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Discovery of Novel Adipocyte-Derived Factors and Their Pathological and Physiological Roles in Humans; Adipocentric Hypothesis in Molecular Basis for the Development of Common Diseases

新型脂肪细胞衍生因子的发现及其在人类中的病理和生理作用；

基本信息

批准号：
12307022
负责人：
MATSUZAWA Yuji
金额：
$ 25.72万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12307022/
关键词：
VISCERAL FAT ADIPOCYTOKINE ADIPONECTIN AQUAPORIN ADIPOSE

项目摘要

Ovemutrition and physical inactivity are the common basis for the development of common human diseases such as type 2 diabetes and atherosclerotic vascular diseases. Recent researches exploited that adipose tissue is not solely energy storage organ but also an endocrine organ to produce various bioactive substances named 'adipocytokines'. This project was designed to prove 'adipocentric hypothesis' that dysregulation of adipocytokines in visceral fat is responsible for the development of common diseases caused by overnutrition. Expression of Plasminogen activator inhibitor and heparin binding EGF-like growth factor were upregulated by accumulated visceral fat. Overproduction of these adipocytokines will lead thrombotic tendency and enhanced proliferation of vascular smooth muscle cells. In contrast, plasma concentration of adiponectin, which we discovered in human adipose cDNA project, was decreased in the subjects with visceral fat accumulation. Adiponectin exhibited anti-atherogenic and insulin sensitizing activities in vitro. Mice lacking adiponectin gene showed diet-induced insulin resistance and severe neointimal thickening against vascular injury. Humans carrying missense mutation in adiponectin gene showed markedly low plasma adiponectin levels and clinical phenotype of the metabolic syndrome. A series of these studies revealed that adipose tissue produces a self-defense molecule against diabetes and atherosclerotic diseases and hyposecretion of adiponectin in visceral fat accumulation plays a central role, at least in part, in the development of common diseases. This project provided evidences against 'adipocentric hypothesis'.

排卵和缺乏体力活动是2型糖尿病和动脉粥样硬化性血管疾病等人类常见疾病发展的共同基础。近年来的研究发现，脂肪组织不仅是一个能量储存器官，而且还是一个内分泌器官，能产生多种生物活性物质，称为脂肪细胞因子。该项目旨在证明“脂肪中心假说”，即内脏脂肪中脂肪细胞因子的失调是营养过剩引起的常见疾病的发展的原因。血浆纤溶酶原激活物抑制剂和肝素结合EGF样生长因子的表达上调积累内脏脂肪。这些脂肪细胞因子的过量产生会导致血栓形成倾向和血管平滑肌细胞增殖增强。相反，我们在人类脂肪cDNA项目中发现的脂联素的血浆浓度在内脏脂肪堆积的受试者中降低。脂联素在体外具有抗动脉粥样硬化和胰岛素增敏活性。脂联素基因缺失的小鼠表现出饮食诱导的胰岛素抵抗和严重的血管损伤的新生内膜增厚。携带脂联素基因错义突变的人血浆脂联素水平明显降低，代谢综合征的临床表型也明显降低。一系列的这些研究表明，脂肪组织产生的自我防御分子对糖尿病和动脉粥样硬化性疾病和分泌不足的脂联素在内脏脂肪积累起着核心作用，至少部分，在常见疾病的发展。本研究为“脂肪中心假说”提供了证据。