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

营养过剩和缺乏运动是2型糖尿病和动脉粥样硬化性血管疾病等常见人类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，也是一个内分泌器官，可以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导致营养过剩引起的常见疾病的原因。血浆纤溶酶原激活物抑制剂和肝素结合egf样生长因子的表达因内脏脂肪的积累而上调。这些脂肪细胞因子的过量产生将导致血栓形成倾向和血管平滑肌细胞的增殖增强。相比之下，我们在人类脂肪cDNA项目中发现的血浆脂联素浓度在内脏脂肪堆积的受试者中下降。脂联素在体外具有抗动脉粥样硬化和胰岛素增敏活性。缺乏脂联素基因的小鼠表现出饮食诱导的胰岛素抵抗和严重的血管内膜增厚。携带脂联素基因错义突变的人血浆脂联素水平明显降低，临床表现为代谢综合征。一系列研究表明，脂肪组织产生一种防御糖尿病和动脉粥样硬化疾病的自卫分子，而内脏脂肪堆积中脂联素分泌不足在常见疾病的发生中起着核心作用，至少在一定程度上起着核心作用。该项目为反驳“脂肪中心假说”提供了证据。

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'.