| Project/Area Number |
16300216
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Sports science
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| Research Institution | National Institute of Health and Nutrition |
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Principal Investigator |
EZAKI Osamu National Institute of Health and Nutrition, Division of Clinical Nutrition, Division Director, 生活習慣病研究部, 部長 (90191923)
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| Co-Investigator(Kenkyū-buntansha) |
MIURA Shinji National Institute of Health and Nutrition, Chief researcher, 生活習慣病研究部, 主任研究員 (10342932)
KAMEI Yasutomi Tokyo Medical and Dental University, Medical Research Institute, Department of Molecular Medicine and Metabolism, Assistant professor, 難治疾患研究所分子代謝医学分野, 助教授 (70300829)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 2005: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2004: ¥10,400,000 (Direct Cost: ¥10,400,000)
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| Keywords | INSULIN RESITANCE / GLUT4 / EXERCISE / HIGH-FAT DIET / TRANSGENIC MICE / SKELETAL MUSCLE / ADIPOSE TISSUE / 運動 / 肥満 / 生活習慣病 |
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| Research Abstract |
It is known that the occurrence of diabetes mellitus can be completely prevented in high-fat diet and db/db mice by doubling the amount of GLUT4 in muscle tissues. Indeed, regular exercise training increased GLUT4 amount in skeletal muscles and prevented development of diabetes mellitus. We are therefore studying molecular mechanisms for exercise-mediated prevention of diabetes mellitus in relation to GLUT4 regulation.
Previous studies demonstrated that an adipose tissue specific element(s) (ASE) of the murine GLUT4 gene is located between -551 and -506 in the 5'-flanking sequence and that a high-fat responsive element(s) (HFRE) for down-regulation of the GLUT4 gene is located between bases -701 and -552. A binding site for nuclear factor 1 (NF1), that mediates insulin and cAMP-induced repression of GLUT4 in 3T3-L1 adipocytes is located between bases -700 and -688. To examine the role of NF1 in the regulation of GLUT4 gene expression in white adipose tissues (WAT) in vivo, we created two types of transgenic mice harboring mutated either 5' or 3' half-site of NF1 binding sites in GLUT4 minigene constructs. In both cases, the GLUT4 minigene was not expressed in WAT, while expression was maintained in brown adipose tissue, skeletal muscle, and heart. This was an unexpected finding, since a -551 GLUT4 minigene that did not have the NF1 binding site, was expressed in WAT. We propose a model that explains the requirement for both the ASE and the NF1 binding site for expression of GLUT4 in WAT.
In addition, we created of transgenic mice harboring MEF2 binding sites in GLUT4 minigene constructs. In these transgenic mice, the GLUT4 minigene was not expressed in heart, while expression was lower but maintained in brown adipose tissue, skeletal muscle, and WAT. MEF 2 binding site is necessary for GLUT4 expression in heart.
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