Role of Lipoprotein Receptors in Diet-induced Obesity and Diabetes

描述（由申请人提供）：LDL受体家族蛋白在脂质代谢和预防心血管和阿尔茨海默病中的重要性在文献中得到了很好的证实。然而，这些受体功能在调节对饮食引起的肥胖和肥胖相关糖尿病的敏感性方面的重要性尚未得到探讨。本项目将重点研究LDL受体家族蛋白中VLDL受体（VLDLR）和LDL受体相关蛋白LRP-1在饮食性肥胖和糖尿病中的影响。初步结果表明，饲喂高脂高糖致糖尿病饮食后，VLDLR'/~小鼠对肥胖和糖尿病具有抗性。相比之下，受体相关蛋白（RAP）缺陷的LRPAP'~小鼠即使维持基础低脂/低糖饮食，也会表现出整体LRP-1功能受损，但在脂肪和骨骼肌中维持VLDLR功能。有趣的是，含有载脂蛋白e的循环水平升高的小鼠（肝脏特异性apoE3转基因小鼠）在对糖尿病饮食的反应中体重增加与野生型小鼠相似，但仍保持胰岛素敏感，无高血糖。基于这些观察结果，本项目的总体假设是，这些LDL受体家族蛋白在各种高能量代谢组织中的表达水平调节了这些组织中的脂质和葡萄糖分配以及脂肪细胞中脂肪因子的产生，因此是饮食诱导的肥胖和糖尿病的重要决定因素。目的1将描述野生型、VLDLR‘’和apoe转基因（apoE-tg）小鼠在饮食诱导的肥胖和糖尿病中的差异的机制，验证VLDLR介导的脂质摄取途径是心脏、肌肉和脂肪组织对脂肪和葡萄糖利用的关键调节剂，因此有助于饮食诱导的肥胖和糖尿病的假设。这一目标也将验证apoE的抗炎和抗氧化特性可以预防肥胖相关糖尿病的假设，而不依赖于脂质转运。目的2将在VLDLR*'*和VLDLR ' 7背景下产生组织特异性的VLDLR转基因小鼠，以评估VLDLR在肌肉、心脏和脂肪组织中的表达在调节饮食诱导的肥胖和糖尿病中的重要性。Aim 3将产生肝脏、肌肉和脂肪特异性敲除LRP-1，以评估其在每个组织中与饮食诱导的肥胖和胰岛素抵抗相关的特定作用，验证脂肪中LRP-1表达对该组织中的脂质沉积和储存至关重要并保护糖尿病，而肌肉中的LRP-1通过促进该组织的脂质摄取来促进糖尿病的假设。这些研究的结果将为设计优化脂肪和葡萄糖分布、限制胰岛素抵抗和肥胖的新疗法提供策略。

DESCRIPTION (provided by applicant): The importance of the LDL receptor family proteins in lipid metabolism and protection against cardiovascular and Alzheimer's diseases is well established in the literature. However, the importance of these receptor functions in modulating sensitivity to diet-induced obesity and obesity-related diabetes has not been explored. This project will focus on the influence of two members of the LDL receptor family proteins, namely VLDL receptor (VLDLR) and LDL receptor-related protein LRP-1, in diet-induced obesity and diabetes. Preliminary results showed that VLDLR'/~ mice were resistant to obesity and diabetes after feeding a high fat-high sucrose diabetogenic diet. In contrast, the receptor associated protein (RAP)-deficient LRPAP'~ mice, which displayed compromised overall LRP-1 functions but maintained VLDLR functions in adipose and skeletal muscle, were insulin resistant even when maintained on a basal low fat/low sucrose diet. Interestingly, mice with increased circulating levels of apoE-containing lipoproteins (liver-specific apoE3 transgenic mice) were similar to wild type mice in body weight gain in response to the diabetogenic diet, but remained insulin sensitive without hyperglycemia. Based on these observations, the overall hypothesis of this project is that the level of expression of these LDL receptor family proteins in various high energy metabolism tissues modulates lipid and glucose partitioning in these tissues and adipokine production in adipocytes, and thus is an important determinant of diet-induced obesity and diabetes. Aim 1 will delineate the mechanism responsible for the difference between wild type, VLDLR''', and apoE-transgenic (apoE-tg) mice in diet-induced obesity and diabetes, testing the hypothesis that the VLDLR-mediated lipid uptake pathway is a key modulator of fat versus glucose utilization by heart, muscle, and adipose tissues, and thus is contributory to diet-induced obesity and diabetes. This aim will also test the hypothesis that the anti- inflammatory and anti-oxidative properties of apoE protect against obesity-related diabetes independent of lipid transport. Aim 2 will generate tissue specific VLDLR transgenic mice in VLDLR*'* and VLDLR"7 background to evaluate the importance of VLDLR expression in muscle, heart, versus adipose tissue in modulating diet-induced obesity and diabetes. Aim 3 will produce liver-, muscle-, and adipose-specific knockouts of LRP-1 to evaluate its specific role in each tissue in relationship to diet-induced obesity and insulin resistance, testing the hypothesis that LRP-1 expression in adipose is essential for lipid deposition and storage in this tissue and protects against diabetes whereas LRP-1 in muscle promotes diabetes by facilitating lipid uptake by this tissue. Results from these studies will offer strategies toward designing novel therapeutics that optimize fat and glucose distribution and limit insulin resistance and obesity.