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，我们主要将注意力集中在肥胖和相关代谢性疾病的病理生理学中瘦素受体信号传导的分子基础上。值得注意的是，我们已经成功地确定了一种新型黑色皮质素4型受体（MC4R）的新型纯合突变，早期发病的病态肥胖女人。这正是日本有严重肥胖的MC4R突变体的第一份报告。此外，使用过表达瘦素的转基因瘦小鼠（LEP TG）和A-ZIP Transformics是人脂肪营养不良的代表性小鼠模型，我们揭示了β-肾上腺素激活和抑制下丘脑 - 肾上腺肾上腺轴轴对Glucose glucose glucose lectabolism a inspiencim a inspitrip-肾上腺轴对有益的作用。此外，通过使用LEP TG，我们探索了瘦素在治疗缺乏胰岛素或1型糖尿病方面的治疗用途。数据强烈表明，瘦素可以通过胰岛素敏化作用和厌食作用来改善葡萄糖dyshomeostasis，从而在中心介导的葡萄糖代谢。我们的研究进一步强调了瘦素信号传导在与肥胖相关的代谢失调的病理生理学中的重要性，并提供了证据表明，克服拟议瘦素耐药性的治疗方法应该是治疗这种普遍疾病的强大工具。