Effects of Macronutrients on Regulation of Endoplasmic Reticulum Stress in Human

描述(申请人提供)：内质网应激最近被认为是肥胖相关的胰岛素抵抗和炎症的原因，因为观察到内质网应激可在遗传和饮食诱导肥胖的啮齿动物模型的肝脏和脂肪组织以及肥胖受试者的皮下脂肪中被证明。然而，肥胖与内质网压力相关的原因尚不清楚。我们在初步研究中发现，静脉注射大量营养素(葡萄糖和脂肪)会在人类皮下脂肪组织中产生内质网应激。这表明，人体脂肪组织中的内质网应激可以被大量营养素急性诱导。这项建议的具体目的是检验假设：1)3种常量营养素、碳水化合物、脂肪和氨基酸可以在人体皮肤脂肪组织中产生ER应激；2)大量营养素诱导的ER应激是卡路里/能量依赖的；3)较大的常量营养素负荷(&gt；3,000千卡/10小时)将激活近端的ER应激传感器IRE-1，它与应激蛋白激酶(包括JNK和p38MAPK)的激活有关，已知的应激蛋白激酶抑制胰岛素信号转导，刺激促炎细胞因子的合成和释放。我们将通过评估葡萄糖、脂肪和氨基酸以递增速度(在10小时内从900-3,600千卡)注入静脉和口服混合膳食对内质网应激相关蛋白的蛋白质转录、翻译和翻译后修饰以及在这些研究前后获得的皮肤脂肪组织活检样本中应激蛋白激酶和促炎细胞因子的影响来检验这些假说。总而言之，这些研究将加深我们对过量营养摄入的影响，特别是不同常量营养素过量摄入对内质网应激、胰岛素抵抗和炎症的影响，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。 公共卫生相关性：肥胖与胰岛素抵抗(IR)和炎症(IF)密切相关。两者都会导致2型糖尿病、高血压、血脂异常以及凝血和纤溶障碍，所有这些都是心脏病发作、中风和外周动脉疾病的独立危险因素。因此，重要的是要了解肥胖是如何与IR和IF联系在一起的。在拟议的研究中，我们将研究过度营养摄入是如何显著地产生IR和IF的，这是肥胖的主要原因。

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. PUBLIC HEALTH RELEVANCE: Obesity is tightly linked to insulin resistance (IR) and inflammation (IF). Both contribute to the development of type 2 diabetes, hypertension, dyslipidemia and disorders of coagulation and fibrinolysis, all of which are independent risk factors for heart attacks, strokes and peripheral arterial disease. Therefore, it is important to understand how obesity is linked with IR and IF. In the proposed studies we will examine how excess nutrient intake, the major cause for obesity, can acutely produce IR and IF.