| Project/Area Number |
13307033
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
NAKAO Kazuwa Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (00172263)
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| Co-Investigator(Kenkyū-buntansha) |
HOSODA Kiminori Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (40271598)
INOUE Gen Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (20260606)
OGAWA Yoshihiro Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (70291424)
HAYASHI Tatsuya Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (00314211)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥55,250,000 (Direct Cost: ¥42,500,000、Indirect Cost: ¥12,750,000)
Fiscal Year 2003: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000)
Fiscal Year 2002: ¥12,610,000 (Direct Cost: ¥9,700,000、Indirect Cost: ¥2,910,000)
Fiscal Year 2001: ¥29,900,000 (Direct Cost: ¥23,000,000、Indirect Cost: ¥6,900,000)
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| Keywords | leptin / obesity / melanocortin type 4 receptor / Lep Tg / hypothalamic-pituitary-adrenal axis / insulin-deficient or type 1-like diabetes / obesity-associated metabolic dysregulation / leptin resistance / 脂肪萎縮性糖尿病 / 糖代謝 / インスリン分泌低下型糖尿病 / 視床下部接触調節ペプチド / 中枢性エネルギー代謝調節 / 交感神経 / 副腎 / β交感神経 / 糖質コルチコイド / メラノコルチン / 視床下部 / MC4R |
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| Research Abstract |
In the past three years, we have mainly focused our attention on the molecular basis of the leptin receptor signaling in the pathophysiology of obesity and related metabolic disorders. Of note, we have successfully identified a novel homozygous mutation on the gene of melanocortin type 4 receptor (MC4R) in the early-onset, morbid obese woman. This is exactly the first report of MC4R mutant with severe adiposity in Japan. Furthermore, using transgenic skinny mice overexpressing leptin (Lep Tg) and A-ZIP transgenics, a representative mouse model for human lipodystrophy, we have revealed that both β-adrenergic activation and suppression of the hypothalamic-pituitary-adrenal axis strongly contribute to beneficial effect on glucose metabolism by leptin. Moreover, by use of Lep Tg, we have explored the therapeutic usefulness of leptin for the treatment of insulin-deficient or type 1-like diabetes. Data strongly suggested that leptin can ameliorate glucose dyshomeostasis via both insulin-sensitizing effect and anorectic effect, thus implicating coordinated role of leptin and insulin.
In centrally-mediated glucose metabolism. Our studies further highlight the importance of leptin signaling in the pathophysiology of obesity-associated metabolic dysregulation and provide evidence that therapeutic modalities which overcome the proposed leptin resistance should be powerful tools to treat such prevalent diseases.
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