High‐Fat Diet Disrupt Nerve Function by Targeting Schwann Cells

ABSTRACT Background and Aims Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes, with Schwann cell dysfunction increasingly implicated in disease progression. This study aimed to investigate how high‐fat diet (HFD)‐induced metabolic syndrome (MetS) affects Schwann cells and peripheral nerve function in male and female mice. Methods Male and female C57BL/6J mice were fed a standard diet (SD) or HFD for 33 weeks. Metabolic phenotyping included body weight, fasting blood glucose, and glucose tolerance tests. Peripheral nerve function was assessed via motor and sensory nerve conduction velocities (NCVs), behavioral tests (grip strength, thermal preference, Von Frey), intraepidermal nerve fiber density (IENFD) counts, and sciatic nerve morphological analysis. Myelin protein expression was analyzed by Western blotting and immunohistochemistry. Results Both sexes developed MetS features, though males exhibited more pronounced hyperglycemia. HFD mice showed thermal hyperalgesia, reduced IENFD, and slowed NCVs, consistent with DPN. Morphological studies revealed sex‐specific myelin thinning and structural abnormalities without significant axonal degeneration. In males, HFD was associated with reduced muscular strength, a decrease in myelin thickness of small‐caliber axons, and an increase in the Peripheral Myelin Protein 2 (PMP2), a fatty acid chaperone. In females, although HFD led to myelin decompaction, it was not associated with muscle strength deficits or changes in myelin composition. Interpretation HFD‐induced MetS impairs Schwann cell function and peripheral nerve health in a sex‐dependent manner. Myelin defects and PMP2 upregulation suggest that altered lipid metabolism contributes to neuropathy progression. These findings highlight Schwann cells as key mediators of MetS‐associated peripheral neuropathy and underscore the need for sex‐specific therapeutic strategies.