Importance of obese gene product, leptin in physiological significance and application of therapeutics

肥胖基因产物瘦素的生理意义和治疗应用的重要性

• 批准号: 10557241
• 负责人: TOKUMITSU Yukiko
• 金额: $ 7.81万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557241/
• 关键词: Obese gene; Leptin; Rat adipocytes; 3T3-L1 adipocytes; Human obesity; 肥満; レプチン分泌; インスリン分泌; 脂肪細胞; TNF-α

We studied the regulation of plasma leptin concentration and the appearance of insulin resistance in obesity. The results were described below.(1) Wistar fatty rats used as a good model of NIDDM were increased the plasma levels of insulin, glucose, lipids, and obese gene product leptin. Especially, the levels of leptin and insulin were markedly increased at the early stage of obesity accompanied with the exclusive expression of ob gene mRNA in the adipocytes of fatty rats. Secretory patterns of leptin showed circadian rhythms, lowest secretion during daytime and highest elevation in midnight in lean rats, but did not show it in fatty rats. Plasma TNF-α concentration was also correlated with obesity and insulin resistance indicating the contribution to the development of NIDDM.(2) Human obese subjects were increased plasma levels of insulin, leptin, lipids and TNF-α showing the being accompanied by insulin resistance. Insulin resistance is associated with increase in insulin secretion to preserve normo-glysemia. On the other hand, leptin concentration was correlated closely with percentage body fat in human obesity. Fortunately, it was shown that control of food intake and exercise improve these abnormal conditions and decrease the body weight.(3) 3T3-L1 adipocytes differentiated by insulin/dexamethasone/IMBX secreted leptin. TNF-α prevented differentiation to adipocytes by inhibition of insulin action. Thiazolidinedione derivatives leading to the improvement of insulin sensitivity in human prevented the TNF-α action. These facts indicated that TNF-α induces insulin resistance and develops NIDDM and thiazolidinedione derivatives prevent the appearance of NIDDM.

我们研究了肥胖患者血浆瘦素浓度的调节和胰岛素抵抗的出现。结果如下所述。(1)Wistar肥胖大鼠可作为NIDDM的良好模型，其血浆胰岛素、血糖、血脂及肥胖基因产物瘦素水平升高。肥胖大鼠脂肪细胞中瘦素和胰岛素水平在肥胖早期明显升高，肥胖大鼠脂肪细胞中ob基因mRNA表达明显增加。瘦大鼠瘦素的分泌模式具有昼夜节律，白天最低，午夜最高，而肥胖大鼠则无此节律。血浆TNF-α浓度与肥胖和胰岛素抵抗相关，提示TNF-α参与了NIDDM的发生。(2)肥胖者血浆胰岛素、瘦素、血脂及TNF-α水平升高，提示肥胖者存在胰岛素抵抗。胰岛素抵抗与增加胰岛素分泌以保持正常血糖有关。另一方面，瘦素浓度与人体肥胖的体脂百分比密切相关。幸运的是，研究表明，控制食物摄入量和运动可以改善这些异常状况并降低体重。(3)胰岛素/地塞米松/IMBX诱导分化的3 T3-L1脂肪细胞分泌瘦素。TNF-α通过抑制胰岛素作用阻止向脂肪细胞的分化。噻唑烷二酮衍生物可改善人的胰岛素敏感性，阻止TNF-α的作用。这些事实表明TNF-α诱导胰岛素抵抗并发展为NIDDM，噻唑烷二酮衍生物可预防NIDDM的发生。

项目成果

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Sugimura A.: "Troglitazone suppresses cell growth of myeroid leukemia cell lines by induction of cyclin-dependent kinase inhibitor"Biochem Biophys Res Commun. 261. 833-837 (1999)

Sugimura A.：“曲格列酮通过诱导细胞周期蛋白依赖性激酶抑制剂抑制粒细胞白血病细胞系的细胞生长”Biochem Biophys Res Commun。

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Murakami T.et al: "Threshold-dependent DNA synthesis by pure pressure in human aortic smooth muscle cells: gialpha-dependent and -independent pathways." Biochem.Biophys.Res.Commun.256. 212-217 (1999)

Murakami T.等人：“人主动脉平滑肌细胞中纯压力下的阈值依赖性 DNA 合成：gialpha 依赖性和独立途径。”

Sugimura A et al.: "Troglitazone suppresses cell growth of myeroid leukemia cell lines by induction of cyclin-dependent kinase inhibitor."Biochem Biophys Res Commun. 261. 833-837 (1999)

Sugimura A 等人：“曲格列酮通过诱导细胞周期蛋白依赖性激酶抑制剂来抑制粒细胞白血病细胞系的细胞生长。”Biochem Biophys Res Commun。