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ELUCIDATION OF SIGNIFICANCE OF UCP3 IN DIABETES AND OBESITY USING TRANSGENIC MICE

使用转基因小鼠阐明 UCP3 在糖尿病和肥胖症中的意义

基本信息

批准号：
12671110
负责人：
HOSODA Kiminori
金额：
$ 1.92万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671110/
关键词：
obesity diabetes UCP energy metabolism energy consumption 脱共役蛋白質3 骨格筋

项目摘要

Energy metabolism consists of food intake and energy consumption. Its imbalance leads to diabetes and obesity. Skeletal muscle is one of the vital organs of energy metabolism. Although approximately 40 % of energy consumption of whole body is explained by that of skeletal muscle, the detail of molecular mechanism remains to be elucidated. We identified uncoupling protein 3 (UCP3), which is highly expressed in the skeletal muscle. In the present study, we elucidated regulatory mechanism of UCP3 gene expression, and functional significance of UCP3 using skeletal muscle-specific UCP3-overexpressed transgenic mice.UCP3 gene expression is increased in the skeletal muscle in vivo by fatty acid. Since fatty acid is an agonist for peroxisome Proliferator-Activated Receptor (PPAR), PPAR appears to be involved in the regulation of UCP gene expression. In the present study, we demonstrated that UCP3 gene expression is increased in L6 cultured cell line of skeletal muscle not by agonists for PPARα … More or PPARγ but by PPARδ agonist, L-165041, and that major PPAR in L6 cells is PPARδ, indicating that UCP3 gene expression is regulated via PPARδ. Since major PPAR in skeletal muscle in vivo is PPARδ, PPARδ is involved in the regulation ofUCP3 gene expression in the skeletal muscle in vivo.We created skeletal muscle-specific UCP3-overexpressed transgenic mice. UCP3 is expressed in the skeletal muscle of transgenic mice at 18 fold levels in mRNA and 15 fold levels in protein of the line with the highest expression. Under normal chow, the transgenic mice show no obvious phenotype as compared with control mice. Under high fat diet, the body weight of the transgenic mice is approximately 15 % less than that of control mice. The weight of epididymal white adipose tissue is approximately 20 % less than that of control mice. Since there is no significant difference in weight of other tissues, the significant reduction of body weight appears to be due to the decrease of weight of white adipose tissue. Although there is no significant difference in food intake and in body temperature, oxygen consumption is approximately 25 % increased in the transgenic mice as compared with control mice, indicating that the reduction of body weight is due to increase of energy consumption. Glucose tolerance is improved in the transgenic mice as compared with control mice. There is no obvious phenotype it blood profile of sugar and lipid and in histology. These results indicate that under high-fat food, increase of energy consumption and decrease of body weight are caused by increase of UCP3 gene expression within physiologica range. Since the induction of UCP3 gene expression as such can be attainable by pharmacologic agents, the present study suggests clinical application of UCP3 for treatment of obesity and diabetes. Less

能量代谢包括食物摄入和能量消耗。它的失衡会导致糖尿病和肥胖。骨骼肌是人体能量代谢的重要器官之一。虽然骨骼肌的能量消耗约占全身能量消耗的40%，但其分子机制的细节仍有待阐明。我们发现了解偶联蛋白3 (UCP3)，它在骨骼肌中高度表达。在本研究中，我们利用骨骼肌特异性过表达UCP3的转基因小鼠，阐明了UCP3基因表达的调控机制，以及UCP3的功能意义。体内脂肪酸可增加骨骼肌中UCP3基因的表达。由于脂肪酸是过氧化物酶体增殖物激活受体（PPAR）的激动剂，PPAR似乎参与了UCP基因表达的调控。在本研究中，我们发现UCP3基因在L6培养的骨骼肌细胞系中表达的增加不是由PPARα…More或PPARγ激动剂引起的，而是由PPARδ激动剂L-165041引起的，并且L6细胞中主要的PPAR是PPARδ，表明UCP3基因的表达是通过PPARδ调节的。由于体内骨骼肌中主要的PPAR是PPARδ，因此PPARδ参与体内骨骼肌中ucp3基因表达的调控。我们创建了骨骼肌特异性ucp3过表达转基因小鼠。UCP3在转基因小鼠骨骼肌中mRNA表达量为18倍，蛋白表达量为最高系的15倍。正常饲料条件下，转基因小鼠与对照小鼠相比无明显表型。在高脂肪饮食条件下，转基因小鼠的体重比对照小鼠约减少15%。附睾白色脂肪组织重量较对照组减轻约20%。由于其他组织的重量没有显著差异，体重的显著减少似乎是由于白色脂肪组织的重量减少。虽然在食物摄入量和体温上没有显著差异，但与对照组相比，转基因小鼠的耗氧量增加了约25%，说明体重的减轻是由于能量消耗的增加。与对照小鼠相比，转基因小鼠的糖耐量得到改善。血糖、血脂及组织学无明显表型。上述结果表明，在生理范围内，高脂肪食物下能量消耗的增加和体重的下降是由UCP3基因表达的增加引起的。由于UCP3基因表达的诱导可以通过药物实现，因此本研究建议UCP3用于治疗肥胖和糖尿病的临床应用。少