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

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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'.