Discovery of adipose specific glycerol channel and its application to obesity therapy

脂肪特异性甘油通道的发现及其在肥胖治疗中的应用

• 批准号: 12557090
• 负责人: MATSUZAWA Yuji
• 金额: $ 7.81万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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/en/grant/KAKENHI-PROJECT-12557090/
• 关键词: visceral fat; aquaporin adipose; glycerol; insulin resistance; 肥満; グリセロール

Aquaporin adipose is a fat-specific glycerol channel.We identified the PPRE (peroxisome proliferator response element) in the promoter region of the mouse AQPap gene. Binding and activation of PPARγ (peroxisome proliferator activated receptor_γ) to this element was suggested to explain the fat-specific expression of AQPap mRNA.AQPap gene expression was negatively regulated by insulin in vivo and in tissue cultures. In the analysis of AQPap promoter, we showed there was an insulin negative response element composed of seven nucleotides.In the search of genetic mutations of AQPap in 160 human subjects, we found three types of missense mutation (R12C, V59L, G264V) and two types of silent mutations (A103A, Q250G). By the functional analysis, the G264V-type AQPap was not capable of transporting glycerol using the xenopus oocyte system. The homozygous subject for G264V AQPap failed to raise the concentrations of plasma glycerol in response to vigorous exercise, while there was an equivalent serge of plasma adrenalin, which suggested that the AQPap is mediating the glycerol release from fat by exercise in human.We are now investigating the phenotypes of AQPap knockout mice to clarify the physiological significance of AQPap and glycerol metabolism in whole body.

脂肪水通道蛋白是一种脂肪特异性甘油通道，我们在小鼠AQPap基因启动子区发现了过氧化物酶体增殖反应元件（PPRE）。AQPap mRNA的脂肪特异性表达可能与过氧化物酶体增殖物激活受体γ（peroxisome proliferator activated receptor γ，PPAR γ）的结合和激活有关。对160例健康人AQPap基因突变进行了研究，发现3种错义突变（R12C，V59L，G264V）和2种沉默突变（A103A，Q250G）。通过功能分析，G264V型AQPap不能利用爪蟾卵母细胞系统转运甘油。G264 V AQPap纯合受试者在剧烈运动时未能提高血浆甘油浓度，而血浆肾上腺素则出现相当的分泌，这表明AQPap正在介导人体运动时脂肪中的甘油释放。我们正在研究AQPap基因敲除小鼠的表型，以阐明AQPap和全身甘油代谢的生理意义。

项目成果

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Zhu Q,Yamagata K,Yu L,Tomura H,Hanafusa T,Matsuzawa Y. et al: "Identification of missense mutations in the hepatocyte nuclear factor-3beta gene in Japanese subjects with late-onset Type II diabetes mellitus."Diabetologia.. 43. 1197-1200 (2000)

Zhu Q、Yamagata K、Yu L、Tomura H、Hanafusa T、Matsuzawa Y. 等人：“日本迟发性 II 型糖尿病受试者肝细胞核因子 3β 基因错义突变的鉴定。”Diabetologia..

Hirano K,Matsuura F,Tsukamoto K,Matsuzawa Y et al: "Decreased expression of a member of the Rho GTPasc family, Cdc42Hs, in cells from Tangier disease-the small G protein may play a role in cholesterol efflux."FEBS Lett.. 484. 275-279 (2000)

Hirano K、Matsuura F、Tsukamoto K、Matsuzawa Y 等人：“丹吉尔病细胞中 Rho GTPasc 家族成员 Cdc42Hs 的表达减少，小 G 蛋白可能在胆固醇流出中发挥作用。”FEBS Lett。

Imagawa A,Hanafusa T,Miyagawa J,Matsuzawa Y.: "A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies."N Engl J Med.. 342. 301-307 (2000)

Imakawa A、Hanafusa T、Miyakawa J、Matsuzawa Y.：“1 型糖尿病的一种新亚型，其特征是快速发病且缺乏糖尿病相关抗体。”N Engl J Med.. 342. 301-307 (2000

Kishida K et al.: "Aquaporin adipose, a putative glycerol channel in adipocytes"J. Biol. Chem.. 275. 20896-20902 (2000)

Kishida K 等人：“水通道蛋白脂肪，脂肪细胞中假定的甘油通道”J.