Novel regulators of fat cell differentiation

超重和肥胖在澳大利亚是流行病，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，消耗过多的热量。身体对过量营养供给的一种反应是在脂肪组织中储存能量，为了达到这个目的，身体也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）。在许多体重增加过多的人身上，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。这种胰岛素抵抗性脂肪组织尤其存在于中央身体（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导致的过早死亡。因此，了解脂肪组织是如何形成的，以及它是如何引起胰岛素抵抗的，对人类健康非常重要。脂肪中阻止脂肪组织正常发育并诱导胰岛素抵抗的因子之一是转化生长因子- (TGF-)。我们获得的新数据显示，TGF-增加的两种蛋白质，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)，可以阻止脂肪形成。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，CTGF和IGFBP-3在内脏脂肪中增加。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起作用，以防止脂肪形成。本提案将确定TGF-是否通过CTGF和IGFBP-3阻断脂肪生成，并明确CTGF和IGFBP-3如何抑制脂肪细胞分化。利用培养细胞，建立饮食性肥胖和胰岛素抵抗的动物模型，将有助于确定CTGF和IGFBP-3是否能在体内阻止脂肪形成，从而进一步了解异常脂肪组织的形成机制。

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.