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Molecular Basis of Centrally-controled Energy Homeostasis -Focusing on Leptin Resistance-

中央控制能量稳态的分子基础 - 关注瘦素抵抗 -

基本信息

批准号：
13307033
负责人：
NAKAO Kazuwa
金额：
$ 35.36万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

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.

在过去的三年中，我们主要关注瘦素受体信号传导在肥胖和相关代谢紊乱的病理生理学中的分子基础。值得注意的是，我们已经成功地在早发病态肥胖女性的黑皮质素 4 型受体 (MC4R) 基因上发现了一种新的纯合突变。这正是日本首次报道MC4R突变体导致严重肥胖。此外，使用过度表达瘦素（Lep Tg）的转基因瘦小鼠和A-ZIP转基因（人类脂肪营养不良的代表性小鼠模型），我们发现β-肾上腺素能激活和下丘脑-垂体-肾上腺轴的抑制都强烈有助于瘦素对葡萄糖代谢的有益影响。此外，通过使用 Lep Tg，我们探索了瘦素在治疗胰岛素缺乏或 1 型糖尿病中的治疗作用。数据强烈表明，瘦素可以通过胰岛素增敏作用和厌食作用改善葡萄糖稳态失衡，从而暗示瘦素和胰岛素在中枢介导的葡萄糖代谢中的协调作用。我们的研究进一步强调了瘦素信号传导在肥胖相关代谢失调的病理生理学中的重要性，并提供了证据，证明克服所提出的瘦素抵抗的治疗方式应该是治疗此类流行疾病的有力工具。