Increased hepatic expression of ganglioside-specific sialidase, NEU3, improves insulin sensitivity and glucose tolerance in mice.
Increased hepatic expression of ganglioside-specific sialidase, NEU3, improves insulin sensitivity and glucose tolerance in mice.
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DOI：
10.1016/j.metabol.2006.10.027
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发表时间：
2007-03
期刊：
影响因子：
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通讯作者：
Shinsuke Yoshizumi;Susumu Suzuki;M. Hirai;Y. Hinokio;Tetsuya Yamada;Takahiro Yamada;Uiko Tsunoda;H. Aburatani;K. Yamaguchi;T. Miyagi;Y. Oka
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文献类型：
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作者：
Shinsuke Yoshizumi;Susumu Suzuki;M. Hirai;Y. Hinokio;Tetsuya Yamada;Takahiro Yamada;Uiko Tsunoda;H. Aburatani;K. Yamaguchi;T. Miyagi;Y. Oka
富含神经节苷脂的膜微结构域被认为对于胰岛素信号传导的正确划分至关重要。质膜相关唾液酸酶 NEU3 是神经节苷脂水解的关键酶。我们之前报道过，主要在肌肉中过度表达 NEU3 的小鼠患上了严重的胰岛素抵抗糖尿病。为了检查 NEU3 对体内胰岛素敏感性和葡萄糖耐量的可能贡献，使用腺病毒载体在标准饮食和高脂肪饮食的 C57BL/6 小鼠以及标准饮食的胰岛素抵抗 KKAy 小鼠的肝脏中表达 NEU3。肝脏NEU3过度表达反而改善了饲喂标准饮食的C57BL/6小鼠的葡萄糖耐量和胰岛素敏感性，以及饲喂高脂肪饮食的C57BL/6小鼠和KKAy小鼠的葡萄糖耐量。在标准和高脂饮食的 C57BL/6 小鼠以及 KKAy 小鼠中，肝脏 NEU3 过表达增加了肝糖原沉积和甘油三酯积累，并增强了肝脏过氧化物酶体增殖物激活受体 γ 和胎球蛋白的表达。薄层色谱分析表明，肝脏 NEU3 过度表达的小鼠（NEU3 小鼠）的肝脏中 GM1 水平升高，而 GM3 水平显着降低。胰岛素受体底物 1 的基础和胰岛素刺激酪氨酸磷酸化显着增加，但 NEU3 肝脏中胰岛素受体和胰岛素受体底物 2 的酪氨酸磷酸化没有变化。 NEU3 小鼠脂肪组织中胰岛素刺激的胰岛素受体酪氨酸磷酸化增加。这些结果表明，肝脏 NEU3 过度表达通过改变神经节苷脂成分和过氧化物酶体增殖物激活受体 γ 信号传导来改善胰岛素敏感性和葡萄糖耐量。我们的研究结果还进一步证明 NEU3 是胰岛素敏感性和葡萄糖耐量的重要调节因子。
Membrane microdomains rich in gangliosides are recognized as being critical for proper compartmentalization of insulin signaling. Plasma membrane–associated sialidase, NEU3, is a key enzyme for ganglioside hydrolysis. We previously reported that mice overexpressing NEU3 mainly in muscles developed severe insulin-resistant diabetes. To examine the possible contributions of NEU3 to in vivo insulin sensitivity and glucose tolerance, NEU3 was expressed by using adenoviral vectors in the livers of C57BL/6 mice on standard and high-fat diets, and insulin-resistant KKAy mice on standard diets. Hepatic NEU3 overexpression paradoxically improved glucose tolerance and insulin sensitivity in the C57BL/6 mice fed standard diets, and glucose tolerance in the C57BL/6 mice fed high-fat diets and in KKAy mice. Hepatic NEU3 overexpression increased hepatic glycogen deposition and triglyceride accumulation, and enhanced the hepatic peroxisome proliferator–activated receptor γ and fetuin expression in the C57BL/6 mice on standard and high-fat diets, and in KKAy mice. Thin-layer chromatographic analysis demonstrated increased levels of GM1 and markedly reduced GM3 in the livers of mice with hepatic NEU3 overexpression (NEU3 mice). Basal and insulin-stimulated tyrosine phosphorylations of insulin receptor substrate 1 were significantly increased, but tyrosine phosphorylations of the insulin receptor and insulin receptor substrate 2 in the NEU3 liver were unchanged. Insulin-stimulated tyrosine phosphorylations of the insulin receptor were increased in adipose tissues of NEU3 mice. These results suggest that hepatic NEU3 overexpression improves insulin sensitivity and glucose tolerance through modification of ganglioside composition and peroxisome proliferator–activated receptor γ signaling. Our findings also provide further evidence that NEU3 is an important regulator of insulin sensitivity and glucose tolerance.