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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.

在过去的三年里，我们主要集中在我们的注意力在肥胖和相关代谢紊乱的病理生理学的瘦素受体信号转导的分子基础。值得注意的是，我们已经成功地确定了一个新的纯合突变的黑皮质素4型受体（MC 4 R）的基因在早发性，病态肥胖的妇女。这是日本首次报道MC 4 R突变型严重肥胖症。此外，使用过表达瘦素的转基因瘦小鼠（Lep Tg）和A-ZIP转基因小鼠（人类脂肪代谢障碍的代表性小鼠模型），我们已经揭示了β-肾上腺素能激活和下丘脑-垂体-肾上腺轴的抑制强烈地有助于瘦素对葡萄糖代谢的有益作用。此外，通过使用Lep Tg，我们已经探索了瘦素用于治疗胰岛素缺乏或1型样糖尿病的治疗有用性。提示瘦素可通过胰岛素增敏作用和减食欲作用改善糖代谢紊乱，提示瘦素与胰岛素在中枢介导的糖代谢中具有协同作用。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，并提供了证据表明，克服瘦素抵抗的治疗方式应该是治疗这种流行疾病的有力工具。