Role of pigment epithelium derived factor (PEDF) in the regulation of body weight

体重和脂肪量的外周分子信号是维持体重的关键机制。除了瘦素之外，已经描述了一对新的蛋白质，包括色素上皮衍生因子（PEDF），其是一种分泌的多效性糖蛋白，具有神经保护、抗血管生成和抗癌症生成特性。该蛋白质主要在脂肪组织和肝脏中合成，其转录和分泌似乎通过胰岛素和葡萄糖受营养状态调节。在动物模型和人类中，全身PEDF水平与脂肪量、肥胖程度和胰岛素抵抗呈正相关。因此，我们假设PEDF本身是体重、脂质和葡萄糖代谢的重要调节剂。为了支持这一假设，我们的初步数据显示，PEDF敲除（KO）小鼠中PEDF的损失导致全身脂肪量和体重增加以及能量消耗减少。此外，如用IPGTT评估的，与对照小鼠相比，8个月大的PEDF-KO小鼠是严重胰岛素抵抗的。该建议旨在确定PEDF介导其对能量分配和能量稳态的影响的机制。我们还将研究PEDF在瘦小鼠和肥胖小鼠中的慢性过度表达是否反映了PEDF缺乏对小鼠的影响。最后，在一个翻译的方法，我们将测试，如果在PEDF浓度的变化在肥胖的人体重减轻后预测成功的体重维持随着时间的推移。我们的研究结果可能会确定新的PEDF为基础的概念，在调节能量代谢和精确的新的药理学方法治疗肥胖和胰岛素抵抗。

Peripheral molecular signals of body weight and fat mass are key mechanisms for body weight maintenance. Besides leptin a couple of new proteins have been described including Pigment epithelium derived factor (PEDF), which is a secreted pleiotropic glycoprotein with neuroprotective, anti-angiogenic and anti-cancerogenic properties. The protein is predominantly synthesized in adipose tissue and the liver, and its transcription and secretion seems to be regulated by the nutritional state via insulin and glucose. Systemic PEDF levels positively correlate with fat mass, the degree of obesity, and insulin resistance in animal models and humans. We therefore hypothesize that PEDF itself is an important regulator of body weight, lipid and glucose metabolism. In support of this hypothesis, our preliminary data show that loss of PEDF in PEDF- knock out (KO) mice leads to an increase in whole body fat mass and body weight and reduced energy expenditure. Moreover, 8 months old PEDF-KO mice were severely insulin resistant compared to control mice, as assessed with an IPGTT. This proposal is aimed at determining the mechanisms through which PEDF mediates its effects on energy partitioning and energy homeostasis. We will also investigate whether chronic over-expression of PEDF in lean and obese mice mirrors the effects of PEDF deficiency in mice. Finally, in a translational approach, we will test if changes in PEDF concentrations in obese humans after weight loss are predictive of successful body weight maintenance over time. Our findings might identify new PEDF based concepts in the regulation of energy metabolism and pinpoint novel pharmacological approaches for the treatment of obesity and insulin resistance.