Novel regulators of fat cell differentiation

在澳大利亚，超重和肥胖的比例很普遍，这反映了发达国家和发展中国家的模式。主要原因似乎是能量不匹配，热量消耗过高。身体对过量营养供应的一种反应是脂肪组织中的能量储存，为了帮助这一点，身体还会产生新的脂肪组织，称为脂肪生成(在细胞中也称为脂肪细胞分化)。在许多体重超标的人中，脂肪组织异常，对化学胰岛素反应不佳，从而导致胰岛素抵抗。这种抵抗胰岛素的脂肪组织尤其存在于身体的中央(内脏)部位。与这种内脏脂肪相关的胰岛素抵抗容易导致糖尿病和心血管疾病的过早死亡。因此，了解脂肪组织是如何发育的，以及它可能如何导致胰岛素抵抗，对人类健康非常重要。脂肪中阻碍脂肪组织正常发育并导致胰岛素抵抗的因素之一是转化生长因子-(TGF-)。我们已经产生了新的数据显示，两种由转化生长因子-1增加的蛋白质，称为结缔组织生长因子(CTGF)和胰岛素样生长因子结合蛋白-3(IGFBP-3)，可以防止脂肪形成。我们已经在培养的细胞中证明了这一点，并发现在肥胖和胰岛素抵抗的动物模型中，内脏脂肪中CTGF和IGFBP-3的表达增加。我们的初步工作进一步表明，CTGF和IGFBP-3可能各自在脂肪细胞中发挥作用，以防止脂肪生成。这项建议将确定转化生长因子-3是否通过CTGF和IGFBP-3抑制脂肪生成，并将确定CTGF和IGFBP-3如何抑制脂肪细胞分化。培养中的细胞将被利用，饮食诱导肥胖和胰岛素抵抗的动物模型将有助于确定CTGF和IGFBP-3是否在体内阻止脂肪生成，进一步加深我们对异常脂肪组织如何发展的理解。

Overweight and obesity are at epidemic proportions in Australia, reflecting the pattern in the developed and developing world. The main cause appears to be an energy mismatch, with excessive caloric consumption. One response of the body to excessive nutrient supply is energy storage in fat tissue and to aid in this the body also generates new fat tissue, termed adipogenesis (also known in cells as fat cell differentiation). In many people who gain excess body weight, fat tissue is abnormal and does not respond well to the chemical insulin, thus causing insulin resistance. This insulin resistant fat tissue is especially present in a central body (visceral) site. Insulin resistance related to this visceral fat predisposes to both diabetes and premature death from cardiovascular disease. Understanding how fat tissue develops and how it might cause insulin resistance is thus important in human health. One of the factors in fat that prevents normal development of fat tissue and which induces insulin resistance is transforming growth factor- (TGF- ). We have generated new data showing that two proteins which are increased by TGF- , termed connective tissue growth factor (CTGF) and insulin like growth factor binding protein-3, (IGFBP-3), prevent adipogenesis. We have shown this in cultured cells, and have found that CTGF and IGFBP-3 are increased in visceral fat in animal models of obesity and insulin resistance. Our preliminary work has further indicated how CTGF and IGFBP-3 might each work in the fat cell to prevent adipogenesis. This proposal will determine if TGF- works through CTGF and IGFBP-3 to block adipogenesis, and it will define how CTGF and IGFBP-3 have their inhibitory effects on fat cell differentiation. Cells in culture will be utilised and an animal model of dietary induced obesity and insulin resistance will help to define whether CTGF and IGFBP-3 prevent adipogenesis in vivo, furthering our understanding in how abnormal fat tissue may develop.