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(T2D)、糖尿病前期和肥胖的常见并发症， 包括代谢综合征(METS)各方面的条件。严格的血糖控制不能治疗PN 新的临床指南转而侧重于通过修改蛋氨酸来改善代谢健康 虽然改变生活方式如何改善PN还不清楚，但通过饮食和运动来改善Pn。有一个 迫切需要阐明蛋氨酸营养不良的病理生理学机制，以建立有效的， 基于机理的PN处理。肌肉和脂肪等代谢活跃的组织会出现胰岛素抵抗 (IR)对METS的反应；然而，饮食和/或运动增加了能量消耗和/或降低了IR， 逆转大都会队。像肌肉和脂肪一样，神经系统细胞在蛋氨酸的条件下发展IR，这与 多个小鼠模型中的PN。我们最近报道了高脂饮食(HFD)小鼠的饮食逆转(DR) 蛋氨酸模型改善Pn，纠正Pn诱导的脂体和转录组改变。我们的新产品 初步数据还证实了来自同一动物模型的坐骨神经中显著的IR。尽管我们 在小鼠中的发现和运动对患有蛋氨酸和PN的个体的有益影响的报道，机制 改善全身代谢健康与改善神经健康之间的联系仍然知之甚少。尤其是， 外周神经系统神经胶质细胞，雪旺细胞(SCs)的作用尚未被研究。 新陈代谢获得的PN，尽管PN的非细胞自主性和SC的日益重要性- 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HIGH的效果。 单细胞水平和全神经水平神经转录的强度间歇训练(HIIT) 定义神经代谢偶联和SC轴突作用的生物能量学、代谢流量和功能 PN中的代谢串扰。我们的中心假设是，饮食和运动通过使蛋氨酸正常化来改善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 从干细胞到轴突，使周围神经的生物能量和功能正常化。目标1将评估以下方面的效果 纵向评估DR和HIIT对HFD蛋氨酸小鼠全脑神经生物能量学和PN的影响 代谢参数和PN表型，进行SC单细胞RNA测序和体外评估 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。Aim 2将通过以下特征评估Mets PN体外模型中SC-轴突代谢的串扰 SC糖酵解和β氧化、神经元线粒体动力学和全球SC轴突生物能量学。目标3将 确定SC限制性胰岛素信号转导或能量转移消融对HFD蛋氨酸小鼠PN的影响 使用可诱导的SC限制性胰岛素受体/IGF-I受体或单羧酸转运体1基因敲除小鼠。 这项研究将通过阐明改善系统的潜在机制而产生重大影响 代谢健康配合饮食和运动改善神经功能和改善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.