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，因为我们正在与目前的顺从环境作斗争。然而，有些动物抵制肥胖，就像有些动物抵制肥胖一样。动物和人类的研究表明，自发的身体活动(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，是研究人类多基因肥胖的理想模型。SPA升高的瘦人在卡路里挑战期间抵抗肥胖，而人类肥胖的特征是SPA显著降低，这通过降低消耗的能量对体重产生实质性影响。大脑机制控制着SPA的水平，并由此产生整齐的SPA。食欲素神经元似乎扮演着关键角色，因为它们投射到与觉醒和活动有关的大脑区域，大脑食欲素活动的丧失会增加体重指数。对食欲素A(OXA)SPA促进的敏感性是OR大鼠固有的，在抵抗肥胖方面可能是至关重要的。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。我们推测，1)增食欲素在DR和LC中的作用是介导SPA和NEAT的关键机制；2)病毒介导的增食欲素受体(S)在肥胖啮齿动物中的过表达会减轻体重；3)鼻腔给药通过提高大鼠大脑中的增食欲素水平，将产生增强的NEAT。我们将用三个具体的目标来测试这些想法：目标1将确定DR和LC增食欲素在调节肥胖倾向和抵抗大鼠的SPA和NEAT中的作用。我们将首先验证肥胖抵抗大鼠(1A)DR和LC中食欲素受体基因的表达增加；确定肥胖倾向和肥胖抵抗大鼠(1B)对DR和LC食欲素A注射的敏感性；测试肥胖抵抗大鼠DR或LC食欲素受体功能降低是否会促进体重增加(1C)；确定刺激DR和LC中的食欲素A是否减少肥胖倾向大鼠(1D)的体重增加。在目标2中，我们计划使用病毒介导的增食欲素受体在LC或DR中的过表达来增强NEAT。子目标将测试肥胖倾向大鼠的LC或DR中OX1R和OX2R的单一(2A和2B)和联合(2C)过度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，以确定其在增加NEAT方面的有效性。子目标将确定什么有效剂量和时间会增加LC和DRN orexin A水平，以及对肥胖大鼠急性注射IN(3B)或长期给予IN(3C)是否会增加SPA和NEAT。这些研究将填补关于SPA背后的大脑机制的知识空白，SPA对肥胖抵抗非常重要，并将为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： 关于大脑调节自发身体活动(SPA)的机制、SPA的能量后果以及对体重调节的贡献，生物学问题仍然存在。这些问题是与日常运动相关的卡路里支出刚刚确定的整体背景的一部分，对于科学理解能量平衡的组成部分非常有意义。超重和肥胖是与许多疾病相关的发病率的重要原因。我们相信，这些研究可以开始解决这一知识差距。超重和肥胖本身就是退伍军人群体中的一种重大疾病，也是导致发病率的重要因素。能量平衡的变化，特别是肥胖症的发展，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处理这一国家健康问题带来了希望。

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.