Endoplasmic Reticulum Stress, Brain and Obesity

描述(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。尽管与胰岛素抵抗、2型糖尿病、动脉粥样硬化和心血管疾病等衰弱疾病有因果关系，但肥胖症的有效治疗仍然有限。瘦素是一种脂肪组织衍生的激素，它将外周能量储备的状态传达给大脑，对抑制食欲和增加能量消耗具有强大的影响。瘦素的这些特性最初为肥胖症的治疗带来了极大的兴奋；然而，肥胖者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手段的使用。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了解仍然难以捉摸。我们的初步观察表明，肥胖过程中内质网(ER)压力的增加在瘦素抵抗的发展中起着至关重要的作用，而一种名为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。我们之前也曾证明，在严重肥胖和瘦素抵抗的小鼠中，使用化学伴侣减少内质网应激会增加瘦素的敏感性。我们的建议是基于这些先前的观察结果，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相关蛋白复合体的变化，并研究内质网应激是否上调了阻止瘦素作用的抑制性蛋白或下调了瘦素作用所需的蛋白。此外，我们还将确定ER在LepRb和/或JAK2上创建的任何翻译后修改是否会降低它们的活性。第二个目标将使用XBP1的条件基因敲除模型来描述XBP1主要参与瘦素作用的主要神经元群体。在我们应用程序的最终目标中， 通过遗传方法和急性功能获得实验，我们将探索上调内质网容量和减少内质网应激对大脑中瘦素敏感性的影响。

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.