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

摘要 周围神经病变（PN）是2型糖尿病（T2 D）、前驱糖尿病和肥胖症的常见并发症， 包括代谢综合征（MetS）方面的病症。严格的血糖控制不能治疗PN 而新的临床指南则侧重于通过修改MetS来改善代谢健康 通过饮食和运动，虽然生活方式的改变如何改善PN尚不清楚。有一个 迫切需要阐明MetS中PN病理生理学的潜在机制， 基于机制的PN治疗。代谢活跃的组织如肌肉和脂肪会产生胰岛素抵抗 (IR)然而，饮食和/或运动增加能量消耗和/或降低IR， 逆转MetS。像肌肉和脂肪一样，神经系统细胞在MetS条件下发展IR，这与 PN在多种小鼠模型中。我们最近报道了高脂饮食（HFD）小鼠的饮食逆转（DR）， MetS模型改善PN并纠正PN诱导的脂质组和转录组变化。我们的新 初步数据还证实了来自该相同动物模型的坐骨神经中的显著IR。尽管我们 在小鼠中的发现和运动对MetS和PN患者的有益作用的报告， 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。尤其是， 外周神经系统胶质细胞，雪旺细胞（SC）的作用尚未在 代谢获得性PN，尽管PN的非细胞自主性质和SC的重要性日益增加， 轴突代谢串扰对神经健康的影响。我们的目标是严格评估DR和高血压的影响 强度间歇训练（HIIT）在单细胞水平和整个神经上对神经转录组学的影响 生物能量学、代谢通量和功能，以确定神经代谢偶联和SC-轴突的作用 PN中的代谢串扰。我们的中心假设是饮食和运动通过使MetS正常化来改善PN 和神经胰岛素敏感性，恢复关键的SC-轴突代谢串扰和能量底物转移 从SC到轴突，使外周神经生物能量学和功能正常化。目标1将评估 DR和HIIT对HFD MetS小鼠的整体神经生物能量学和PN的影响，通过纵向评估基础 代谢参数和PN表型，进行SC单细胞RNA测序，并离体评价 坐骨神经生物能量学，能量底物通量组学（糖酵解和脂肪酸β-氧化），以及 代谢组学目的2将通过表征MetS PN体外模型中的SC-轴突代谢串扰， SC糖酵解和β-氧化，神经元线粒体动力学和整体SC轴突生物能量学。目标3将 确定SC限制的胰岛素信号传导或能量转移消融对HFD MetS小鼠中PN的影响， 使用可诱导SC限制性胰岛素受体/IGF-I受体或单羧酸转运蛋白1敲除小鼠。 这项研究将通过阐明如何改善系统性的潜在机制产生重大影响。 代谢综合征患者的饮食和运动的代谢健康改善了神经功能并改善了PN。

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.