Elucidation of molecular mechanism of exocytosis in adipocytes

阐明脂肪细胞胞吐作用的分子机制

• 批准号: 15081206
• 负责人: HORIUCHI Hisanori
• 金额: $ 24.58万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15081206/
• 关键词: adipocytes; Ral; GLUT4; gene trap; adiponectin; AMPK; exocyst complex; GAP; インスリン; 開口放出; streptolysin-O; 脂肪滴; 分化因子; Rab; adiponectin; lipolysis; Munc13-4; グルコーストランスポータ4; エクソサイトーシス; ストレプトライシン-O; Rab27

By exocytosis, adipocytes release adiponectin and increase of surface expression of glucose transporter-4 (GLUT4) molecules. We have developed assays for evaluating GLUT4 translocation in 3T3 adipocytes and cardiac muscle cells and found that H_2O_2, an oxidative stress, induced GLUT4 translocation via AMP-dependent protein kinase (AMPK) pathway in cardiac muscle cells. The small GTPase Ral have been demonstrated to play an important role in the regulation of GLUT4 translocation in adipocytes. We have demonstarated that Ral regulates the granule secretion via its effector, the exocyst tethering factor complex, by enhancing the calcium-ion sensitivity of the exocytosis in our established granule secretion assay using permeabilized platelets. We then identified Ral GAPs, the inhibitory regulators for Ral, for the first time. We have generated mice lacking Ral GAPs. We are investigating their adipose tissue structures and their serum glucose levels in response to insulin. On the other hand, we have established a gene trap method for identification of adipocyte differentiation factors using retrovirus insertion-mediated random mutagenesis. With the method, we have identified several molecules including TG-interacting factor and enkepharin. Hypoadiponectinemia is a risk of atherosclerotic diseases. We have found that serum adiponectin levels are associated with higher motality in chronic heart failure patients.

通过胞吐作用，脂肪细胞释放脂联素并增加葡萄糖转运蛋白-4（GLUT 4）分子的表面表达。我们建立了3 T3脂肪细胞和心肌细胞GLUT 4转位的检测方法，发现H_2O_2通过AMP依赖性蛋白激酶（AMPK）途径诱导心肌细胞GLUT 4转位。已经证明小的GTfR α 1在脂肪细胞中GLUT 4易位的调节中起重要作用。我们已经证明，Ral调节颗粒分泌通过其效应器，外囊栓系因子复合物，通过提高钙离子敏感性的胞吐在我们建立的颗粒分泌测定使用透化血小板。然后，我们首次确定了Ral GAP，即Ral的抑制性调节剂。我们已经产生了缺乏Ral GAP的小鼠。我们正在研究他们的脂肪组织结构和他们的血清葡萄糖水平对胰岛素的反应。另一方面，我们已经建立了一个基因陷阱的方法来鉴定脂肪细胞分化因子使用逆转录病毒插入介导的随机突变。用这种方法，我们已经鉴定了几个分子，包括TG-相互作用因子和脑啡肽。低脂联素血症是动脉粥样硬化性疾病的危险因素。我们发现血清脂联素水平与慢性心力衰竭患者的高死亡率相关。

项目成果

Recent advance in antiplatelet therapy : mechanisms. evidence and approach to the problems. (a review)

抗血小板治疗的最新进展：机制。

• 发表时间: 2006
• 期刊: Ann Med 38
• 作者: 石橋 智子;ら;Horiuchi
• 通讯作者: Horiuchi

Primary cardiovascular event and serum lipid levels in elderly Japanese with hypercholesterolemia under 6-Year simvastatin treatment : A sub-analysis of the J-LIT Study.

接受 6 年辛伐他汀治疗的日本老年人高胆固醇血症的主要心血管事件和血清脂质水平：J-LIT 研究的子分析。

• 发表时间: 2004
• 期刊: J Am Geriatr Soc 52
• 作者: H. Horiuchi;et al.
• 通讯作者: et al.

Serotonin in adipose tissue acts as an autocrine factor required for adipocyte differentiation and lipolysis

脂肪组织中的血清素充当脂肪细胞分化和脂肪分解所需的自分泌因子

• 发表时间: 2007
• 作者: Ono K;et al
• 通讯作者: et al

Identification of genes required for adipocyte differentiation by retrovirus insertion-mediated random mutagenesis

通过逆转录病毒插入介导的随机诱变鉴定脂肪细胞分化所需的基因

• 发表时间: 2005
• 作者: K. Ono;Y. Abe;T Kawamura;A Shimatsu;T Morimoto;T Kita;K Hasegawa.
• 通讯作者: K Hasegawa.

Aspirin action on whole blood-aggregation evaluated by the screen filtration pressure method

通过筛滤压力法评估阿司匹林对全血聚集的作用

• 发表时间: 2008
• 期刊: Circ J 72
• 作者: A. Tabuchi;R. Taniguchi;K. Takahashi;H. Kondo;M. Kawato;T Morimoto;T. Kimura;T. Kita;H. Horiuchi
• 通讯作者: H. Horiuchi