylate transporter 1 knockout mice. This research will have a significant impact by elucidating mechanisms underlying how improving systemic metabolic health with diet and exercise in MetS patients improves nerve function and ameliorates PN.

抽象的 周围神经病（PN）是2型糖尿病（T2D），糖尿病前和肥胖症的常见并发症， 包括代谢综合征（METS）方面的条件。严格的血糖控制不治疗PN 在大都会和新的临床指南中，重点是通过修改大都会 通过饮食和运动的组成部分，尽管生活方式改变如何改善PN是未知的。有一个 阐明大都会PN病理生理的机制以建立有效的， 基于机制的PN处理。代谢活性组织，例如肌肉和脂肪发育胰岛素抵抗 （IR）回应大都会；但是，饮食和/或运动增加了能耗和/或减少IR， 反向大都会队。像肌肉和脂肪一样，神经系统细胞在MetS条件下发展IR，与 多种鼠标模型中的PN。我们最近报道了高脂饮食（HFD）小鼠中的饮食逆转（DR） MetS的模型改善了PN并纠正PN诱导的脂质组和转录组变化。我们的新 初步数据还证实了同一动物模型的坐骨神经中的显着IR。尽管我们 小鼠的发现以及运动对MetS和PN个体的有益作用的报告，机制 将改善的全身代谢健康与改善的神经健康联系起来仍然知之甚少。特别， 周围神经系统神经胶质细胞（SCS）的贡献尚未在 代谢可获得的PN希望PN的非单元自主性质以及SC-的重要性日益严重 关于神经健康的轴突代谢串扰。我们的目标是严格评估DR和高级的影响 在单个细胞水平和整体神经上的神经转录组学上的强度间隔训练（HIIT） 生物能力，代谢通量和功能，以定义神经代谢耦合和SC-axon的作用 PN中的代谢串扰。我们的中心假设是饮食和运动通过标准化大都会 和神经胰岛素敏感性，它恢复了关键的SC-Axon代谢串扰和能量底物转移 从SC到轴突，将周围神经生物能学和功能正常化。 AIM 1将评估 通过纵向评估基本 代谢参数和PN表型，执行SC单细胞RNA测序并评估离体 坐骨神经生物能学，能量底物通量（糖酵解和脂肪酸β氧化）和 代谢组学。 AIM 2将通过表征在MetS PN的体外模型中评估SC-Axon代谢串扰 SC糖酵解和β-氧化，神经元线粒体动力学和全球SC-Axon生物能学。目标3意志 确定由HFD MetS小鼠中PN的SC限制胰岛素信号传导或能量转移消融的影响 使用可诱导的SC限制胰岛素受体/IGF-I受体或单羧酸盐转运蛋白1基因敲除小鼠。 这项研究将通过阐明如何改善系统性的基础机制产生重大影响 大都会患者的饮食和运动代谢健康可改善神经功能并改善PN。