Neuropathy, a crippling diabetic complication, was initially purported to result from lack of glycemic control. However, recent research has linked neuropathy to obesity in individuals without diabetes. Furthermore, evidence indicates mice show signs of neuropathy after high fat feeding. However, the pathogenesis of neuropathy induced by a high fat diet is still unknown.PURPOSEThe purpose of this study was to determine if early neuronal inflammation is a contributing factor to changes in epidermal innervation and mechanical hypersensitivity associated with neuropathy in prediabetic mice fed a high fat diet.METHODSMale C57Bl/6 mice were randomized to a standard diet (Std, 15% kcal from fat) or high fat diet (HF, 54% kcal from fat) for 2, 4, or 8 weeks (n = 11–12 mice per group). Inflammatory mediators (IL‐1α, IL‐1β, IL‐2, IL‐3, IL‐4, IL‐5, IL‐6, IL‐10, IL‐12p70, IL‐17, MCP‐1, IFN‐γ, TNF‐α, MIP‐1α, GMCSF, RANTES) were quantified in the lumbar dorsal root ganglia (DRG) using Multiplex ELISA. Additionally, qRT‐PCR was performed to measure mRNA expression of genes associated with inflammation (IL‐1β, IL‐6, IL‐10, MCP‐1, TNF‐α, RANTES) in epididymal adipose. Mechanical sensitivity associated with neuropathy was determined using the von Frey test and measured every other week, beginning the week before the dietary intervention. In order to quantify intraepidermal nerve fiber (IENF) density and a specific population of peptidergic nociceptive nerve fibers (TrkA) in the hindpaw footpad skin, fluorescence immunohistochemistry was performed.RESULTSCompared to Std, HF had greater bodyweight, fasting blood glucose, and insulin after 8 wks. After 2 wks, IL‐1α was higher in HF compared to Std. After 4 wks, IL‐5, IENF, and TrkA nerve fiber density were higher in HF compared to Std. There were no significant differences in hindpaw sensitivity or adipose mRNA expression of IL‐1β, IL‐10, IL‐6, TNF‐α, RANTES, or MCP‐1 after 2, 4, or 8 wks.CONCLUSIONIn mice fed a high fat diet for 4 wks, increased IENF and TrkA nerve fiber density was accompanied by an increase in the inflammatory mediators IL‐1α and IL‐5 in the lumbar DRG despite lack of increased inflammatory gene expression in the adipose. This suggests a high fat diet causes an early increase in neuronal inflammation and increased nociceptive nerve fiber density that may be responsible for mechanical hypersensitivity, a sign associated with “painful” neuropathy in prediabetic miceSupport or Funding InformationSupported by Southern Illinois University Edwardsville Seed Grants for Transitional and Exploratory ProjectsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.