Enhancing NEAT to Treat Obesity

描述（由申请人提供）： 肥胖和超重影响着大多数美国人，因为我们正在与当前的肥胖环境作斗争。然而，有些人抵制肥胖，就像有些动物抵制肥胖一样。动物和人类研究表明，自发性身体活动（SPA），产生非运动活动产热（NEAT），是防止体重增加的重要防御措施。我们已经证明，肥胖抵抗（OR）大鼠比肥胖倾向（OP）大鼠具有更大的SPA。OP和OR大鼠作为对肥胖敏感性不同的多基因品系，是多基因人类肥胖的良好模型。具有升高的SPA的瘦人在热量挑战期间抵抗肥胖，而人肥胖的特征在于显著降低的SPA，其通过降低消耗的能量对体重具有实质性影响。大脑机制控制SPA的水平，以及由此产生的NEAT。食欲素神经元似乎起着关键作用，因为它们投射到涉及唤醒和活动的大脑区域，并且大脑食欲素活性的丧失增加体重指数。对食欲素A（OxA）SPA促进的敏感性是OR大鼠固有的，并且在抵抗肥胖中可能至关重要。最近的证据和我们的初步数据表明，中缝背核（DR）和蓝斑（LC）中的食欲素作用可能介导SPA和NEAT。我们假设1）在DR和LC中的食欲素作用是介导SPA和NEAT的关键机制; 2）肥胖啮齿动物中病毒介导的食欲素受体的过表达将降低体重; 3）鼻内施用食欲素A，通过增强大鼠脑中的食欲素水平，将产生NEAT的增强。我们将测试这些想法与三个具体的目标：目标1将确定DR和LC食欲素在调节SPA和NEAT在肥胖易感和抵抗大鼠的作用。我们将首先验证在肥胖抵抗大鼠中DR和LC中的食欲素受体基因表达增加（1A）;确定在肥胖倾向和肥胖抵抗大鼠中对DR和LC食欲素A输注的敏感性（1B），测试在肥胖抵抗大鼠中降低的DR或LC食欲素受体功能是否会促进体重增加（1C）;确定食欲素A刺激DR和LC是否减少肥胖倾向大鼠的体重增加（1D）。在目标2中，我们计划在LC或DR中使用病毒介导的食欲素受体过表达来增强NEAT。子目标将测试在肥胖倾向大鼠的LC或DR中Ox 1 R和Ox 2 R的单一（2A和2B）和组合（2C）过表达是否会减少体重增加。最后，在目标3中，我们将进行OxA的鼻内（IN）递送，以确定其增加NEAT的有效性。子目标将确定什么有效剂量和时间将增加LC和DRN食欲素A水平，以及向肥胖大鼠施用急性IN（3B）或慢性IN（3C）是否增加SPA和NEAT。这些研究将填补对肥胖抵抗很重要的SPA潜在脑机制知识的差距，并将为退伍军人和整个人群开发新的肥胖疗法提供必要的信息。 公共卫生相关性： 生物学问题仍然是关于大脑机制调节自发性身体活动（SPA），SPA的能量后果和对体重调节的贡献。这些问题是与日常运动相关的热量消耗刚刚被定义的整体背景的一部分，并且对于科学地理解能量平衡的组成部分非常感兴趣。超重和肥胖是许多疾病发病的重要原因。我们相信这些研究可以开始解决这一知识差距。超重和肥胖本身是退伍军人群体中的一种重要疾病，并显著导致发病率。能量平衡的变化，特别是肥胖的发展加剧了退伍军人中几种疾病的发病率。确定未来治疗的潜在途径为解决这一国家健康问题提供了希望。

DESCRIPTION (provided by applicant): Obesity and overweight affect most Americans as we struggle with the current obesigenic environment. Yet some resist obesity, just as some animals resist obesity. Animal and human studies indicate that spontaneous physical activity (SPA), which generates non-exercise activity thermogenesis (NEAT), is an important defense against weight gain. We have demonstrated that obesity resistant (OR) rats have greater SPA than obesity prone (OP) rats. OP and OR rats, as polygenic strains differing in sensitivity to obesity, are excellent models for polygenic human obesity. Lean humans with elevated SPA resist obesity during caloric challenge, while human obesity is characterized by dramatically reduced SPA, which, by lowering expended energy has a substantial influence on body weight. Brain mechanisms control the level of SPA, and the NEAT so generated. Orexin neurons appear to play a key role as they project to brain areas involved in arousal and activity and loss of brain orexin activity increases body mass index. Sensitivity to orexin A (OxA) SPA promotion is inherent to OR rats and may be critically important in resisting obesity. Recent evidence and our preliminary data suggest that orexin action in the dorsal raphe nucleus (DR) and the locus coeruleus (LC), may mediate SPA and NEAT. We hypothesize that 1) orexin action in DR and LC are key mechanisms mediating SPA and NEAT; 2) viral- mediated overexpression of orexin receptor(s) in obese rodents will reduce body weight; 3) intranasal administration of orexin A, by enhancing orexin levels in brains of rat, will produce enhancement of NEAT. We will test these ideas with three specific aims: Aim 1 will define the role of DR and LC orexin in regulating SPA and NEAT in obesity prone and resistant rats. We will first verify that orexin receptor gene expression in DR and LC is increased in obesity resistant rats (1A); determine sensitivity to DR and LC orexin A infusion in obesity prone and obesity resistant rats (1B), test whether reduced DR or LC orexin receptor function in obesity resistant rats will promote weight gain (1C); determine if orexin A stimulation of DR and LC reduces weight gain in obesity prone rats (1D). In Aim 2 we plan the use of virus-mediated overexpression of orexin receptors in LC or DR to enhance NEAT. Sub-aims will test whether single (2A and 2B) and combined (2C) overexpression of Ox1R and Ox2R in LC or DR of obesity prone rats will reduce weight gain. Finally, in Aim 3 we will perform intranasal (IN) delivery of OxA to determine its effectiveness at increasing NEAT. Sub-aims will determine what effective dose and timing will increase LC and DRN orexin A levels, and whether acute IN (3B) or chronic IN (3C) administration into obese rats increases SPA and NEAT. These studies will fill the gap in knowledge of brain mechanisms underlying SPA, which is important to obesity resistance, and will provide information necessary to developing new obesity therapies for Veterans and the population as a whole. PUBLIC HEALTH RELEVANCE: Biological questions remain about brain mechanisms regulating spontaneous physical activity (SPA), energetic consequences of SPA and the contribution to body weight regulation. Such questions are part of an overall context in which caloric expenditures associated with routine movements are just being defined, and are of great interest to a scientific understanding of the components of energy balance. Overweight and obesity contribute importantly to morbidity associated with many diseases. We believe these studies can begin to address this gap in knowledge. Overweight and obesity is itself a significant disease presence in the veteran population, and contributes significantly to morbidity. Changes in energy balance and particularly the development of obesity exacerbate morbidity of several diseases in veterans. Determining potential avenues for future treatments provides hope in dealing with this national health issue.