Mondschein Amanda S, DiPersio Mathieu R, Zajaceskowski Julia, Nimmagadda Hasitha, Acheta Jenica, Salinero Abigail E, Haslam Sarah, Poitelon Elwenn, Elston Sophia, McFarland Ethan, Beck Brianna, Zuloaga Kristen L, Rumora Amy E, Poitelon Yannick, Belin Sophie
Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York, USA.
Department of Neurology, Columbia University, New York, New York, USA.
J Peripher Nerv Syst. 2025 Jun;30(2):e70036. doi: 10.1111/jns.70036.
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.
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.
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.
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.
糖尿病周围神经病变（DPN）是糖尿病一种使人衰弱的并发症，雪旺细胞功能障碍在疾病进展中所起的作用越来越受到关注。本研究旨在探究高脂饮食（HFD）诱导的代谢综合征（MetS）如何影响雄性和雌性小鼠的雪旺细胞及周围神经功能。
雄性和雌性C57BL/6J小鼠分别喂食标准饮食（SD）或高脂饮食33周。代谢表型分析包括体重、空腹血糖和葡萄糖耐量试验。通过运动和感觉神经传导速度（NCV）、行为测试（握力、热偏好、von Frey）、表皮内神经纤维密度（IENFD）计数以及坐骨神经形态学分析来评估周围神经功能。通过蛋白质免疫印迹和免疫组织化学分析髓磷脂蛋白表达。
两性均出现了代谢综合征特征，不过雄性的高血糖更为明显。高脂饮食小鼠表现出热痛觉过敏、IENFD降低以及NCV减慢，这与DPN一致。形态学研究显示存在性别特异性的髓鞘变薄和结构异常，但无明显的轴突变性。在雄性中，高脂饮食与肌肉力量降低、小口径轴突的髓鞘厚度减小以及脂肪酸伴侣外周髓磷脂蛋白2（PMP2）增加有关。在雌性中，尽管高脂饮食导致髓鞘松散，但与肌肉力量缺陷或髓鞘组成变化无关。
高脂饮食诱导的代谢综合征以性别依赖的方式损害雪旺细胞功能和周围神经健康。髓鞘缺陷和PMP2上调表明脂质代谢改变促进了神经病变的进展。这些发现突出了雪旺细胞作为代谢综合征相关周围神经病变的关键介质，并强调了针对性别制定治疗策略的必要性。
