Molero Juan C, Turner Nigel, Thien Christine B F, Langdon Wallace Y, James David E, Cooney Gregory J
Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.
Diabetes. 2006 Dec;55(12):3411-7. doi: 10.2337/db06-0955.
Casitas b-lineage lymphoma (c-Cbl) is a multiadaptor protein with E3-ubiquitin ligase activity residing within its RING finger domain. We have previously reported that c-Cbl-deficient mice exhibit elevated energy expenditure, reduced adiposity, and improved insulin action. In this study, we examined mice expressing c-Cbl protein with a loss-of-function mutation within the RING finger domain (c-Cbl(A/-) mice). Compared with control animals, c-Cbl(A/-) mice display a phenotype that includes reduced adiposity, despite greater food intake; reduced circulating insulin, leptin, and triglyceride levels; and improved glucose tolerance. c-Cbl(A/-) mice also display elevated oxygen consumption (13%) and are protected against high-fat diet-induced obesity and insulin resistance. Unlike c-Cbl(A/-) mice, mice expressing a mutant c-Cbl with the phosphatidylinositol (PI) 3-kinase binding domain ablated (c-Cbl(F/F) mice) exhibited an insulin sensitivity, body composition, and energy expenditure similar to that of wild-type animals. These results indicate that c-Cbl ubiquitin ligase activity, but not c-Cbl-dependent activation of PI 3-kinase, plays a key role in the regulation of whole-body energy metabolism.
Casitas B 系淋巴瘤（c-Cbl）是一种多接头蛋白，其RING指结构域具有E3泛素连接酶活性。我们之前报道过，c-Cbl基因缺陷小鼠表现出能量消耗增加、肥胖减轻以及胰岛素作用改善。在本研究中，我们检测了在RING指结构域带有功能丧失性突变的c-Cbl蛋白表达小鼠（c-Cbl(A/-)小鼠）。与对照动物相比，c-Cbl(A/-)小鼠表现出一种表型，包括尽管食物摄入量增加但肥胖减轻；循环胰岛素、瘦素和甘油三酯水平降低；以及糖耐量改善。c-Cbl(A/-)小鼠还表现出耗氧量增加（13%），并且对高脂饮食诱导的肥胖和胰岛素抵抗具有抵抗力。与c-Cbl(A/-)小鼠不同，表达磷脂酰肌醇（PI）3激酶结合结构域缺失的突变型c-Cbl的小鼠（c-Cbl(F/F)小鼠）表现出与野生型动物相似的胰岛素敏感性、身体组成和能量消耗。这些结果表明，c-Cbl泛素连接酶活性而非c-Cbl依赖的PI 3激酶激活在全身能量代谢调节中起关键作用。
