Obesity-associated insulin resistance adversely affects skin function

The aim of this study was to identify changes in skin function associated with obesity and the mechanisms underlying these changes. Functional changes and gene expression in skin were investigated in C57BL/6J mice fed either a control or high-fat diet (HFD). The insulin responsiveness of the skin and skeletal muscle was also evaluated. The effects of inhibiting insulin signaling and altered glucose concentration on skin function-associated molecules and barrier function were analyzed in keratinocytes. HFD-fed mice were not only severely obese, but also exhibited impaired skin barrier function and diminished levels of glycerol transporter aquaporin-3, keratins, and desmosomal proteins involved in maintaining skin structure. Moreover, the expression of cell cycle regulatory molecules was altered. Insulin signaling was attenuated in the skin and skeletal muscle of HFD-fed mice. In keratinocytes, inhibition of insulin signaling leads to decreased keratin expression and diminished barrier function, and higher glucose concentrations increased the expression of CDK inhibitor 1A and 1C, which are associated with cell-cycle arrest. Obesity-associated impairment of skin function can be attributed to structural fragility, abnormal glycerol transport, and dysregulated proliferation of epidermal cells. These alterations are at least partly due to cutaneous insulin resistance and hyperglycemia.本研究旨在明确与肥胖相关的皮肤功能改变及其潜在机制。本研究对喂食对照饮食或高脂饮食（high-fat diet, HFD）的C57BL/6J小鼠的皮肤功能变化与基因表达情况进行了分析，同时还评估了皮肤与骨骼肌的胰岛素响应能力。此外，本研究在角质形成细胞（keratinocytes）中分析了抑制胰岛素信号通路以及改变葡萄糖浓度对皮肤功能相关分子与皮肤屏障功能的影响。喂食高脂饮食的小鼠不仅出现严重肥胖，还表现出皮肤屏障功能受损，以及参与维持皮肤结构的甘油转运蛋白水通道蛋白3（aquaporin-3）、角蛋白与桥粒蛋白水平降低。此外，细胞周期调控分子的表达也发生了改变。喂食高脂饮食的小鼠其皮肤与骨骼肌内的胰岛素信号通路活性减弱。在角质形成细胞中，抑制胰岛素信号通路会导致角蛋白表达降低与屏障功能受损；而较高的葡萄糖浓度则会上调与细胞周期阻滞相关的CDK抑制剂1A和1C（CDK inhibitor 1A and 1C）的表达。肥胖相关的皮肤功能受损可归因于皮肤结构脆弱、甘油转运异常以及表皮细胞增殖失调。上述改变至少部分源于皮肤胰岛素抵抗与高血糖状态。