Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Science, Tokyo University of Science, Chiba, Japan.
Department of Nutrition and Food Science, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan.
FEBS Open Bio. 2023 Jun;13(6):1086-1094. doi: 10.1002/2211-5463.13610. Epub 2023 Apr 20.
Obesity is a metabolic disorder associated with many diseases. WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a HECT-type E3 ubiquitin ligase involved in several diseases. Recently, we found that the level of WWP1 is increased in white adipose tissue in a mouse model of obesity and that obese Wwp1 knockout (KO) mice exhibit improved whole-body glucose metabolism. Here, to determine which insulin-sensitive tissues contribute to this phenotype, we investigated the levels of several insulin signaling markers in white adipose tissue, liver, and skeletal muscle of Wwp1 KO mice, which were fed a normal or high-fat diet and transiently treated with insulin. In obese Wwp1 KO mice, phosphorylated Akt levels were increased in the liver but not in white adipose tissue or skeletal muscle. Moreover, the weight and triglyceride content of the liver of obese Wwp1 KO mice were decreased. These results suggest that systemic deletion of WWP1 improves glucose metabolism via enhanced hepatic insulin signaling and suppressed hepatic fat accumulation. In summary, WWP1 participates in obesity-related metabolic dysfunction and pathologies related to hepatic steatosis via suppressed insulin signaling.
肥胖是一种与许多疾病相关的代谢紊乱。WW 结构域包含 E3 泛素蛋白连接酶 1（WWP1）是一种参与多种疾病的 HECT 型 E3 泛素连接酶。最近，我们发现肥胖小鼠模型的白色脂肪组织中 WWP1 水平升高，肥胖的 Wwp1 敲除（KO）小鼠表现出改善的全身葡萄糖代谢。在这里，为了确定哪些胰岛素敏感组织有助于这种表型，我们研究了正常或高脂肪饮食喂养和短暂胰岛素处理的 Wwp1 KO 小鼠的白色脂肪组织、肝脏和骨骼肌中的几种胰岛素信号标志物的水平。在肥胖的 Wwp1 KO 小鼠中，肝脏中磷酸化 Akt 水平增加，但白色脂肪组织或骨骼肌中没有增加。此外，肥胖的 Wwp1 KO 小鼠的肝脏重量和甘油三酯含量降低。这些结果表明，WWP1 通过增强的肝胰岛素信号和抑制的肝脂肪积累改善葡萄糖代谢。总之，WWP1 通过抑制胰岛素信号参与肥胖相关的代谢功能障碍和与肝脂肪变性相关的病理。
