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疾病和阿尔茨海默病中的重要性在文献中得到了充分证实。然而，这些受体功能在调节对饮食诱导的肥胖和肥胖相关的糖尿病的敏感性中的重要性尚未被探索。本项目将关注LDL受体家族蛋白质的两个成员，即VLDL受体（VLDLR）和LDL受体相关蛋白LRP-1在饮食诱导的肥胖和糖尿病中的影响。初步结果表明，VLDLR-/-小鼠在喂食高脂肪-高糖致糖尿病饮食后对肥胖和糖尿病具有抵抗力。相比之下，受体相关蛋白（RAP）缺陷型LRPAP+小鼠显示受损的总体LRP-1功能，但在脂肪和骨骼肌中维持VLDLR功能，即使在维持基础低脂/低蔗糖饮食时也是胰岛素抗性的。有趣的是，循环中含有apoE的脂蛋白水平增加的小鼠（肝脏特异性apoE 3转基因小鼠）在对致糖尿病饮食的反应中体重增加方面与野生型小鼠相似，但仍保持胰岛素敏感性而无高血糖症。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代谢组织中的表达水平调节这些组织中的脂质和葡萄糖分配以及脂肪细胞中的脂肪因子产生，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、肌肉和脂肪组织利用脂肪与葡萄糖的关键调节剂，因此有助于饮食诱导的肥胖和糖尿病的假设。该目的还将检验apoE的抗炎和抗氧化特性不依赖于脂质转运而防止肥胖相关的糖尿病的假设。目的2将在VLDLR基因和VLDLR基因背景下产生组织特异性VLDLR转基因小鼠，以评估肌肉、心脏和脂肪组织中VLDLR表达在调节饮食诱导的肥胖和糖尿病中的重要性。目的3将产生LRP-1的肝脏、肌肉和脂肪特异性敲除，以评估其在每种组织中与饮食诱导的肥胖和胰岛素抵抗相关的特定作用，测试脂肪中的LRP-1表达对于该组织中的脂质沉积和储存是必需的并防止糖尿病，而肌肉中的LRP-1通过促进该组织的脂质摄取而促进糖尿病的假设。这些研究的结果将为设计优化脂肪和葡萄糖分布并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.