Effects of Macronutrients on Regulation of Endoplasmic Reticulum Stress in Human

描述（由申请人提供）：内质网（ER）应激最近被认为是肥胖症相关的胰岛素抵抗和炎症的原因，这是基于以下观察结果：ER应激可以在遗传和饮食诱导的肥胖症的啮齿动物模型的肝脏和脂肪组织中以及在肥胖人类受试者的皮下（sc）脂肪中得到证实。然而，这种肥胖相关的ER应激的原因尚不清楚。我们已经在初步研究中发现，IV输注的大量营养素（葡萄糖和脂质）在人皮下（sc）脂肪组织中产生ER应激。这表明人体脂肪组织中的ER应激可以由大量营养素急性诱导。 本研究的具体目的是验证以下假设：1）碳水化合物、脂质和氨基酸这3种大量营养素可以在人皮下脂肪组织中产生ER应激，2）大量营养素诱导的ER应激是卡路里/能量依赖性的;以及3）大量营养素的负荷（> 3，000 Kcal/10 h）将激活近端ER应力传感器IRE-1，其与应激激酶（包括JNK和p38 MAPK）的激活有关，已知应激激酶抑制胰岛素信号传导并刺激促炎细胞因子的合成和释放。我们将通过评估葡萄糖、脂质和氨基酸以递增速率（范围为900- 3，600 Kcal，持续10小时）静脉输注以及口服混合膳食对ER应激相关蛋白的蛋白质转录、翻译和翻译后修饰以及对这些研究前后获得的皮下脂肪组织活检样本中的应激激酶和促炎细胞因子的影响来检验这些假设。 总的来说，这些研究将增强我们对过度营养摄入的影响的理解，特别是不同宏量营养素的过度摄入对ER应激，胰岛素抵抗和炎症的差异，这些都是心脏病发作，中风和外周血管疾病发展的重要因素。

DESCRIPTION (provided by applicant): Endoplasmic reticulum (ER) stress has recently been implicated as a cause for obesity associated insulin resistance and inflammation based on the observation that ER stress can be demonstrated in liver and adipose tissue of rodent models of genetic and diet induced obesity and in subcutaneous (sc) fat of obese human subjects. The cause for this obesity associated ER stress, however, is not known. We have found in preliminary studies, that IV infused macronutrients (glucose and lipid) produced ER stress in human subcutaneous (sc) adipose tissue. This suggested that the ER stress in human adipose tissue can be acutely induced by macronutrients. The specific aims of this proposal are to test the hypotheses 1) that the 3 macronutrients, carbohydrates, lipid and amino acids can produce ER stress in human sc adipose tissue, 2) that the macronutrient induced ER stress is calorie/energy dependent; and 3) that larger macronutrient loads (> 3,000 Kcal/10 h) will activate IRE-1, the proximal ER stress sensor, which is connected to activation of stress kinases (including JNK and p38 MAPK) which are known to inhibit insulin signaling and stimulate synthesis and release of proinflammatory cytokines. We will test these hypotheses by assessing the effects of glucose, lipids and amino acids infused IV at increasing rates (ranging from 900-3,600 Kcal over 10 h) and of mixed meals ingested orally, on protein transcription, translation and post-translational modification of ER stress related proteins and on stress kinases and proinflammatory cytokines in sc adipose tissue biopsy samples obtained before and after these studies. Collectively, these studies will enhance our understanding of the effects of excessive nutrient intake, and specifically of differences in excessive intake of different macronutrients, on ER stress, insulin resistance and inflammation which are important contributors to the development of heart attacks, strokes and peripheral vascular disease.