Endoplasmic Reticulum Stress, Brain and Obesity

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。尽管肥胖与胰岛素抵抗、2型糖尿病、动脉粥样硬化和心血管疾病等使人衰弱的疾病有因果关系，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递给大脑，对抑制食欲和增加能量消耗有重要影响。瘦素的这些特性最初为肥胖症的治疗创造了巨大的兴奋；然而，肥胖个体大脑中瘦素抵抗的发展阻碍了它作为一种有效的抗肥胖治疗药物的使用。尽管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）应激的增加在瘦素抵抗的发展中起着至关重要的作用，并且一种称为X-Box结合蛋白1 （XBP1）的转录因子是维持瘦素在大脑中的作用的关键。我们之前也有文献表明，用化学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观察，并有三个具体目标。第一个目标将集中于确定内质网应激诱导的leprb相关蛋白复合物的改变，并研究内质网应激是抑制瘦素作用的抑制蛋白上调还是瘦素作用所需的蛋白下调。此外，我们还将确定ER胁迫是否在LepRb和/或Jak2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XBP1的条件敲除模型来描述主要的神经元群体，其中XBP1主要是瘦素作用所必需的。在我们申请的最终目的中，

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.