Role of Lipoprotein Receptors in Diet-induced Obesity and Diabetes

描述(申请人提供)：低密度脂蛋白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很好的证实。然而，这些受体功能在调节饮食诱导的肥胖和肥胖相关糖尿病的敏感性方面的重要性还没有被探索。本项目将集中于低密度脂蛋白受体家族的两个成员，即极低密度脂蛋白受体(VLDLR)和低密度脂蛋白受体相关蛋白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-高蔗糖糖尿病饮食后，对肥胖和糖尿病具有抵抗力。相比之下，受体相关蛋白(RAP)缺陷的LRPAP‘~小鼠，表现出整体LRP-1功能受损，但在脂肪和骨骼肌中保持VLDLR功能，即使维持基础低脂肪/低蔗糖饮食，也是胰岛素抵抗。有趣的是，循环中含有apoE脂蛋白水平增加的小鼠(肝脏特异的apoE3转基因小鼠)在对糖尿病饮食的反应中体重增加方面与野生型小鼠相似，但仍然对胰岛素敏感，没有高血糖。基于这些观察，本项目的总体假设是，这些低密度脂蛋白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肪和葡萄糖分配以及脂肪细胞中脂肪因子的产生，从而是饮食诱导的肥胖和糖尿病的重要决定因素。目的1阐明野生型、VLDLR‘’和apoE转基因(apoE-TG)小鼠在饮食诱导的肥胖和糖尿病方面存在差异的机制，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因子，从而促进饮食诱导的肥胖和糖尿病。这一目标也将检验载脂蛋白E的抗炎和抗氧化特性独立于脂质运输而预防肥胖相关糖尿病的假设。目的2将在VLDLR和VLDLR“7背景下建立组织特异性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、肌肉和脂肪特异的LRP-1基因敲除，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的表达对该组织中的脂肪沉积和储存以及预防糖尿病至关重要的假设，而肌肉中的LRP-1通过促进该组织的脂质吸收而促进糖尿病。这些研究的结果将为设计新的治疗方法提供策略，以优化脂肪和葡萄糖的分布，并限制胰岛素抵抗和肥胖。

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.