Probing of physiological significance of adipocyte-specific glycerol channel and its application to the treatment of diabetes mellitus.

脂肪细胞特异性甘油通道生理意义的探讨及其在糖尿病治疗中的应用。

• 批准号: 15390287
• 负责人: NAKAMURA Tadashi
• 金额: $ 7.55万
• 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: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390287/
• 关键词: aquaporin adipose; aquaporin 9; glycerol; diabetes mellitus; lipolysis; obesity; knockout mouse; glyconeogenesis; アクアポリンアディポース; PPARγ

Aquaporin adipose(AQPap), which we identified from human adipose tissue, is a glycerol channel in adipocyte (J Biol Chem 2000). The expression of this molecule increased in fasting, decreased in feeding and was inhibited by insulin (j Biol Chem 2001). We also demonstrated that there was a coordinated regulation of AQPap and aquaporin 9(AQP9), as a liver specific glycerol channel, through the inhibitory effect by insulin. However, the channel function was dysregulated in obese mice with insulin resistance, leading to glucose intorelance (Diabetes 2002).In the present study, we investigated glycerol and glucose metabolism in mice lacking AQPap and demonstrated that AQPap functions as a glycerol gateway molecule in vivo. AQPap knockout(KO) mice had lower plasma glycerol levels compared with wild-type(WT) mice but had normal plasma free fatty acid levels. The increase in plasma glycrol level in response to _-adrenergic agonist was severely impaired in KO mice. Epinephrin-stimulated glycerol secretion was also impaired in AQPap knockdown adipocytes. During prolonged fasting, plasma glycerol was elevated and the plasma glucose level was maintained in WT mice. In contrast, KO mice showed a disrupted increase of plasma glycerol and rapid reduction of plasma glucose during prolonged fasting. These findings suggest that the lack of effective glycerol transport from adipocytes by glycerol gateway molecule causes defective adaptation to prolonged fasting. (PNAS 2004).

脂质水通道蛋白（Aquaporin adipose, AQPap）是我们从人类脂肪组织中鉴定出的一种脂肪细胞中的甘油通道（J Biol Chem 2000）。该分子的表达在禁食时增加，在喂食时减少，并被胰岛素抑制（j Biol Chem 2001）。我们还证明了AQPap和水通道蛋白9（AQP9）作为肝脏特异性甘油通道，通过胰岛素的抑制作用协同调节。然而，在胰岛素抵抗的肥胖小鼠中，通道功能失调，导致葡萄糖不耐受（Diabetes 2002）。在本研究中，我们研究了缺乏AQPap的小鼠的甘油和葡萄糖代谢，并证明AQPap在体内作为甘油门户分子发挥作用。AQPap基因敲除（KO）小鼠的血浆甘油水平低于野生型（WT）小鼠，但血浆游离脂肪酸水平正常。在KO小鼠中，肾上腺素能激动剂引起的血浆丙二醇水平升高受到严重损害。肾上腺素刺激的甘油分泌也在AQPap敲低脂肪细胞中受损。在长时间禁食期间，WT小鼠血浆甘油水平升高，血浆葡萄糖水平维持不变。相比之下，KO小鼠在长时间禁食期间表现出血浆甘油的中断增加和血浆葡萄糖的快速降低。这些发现表明，脂肪细胞通过甘油通道分子缺乏有效的甘油运输导致对长时间禁食的适应缺陷。2004年《美国科学院学报》(PNAS)。

项目成果

Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease

• DOI: 10.1016/j.jacc.2003.10.049
• 发表时间: 2004-04-07
• 期刊: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
• 影响因子: 24
• 作者: Ohashi, K;Ouchi, N;Matsuzawa, Y
• 通讯作者: Matsuzawa, Y

Association of hypoadiponectinemia with coronary artery disease in men

• DOI: 10.1161/01.atv.0000048856.22331.50
• 发表时间: 2003-01-01
• 期刊: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
• 影响因子: 8.7
• 作者: Kumada, M;Kihara, S;Matsuzawa, Y
• 通讯作者: Matsuzawa, Y

Ouchi N, et al.: "Reciprocal association of C-reactive protein with adiponectin in bloodstream and adipose tissue"Circulation. 107・5. 671-674 (2003)

Ouchi N 等：“血液和脂肪组织中 C 反应蛋白与脂联素的相互关联”循环 107・5。

Association of hypoadiponectinemia with impaired vasoreactivity

• DOI: 10.1161/01.hyp.0000083488.67550.b8
• 发表时间: 2003-09-01
• 期刊: HYPERTENSION
• 影响因子: 8.3
• 作者: Ouchi, N;Ohishi, M;Matsuzawa, Y
• 通讯作者: Matsuzawa, Y

Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue

• DOI: 10.1161/01.cir.0000055188.83694.b3
• 发表时间: 2003-02-11
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Ouchi, N;Kihara, S;Matsuzawa, Y
• 通讯作者: Matsuzawa, Y