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沿着构成了21世纪世纪最严重的公共卫生问题之一。尽管肥胖与使人衰弱的病症如胰岛素抵抗、2型糖尿病、动脉粥样硬化和心血管疾病有因果关系，但对肥胖的有效治疗仍然有限。瘦素是一种脂肪组织来源的激素，它将外周能量储备的状态传达给大脑，对食欲抑制和增加能量消耗具有强大的影响。瘦素的这些特征最初为肥胖症的治疗创造了巨大的兴奋;然而，肥胖个体的大脑中瘦素抗性的发展阻止了其作为有效的抗肥胖治疗剂的用途。尽管在学术界和工业界都进行了大量的研究，但对瘦素抵抗的分子基础的理解仍然难以捉摸。 我们的初步观察表明，肥胖期间内质网（ER）应激增加在瘦素抵抗的发展中起着至关重要的作用，并且称为X-Box结合蛋白1（XBP 1）的转录因子是维持大脑中瘦素作用的关键。我们以前也曾报道过，用化学分子伴侣减少内质网应激会增加严重肥胖和瘦素抵抗小鼠的瘦素敏感性。 我们的建议是基于这些以前的意见，并有三个具体目标。第一个目标将集中于确定ER应激诱导的LepRb相关蛋白复合物的改变，并研究是否有抑制性蛋白，阻止瘦素的行动是上调或瘦素行动所需的蛋白质是下调ER应激。此外，我们还将确定ER应激是否会在LepRb和/或Jak 2上产生任何翻译后修饰，从而降低其活性。第二个目标将使用条件性敲除模型的XBP 1描绘的主要神经元群体中，XBP 1主要是瘦素行动所需的。在我们申请的最终目的中， 通过使用遗传学方法和急性功能获得实验，我们将探索上调ER能力和降低ER应激对脑中瘦素敏感性的影响。