Endoplasmic Reticulum Stress, Brain and Obesity

内质网应激、大脑和肥胖

• 批准号: 8480078
• 负责人: Umut Ozcan
• 金额: $ 51.61万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-18 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8480078
• 关键词: Academia; Acute; Address; Adipocytes; Adipose tissue; American; Appetite Depressants; Atherosclerosis; Binding Proteins; Body Weight; Body Weight decreased; Boxing; Brain; Ca(2+)-Transporting ATPase; Cardiovascular Diseases; Chemicals; Critical Pathways; Desire for food; Development; Drug Targeting; Endoplasmic Reticulum; Energy Metabolism; Genetic; Homeostasis; Hormones; Hypertension; Hypothalamic structure; Incidence; Individual; Industry; Insulin Resistance; Knock-out; Lead; Leptin; Leptin resistance; Link; Longevity; Mediating; Metabolic; Modeling; Molecular; Molecular Chaperones; Morbidity - disease rate; Mus; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Peripheral; Phenotype; Play; Population; Post-Translational Protein Processing; Proteins; Proteomics; Public Health; Recording of previous events; Research; Resistance; Resistance development; Reticulum; Role; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Therapeutic Agents; Time; Transgenic Mice; Work; activating transcription factor 1; base; effective therapy; endoplasmic reticulum stress; feeding; gain of function; insight; mouse development; mouse model; nestin protein; novel; obesity treatment; overexpression; prevent; promoter; protein complex; public health relevance; research study; response; transcription factor

DESCRIPTION (provided by applicant): Obesity, along with its associated complications, constitutes one of the most serious public health concerns of the 21st century. Although causally linked to debilitating conditions such as insulin resistance, type 2 diabetes, atherosclerosis and cardiovascular disease, there remains limited effective therapeutic treatment for obesity. Leptin, an adipose tissue-derived hormone that communicates the status of peripheral energy reserves to the brain has robust influence on appetite suppression and on increasing energy expenditure. These features of leptin initially created great excitement for the treatment of obesity; however the development of leptin resistance in the brains of obese individuals has prevented its use as an effective anti-obesity therapeutic. Despite significant research efforts both in academia and industry, an understanding of the molecular underpinnings of leptin resistance remains elusive. Our initial observations indicate that increased Endoplasmic Reticulum (ER) stress during obesity has a crucial role in the development of leptin resistance, and that a transcription factor called the X-Box binding protein 1 (XBP1) is key for maintaining leptin action in the brain. We have also previously documented that reducing ER stress with chemical chaperones increases leptin sensitivity in the severely obese and leptin resistant mice. Our proposal is based on these previous observations and has three Specific Aims. The first Aim will focus on determining the ER stress-induced alterations in the LepRb-associated protein complexes and investigate whether an inhibitory protein that blocks leptin action is up regulated or a protein that is required for leptin action is down regulated by ER stress. Furthermore, we will also determine whether any post-translational modifications created on LepRb and/or Jak2 by ER stress that reduces their activity. The second aim will use conditional knockout models of XBP1 to delineate the main neuronal population in which XBP1 is mainly required for leptin action. In the final aim of our application, by both using genetic approaches and acute gain-of-function experiments, we will explore the consequences of up regulating ER capacity and reducing ER stress on leptin sensitivity in the brain.

描述（由申请人提供）：肥胖及其相关并发症构成了21世纪最严重的公共卫生问题之一。尽管因果关系与使人衰弱的疾病（如胰岛素抵抗，2型糖尿病，动脉粥样硬化和心血管疾病）有关，但仍有有效的肥胖治疗治疗效果有限。 Leptin是一种脂肪组织衍生的激素，可传达外围能量储备的状态，对大脑具有强大的影响，对食欲抑制和增加能量消耗。瘦素的这些特征最初引起了肥胖治疗的极大兴奋。然而，肥胖个体大脑中瘦素耐药性的发展已阻止其用作有效的抗肥胖治疗。尽管在学术界和工业方面进行了重大研究，但对瘦素耐药性分子基础的理解仍然难以捉摸。 我们的最初观察结果表明，肥胖期间增加的内质网应激（ER）应力在瘦素耐药性的发展中具有至关重要的作用，而称为X-box结合蛋白1（XBP1）的转录因子是维持大脑中瘦素作用的关键。我们先前还记录到，通过化学伴侣减少ER应激会增加严重肥胖和耐瘦素小鼠的瘦素敏感性。 我们的建议基于这些先前的观察结果，并具有三个具体目标。第一个目标将集中于确定与LEPRB相关蛋白复合物的ER应力诱导的改变，并研究阻断瘦素作用的抑制性蛋白是否受到调节，还是瘦素作用所需的蛋白质受到ER应激的调节。此外，我们还将确定是否通过降低其活性在LEPRB和/或JAK2上创建的任何翻译后修饰。第二个目标将使用XBP1的条件基因敲除模型来描述leptin作用主要需要XBP1的主要神经元种群。在我们应用的最终目标中， 通过使用遗传方法和急性功能获得实验，我们将探索调节ER能力并降低ER对大脑中瘦素敏感性的应力的后果。