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The regulatory mechanism of the arachidonate cascade controlling the differentiation and quality changes in in adipocytes

花生四烯酸级联控制脂肪细胞分化和质量变化的调控机制

基本信息

批准号：
14560099
负责人：
YOKOTA Kazushige
金额：
$ 2.18万
依托单位：
Shimane University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Adipocytes play a critical role in the control of the generation of obesity which is a well-known risk factor leading to the onset of life-style diseases. The obesity is characterized by the excess accumulation of fats through the increase in the number or the size of adipocytes. Recent studies suggested the involvement of the arachidoate cascade to generate eicosanoids, a group of lipid mediators, in the adipocytes and related cells. Some of these are effective to activate a nuclear receptor by acting as active ligands. In light of these advances, we planed to study the gene expression of the arachidonate cascade and the role of endogenous eicosanoids. We made use of mouse 3T3-L1 cells that can differentiate into the mature adipocytes in cell culture system to investigate the regulation of the expression of the arachidonate cyclooxygenase(COX) pathway leading to the formation of prostaglandin(PG)J_2 derivatives, which is a potent agonist of peroxisome proliferator-activated receptor γ in adipocytes. Through these studies, we clarified the specific gene expression patterns of isoforms of biosynthetic enzymes in the COX pathway. In addition, we found that distinct types of PGs were formed during the different stages of the life cycle of adipocytes. The related research led us to the specific roles of prostanoids in the apoptotic cell death and the differentiation of adipocytes. Moreover, we observed the effective actions of conjugated linolenic acid from bitter gourd seeds and abietic acid, a diterpene, as food-derived factors to regulate the life cycle of adipocytes. Separately, we identified the chemical structures of saponin derivatives generated during the food processing of horse chestnuts with wooden ashes, and were successful in finding anti-obese effects.

脂肪细胞在控制肥胖的产生中起关键作用，肥胖是导致生活方式疾病发作的众所周知的危险因素。肥胖症的特征在于通过脂肪细胞的数量或大小的增加而导致脂肪的过度积累。最近的研究表明，花生四烯酸级联反应参与了脂肪细胞和相关细胞中产生类花生酸（一组脂质介质）的过程。其中一些通过作为活性配体有效地激活核受体。鉴于这些进展，我们计划研究花生四烯酸级联反应的基因表达和内源性类花生酸的作用。本研究利用小鼠3 T3-L1脂肪细胞在体外培养体系中可分化为成熟脂肪细胞，研究脂肪细胞中过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ，PGR）的激动剂前列腺素（prostaglandin，PG）J_2衍生物对花生四烯酸环氧化酶（arachidonate cyclooxygenase，考克斯）途径表达的调控。通过这些研究，我们阐明了考克斯途径中生物合成酶亚型的特异性基因表达模式。此外，我们还发现在脂肪细胞生命周期的不同阶段形成了不同类型的PG。相关研究使我们认识到前列腺素类化合物在脂肪细胞凋亡和分化中的特殊作用。此外，我们观察了苦瓜籽共轭亚麻酸和松香酸，一种二萜，作为食物源性因子调节脂肪细胞的生命周期的有效作用。另外，我们鉴定了木灰栗子食品加工过程中产生的皂苷衍生物的化学结构，并成功地发现了抗肥胖作用。