Casitas b-lineage lymphoma-deficient mice are protected against high-fat died-induced obesity and insulin resistance
Casitas b-lineage lymphoma-deficient mice are protected against high-fat died-induced obesity and insulin resistance
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DOI：
10.2337/diabetes.55.03.06.db05-0312
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发表时间：
2006-03-01
期刊：
影响因子：
7.7
通讯作者：
James, DE
中科院分区：
文献类型：
--
作者：
Molero, JC;Waring, SG;James, DE
Casitas b系淋巴瘤（c-Cbl）是一种具有E3-泛素连接酶活性的多接头蛋白，参与调节受体酪氨酸激酶的降解。我们最近报道，c-Cbl（-/-）小鼠表现出瘦的表型和增强的外周胰岛素作用可能是由于能量消耗增加。在这里报道的研究中，我们检查了高脂肪饮食对这些动物能量稳态和葡萄糖代谢的影响。当c-Cbl（-/-）小鼠喂食高脂肪饮食4周时，与喂食相同饮食的野生型动物相比，它们保持了摄食过多，全身耗氧量更高（27%），活动量更大（3倍）。此外，参与线粒体脂肪氧化和乙酰辅酶A羧化酶磷酸化的几种酶的活性显着增加，在高脂肪喂养的c-Cbl缺陷小鼠的肌肉，表明在这些动物的脂肪氧化能力更大。由于这些差异，脂肪喂养的c-Cbl（-/-）小鼠比野生型动物瘦30%，并防止高脂肪饮食诱导的胰岛素抵抗。这些研究与c-Cbl在调节骨骼肌营养分配中的作用一致，并强调了c-Cbl作为治疗肥胖和2型糖尿病的治疗靶点的潜力。
Casitas b-lineage lymphoma (c-Cbl) is a multiadaptor protein with E3-ubiquitin ligase activity involved in regulating the degradation of receptor tyrosine kinases. We have recently reported that c-Cbl(-/-) mice exhibit a lean phenotype and enhanced peripheral insulin action likely due to elevated energy expenditure. In the study reported here, we examined the effect of a high-fat diet on energy homeostasis and glucose metabolism in these animals. When c-Cbl(-/-) mice were fed a high-fat diet for 4 weeks, they maintained hyperphagia, higher whole-body oxygen consumption (27%), and greater activity (threefold) compared with wild-type animals fed the same diet. In addition, the activity of several enzymes involved in mitochondrial fat oxidation and the phosphorylation of acetyl CoA carboxylase was significantly increased in muscle of high-fat-fed c-Cbl-deficient mice, indicating a greater capacity for fat oxidation in these animals. As a result of these differences, fat-fed c-Cbl(-/-) mice were 30% leaner than wild-type animals and were protected against high-fat diet-induced insulin resistance. These studies are consistent with a role for c-Cbl in regulating nutrient partitioning in skeletal muscle and emphasize the potential of c-Cbl as a therapeutic target in the treatment of obesity and type 2 diabetes.