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)、糖尿病前期和肥胖症的常见并发症， 包括代谢综合征（MetS）各个方面的病症。严格血糖控制并不能治疗 PN MetS，而新的临床指南则侧重于通过修改 MetS 来改善代谢健康 尽管改变生活方式如何改善 PN 仍不清楚。有一个 迫切需要阐明 MetS 中 PN 病理生理学的潜在机制，以建立有效的、 基于机制的 PN 治疗。肌肉和脂肪等代谢活跃的组织会产生胰岛素抵抗 (IR) 响应 MetS；然而，饮食和/或运动会增加能量消耗和/或降低 IR， 逆转大都会。与肌肉和脂肪一样，神经系统细胞在 MetS 条件下也会产生 IR，这与 多种鼠标型号中的 PN。我们最近报道了高脂饮食（HFD）小鼠的饮食逆转（DR） MetS 模型可改善 PN 并纠正 PN 诱导的脂质组和转录组变化。我们的新 初步数据还证实同一动物模型的坐骨神经存在显着的 IR。尽管我们的 在小鼠中的发现以及运动对 MetS 和 PN 个体的有益影响的报告，其机制 改善全身代谢健康与改善神经健康之间的联系仍知之甚少。特别是， 周围神经系统神经胶质细胞雪旺细胞 (SC) 的贡献尚未在 尽管 PN 具有非细胞自主性并且 SC 的重要性日益增加，但代谢获得性 PN 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 单细胞水平和整个神经神经转录组学的强度间歇训练（HIIT） 生物能量学、代谢流和功能来定义神经代谢耦合和 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 MetS 正常化来改善 PN 和神经胰岛素敏感性，可恢复关键的 SC 轴突代谢串扰和能量底物转移 从 SC 到轴突，使周围神经生物能和功能正常化。目标 1 将评估以下措施的影响 DR 和 HIIT 通过纵向评估基本情况对 HFD MetS 小鼠的整体神经生物能学和 PN 产生影响 代谢参数和 PN 表型，进行 SC 单细胞 RNA 测序，并进行离体评估 坐骨神经生物能学、能量底物通量组学（糖酵解和脂肪酸 β-氧化），以及 代谢组学。目标 2 将通过表征来评估 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 轴突生物能学。目标3将 通过以下方法确定 SC 限制的胰岛素信号或能量转移消融对 HFD MetS 小鼠 PN 的影响 使用诱导型 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。 MetS 患者的饮食和运动的代谢健康可改善神经功能并改善 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.