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

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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