The prevalence of the metabolic syndrome (MetS) is increasing worldwide due in part to the increased consumption of a Western diet. MetS is associated with peripheral neuropathy (PN) . PN develops in a cell non-autonomous manner with involvement of axons, Schwann cells (SC) and nerve tissue- infiltrating macrophages (TIM) . SC are divided into subtypes with different roles in nerve injury. Our aim in the current study was to determine how gene expression of different types of SC and macrophages are affected in MetS and how these cells communicate with one another. C57BL6/j male mice (6-weeks old) were fed either a standard diet (SD, 10% fat) or high fat diet (HFD, 60%) for 17 weeks. Metabolic and PN phenotyping were performed for all mice and SC were extracted from sciatic nerves for single cell RNA sequencing (scRNA-seq) . Cellular communication was determined using the CellChat tool. Mice on HFD had higher fasting blood glucose (FBG) , glycated hemoglobin (HbA1c) and decreased nerve conduction velocities and intraepidermal nerve fiber densities consistent with PN compared to mice on SD. Analysis of SC scRNA-seq data revealed unique RNA expression signatures for TIM and 4 subpopulations of SC denoted as myelinating SC (mySC) , non-myelinating SC (nmSC) , SC precursors (SCP) and regenerating SC. Inflammatory genes such as Ptprc and Il1b were significantly more expressed in both TIM and mySC in HFD mice compared to SD mice. CellChat analysis of cellular communication revealed more crosstalk between TIM and various types of SC in HFD animals and identified multiple metabolic and inflammatory pathways that were activated in HFD compared to SD mice.

In conclusion, our study shows that there are many subtypes of SC that behave differently in MetS. Their communication with each other and with TIM strongly implicates these two cell types in the pathogenesis of metabolically acquired PN.


S.Eid: None. M.H.Noureldein: None. F.Mendelson: None. E.L.Feldman: None.


Funding was provided by the National Institutes of Health (NIH) (1R24082841 to ELF) , Novo Nordisk Foundation (NNF14OC0011633 to ELF) , the Nathan and Rose Milstein Research Fund (to SAE) , NeuroNetwork for Emerging Therapies at the University of Michigan (to SAE, MHN, and ELF) , and the A. Alfred Taubman Medical Research Institute (to SAE, MHN, and ELF) .

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