Elucidation of molecular mechanism of leptin resistance, using transgenic mice over-expressing leptin

利用过表达瘦素的转基因小鼠阐明瘦素抵抗的分子机制

• 批准号: 12671079
• 负责人: INOUE Gen
• 金额: $ 2.11万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671079/
• 关键词: leptin resistance; high fat diet; hypothalamic feeding behavior regulating neuropeptides; transgenic mice; energy expenditure

Clinical trial of recombinant leptin for the treatment of obesity is on going in the United States. However, it has been reported that the efficacy of leptin treatment by the peripheral administration is quite limited, probably because the most obese people may be in a leptin-resistant state. Recently, we developed transgenic mice over-expressing leptin, which have high sensitivity to leptin, despite an increased concentration of serum leptin comparable to that in obese people. In this project, we explored the pathogenic mechanism of leptin resistance by high fat meal using the transgenic mice and ob/ob mice, because we found that the transgenic mice also became obese by the load of high fat meal. However, we found that the induction of obesity by the high fat meal load was comparable in mice with different concentrations of serum leptin. Therefore, it is the most likely that leptin is neutral in the induction of obesity by high fat meal.

重组瘦素治疗肥胖症的临床试验正在美国进行。然而，据报道，通过外周给药的瘦素治疗的功效是相当有限的，这可能是因为最肥胖的人可能处于瘦素抵抗状态。最近，我们开发了过表达瘦素的转基因小鼠，尽管血清瘦素浓度增加，但其对瘦素具有高敏感性。本课题利用转基因小鼠和ob/ob小鼠探讨了高脂膳食导致瘦素抵抗的致病机制，因为我们发现转基因小鼠也会因高脂膳食的负荷而变得肥胖。然而，我们发现，诱导肥胖的高脂肪膳食负荷是可比的小鼠与不同浓度的血清瘦素。因此，瘦素在高脂膳食诱导肥胖中最有可能是中性的。

项目成果

Yura S, et al.: "Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin"J Clin. Invest.. 105(6). 749-755 (2000)

Yura S 等人：“过度表达瘦素的雌性转基因瘦小鼠加速青春期和迟发性下丘脑性腺功能减退症”J Clin。

黄 真, 井上 元: "インスリン抵抗性症候群"糖尿病の治療と看護. (in press). (2002)

Shin Huang，Gen Inoue：“胰岛素抵抗综合征”糖尿病治疗和护理（印刷中）。

C. Son, K. Hosoda, J. Matsuda, J. Fujikura, S. Yonemitsu, H. Iwakura, H. Masuzaki, Y. Ogawa, T. Hayashi, H. Itoh, H. Nishimura, G. Inoue, Y. Yoshimasa, Y. Yamori, K. Nakao: "Up-regulation of uncoupling protein 3 gene expression by fatty acids and agonists

C. Son、K. Hosoda、J. Matsuda、J. Fujikura、S. Yonemitsu、H. Iwakura、H. Masuzaki、Y. Okawa、T. Hayashi、H. Itoh、H. Nishimura、G. Inoue、Y.

Inoue G, et al.: "Simultaneous onset of type I diabetes mellitus and painless thyroiditis following acute pancreatitis"Intern. Med.. 40(6). 515-518 (2001)

Inoue G等人：“急性胰腺炎后I型糖尿病和无痛性甲状腺炎同时发作”实习生。

Yura S, Ogawa Y, Sagawa N, Masuzaki H, Itoh H, Ebihara K, Aizawa-Abe M, Fujii S, Nakao K.: "Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin"J Clin Ihvest.. 105 : 6. 749-755 (2000)

Yura S、Okawa Y、Sakawa N、Masuzaki H、Itoh H、Ebihara K、Aizawa-Abe M、Fujii S、Nakao K.：“过度表达瘦素的雌性转基因瘦小鼠加速青春期和迟发性下丘脑性腺功能减退症”J Clin Ihvest