Introduction and Objective: Inflammation is a key component in the pathogenesis of diabetic peripheral neuropathy (DPN), but underlying mechanisms are poorly understood. We previously identified a nerve-associated macrophage population that responds to neuroinflammatory signaling and expresses the brown adipocyte-related factors beta 3-adrenergic receptor (ADRβ3) and uncoupling protein 1 (UCP1) during tissue regeneration. These studies investigate the role of these cells in DPN.Methods: We used an established mouse model of pre-DPN. Mice were fed a high-fat diet (HFD) to induce neuropathy and compared to age-matched mice on a standard diet (SD). Metabolic and neuropathy phenotypes were confirmed by glucose tolerance and von Frey testing. Sciatic nerve segments were isolated, digested and analyzed for ADRβ3 expression by flow cytometry from 10-16 weeks on the HFD. Blood nerve barrier (BNB) integrity was assessed by Evans Blue permeability. ANOVA with Tukey’s post-test was used for statistical analyses.Results: The percentage of ADRβ3+ cells gradually increased in nerves of HFD-fed mice. Mice exhibited impaired glucose tolerance and mechanical allodynia at this time. This also correlated with enhanced dye extravasation into the nerve indicative of BNB compromise. Sorted ADRβ3+ cells expressed UCP1. Immunohistochemical analysis of human nerves suggests expansion of ADRβ3/UCP1+ cells in type 2 diabetes.Conclusion: ADRβ3+ nerve-associated cells expand during DPN and may impact BNB integrity. Further studies will confirm the phenotype and functional role of these cells in DPN. These cells represent a new target in DPN pathogenesis.
M. White: None. S.N. Vodnala: None. Z. Gugala: None. E.A. Salisbury: None.
U.S. Department of Defense (W81XWH-22-1-0004)
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