Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee.
Department of Veterans Affairs , Nashville, Tennessee.
Am J Physiol Endocrinol Metab. 2018 Oct 1;315(4):E583-E593. doi: 10.1152/ajpendo.00166.2018. Epub 2018 Jun 26.
ErbB4, a member of the EGF receptor family, plays a variety of roles in physiological and pathological states. Genetic studies have indicated a link between ErbB4 and type 2 diabetes and obesity, but its role in metabolic syndrome (MetS) has not been reported. In the current study we found that mice with ErbB4 deletion developed MetS after 24 wk on a medium-fat diet (MFD), as indicated by development of obesity, dyslipidemia, hepatic steatosis, hyperglycemia, hyperinsulinemia, and insulin resistance, compared with wild-type mice. ErbB4 deletion mice also exhibited increased amounts of subcutaneous and visceral fat, with increased serum leptin levels, compared with wild-type mice, whereas levels of adiponectin were not significantly different. Histologically, severe inflammation, indicated by F4/80 immunostaining and M1 macrophage polarization, was detected in inguinal and epididymal white adipose tissue in ErbB4 deletion mice. ErbB4 expression decreased during 3T3-L1 preadipocyte differentiation. Administration of neuroregulin 4, a specific ligand for ErbB4, to 3T3-L1 adipocytes had no effect on adipogenesis and lipolysis but significantly inhibited lipogenesis, promoted browning, induced GLUT4 redistribution to the cell membrane, and increased glucose uptake. Neuroregulin 4 also significantly increased glucose uptake in adipocytes isolated from wild-type mice, while these effects were significantly decreased in adipocytes isolated from ErbB4 deletion mice. In conclusion, our results indicate that ErbB4 may play an important role in glucose homeostasis and lipogenesis. ErbB4 deficiency-related obesity and adipose tissue inflammation may contribute to the development of MetS.
表皮生长因子受体 4（ErbB4）是表皮生长因子受体家族的一员，在生理和病理状态下发挥多种作用。遗传研究表明 ErbB4 与 2 型糖尿病和肥胖之间存在关联，但它在代谢综合征（MetS）中的作用尚未报道。在本研究中，我们发现 ErbB4 缺失的小鼠在高脂饮食（MFD）24 周后发展为 MetS，表现为肥胖、血脂异常、肝脂肪变性、高血糖、高胰岛素血症和胰岛素抵抗，与野生型小鼠相比。与野生型小鼠相比，ErbB4 缺失的小鼠还表现出更多的皮下和内脏脂肪，血清瘦素水平升高，而脂联素水平没有显著差异。组织学上，在 ErbB4 缺失的小鼠腹股沟和附睾白色脂肪组织中，通过 F4/80 免疫染色和 M1 巨噬细胞极化检测到严重的炎症。在 3T3-L1 前体脂肪细胞分化过程中，ErbB4 的表达减少。神经调节蛋白 4（一种特异性 ErbB4 配体）给药到 3T3-L1 脂肪细胞对脂肪生成和脂肪分解没有影响，但显著抑制脂肪生成，促进棕色化，诱导 GLUT4 向细胞膜重新分布，并增加葡萄糖摄取。神经调节蛋白 4 还显著增加了来自野生型小鼠的脂肪细胞中的葡萄糖摄取，而这些作用在来自 ErbB4 缺失小鼠的脂肪细胞中显著降低。总之，我们的结果表明 ErbB4 可能在葡萄糖稳态和脂肪生成中发挥重要作用。ErbB4 缺乏相关的肥胖和脂肪组织炎症可能导致 MetS 的发生。
