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

色素上皮衍生因子（PEDF）在体重调节中的作用

• 批准号: 225914820
• 负责人: Professor Dr. Andreas L. Birkenfeld
• 金额: --
• 依托单位: Innere Medizin IV: Endokrinologie und Diabetologie, Angiologie, Nephrologie und Klinische Chemie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/225914820?language=en
• 关键词: Role; pigment; epithelium; derived; factor

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.

体重和脂肪质量的外周分子信号是维持体重的关键机制。除了瘦素之外，还描述了几种新的蛋白质，包括色素上皮衍生因子(PEDF)，它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，其转录和分泌似乎受到营养状态的调节，通过胰岛素和葡萄糖。在动物模型和人类中，全身PEDF水平与脂肪质量、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、脂肪和葡萄糖代谢的重要调节因子。为了支持这一假设，我们的初步数据显示，PEDF基因敲除(KO)小鼠中PEDF的丢失会导致全身脂肪质量和体重的增加，以及能量消耗的减少。此外，根据IPGTT的评估，8个月大的PEDF-KO小鼠与对照组小鼠相比存在严重的胰岛素抵抗。这一建议旨在确定PEDF调节其对能量分配和能量动态平衡的影响的机制。我们还将研究PEDF在瘦小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，在一种转换方法中，我们将测试肥胖人类在减肥后PEDF浓度的变化是否预示着随着时间的推移成功地保持体重。我们的发现可能确定基于PEDF的能量代谢调节的新概念，并确定治疗肥胖症和胰岛素抵抗的新药理学方法。