Spontaneous physical activity in obesity

描述（由申请人提供）：肥胖和超重影响着大多数美国人，但也有一些人抵制肥胖，就像一些动物抵制肥胖一样。动物和人体研究表明，自发身体活动（SPA）产生非运动活动产热（NEAT）是防止体重增加的重要手段。大脑机制控制着SPA关卡，以及由此产生的NEAT，但具体机制却不明确。我们提出下丘脑食欲素A （OxA）是SPA调控通路的重要组成部分，对OxA信号的敏感性增强SPA和NEAT有助于决定肥胖倾向。本应用的目的是验证以下假设：(1)升高的OxA介导的SPA可以防止体重增加；(2)肥胖抵抗（OR）大鼠中OxA介导的SPA的增加是由于食欲素受体表达的增加。我们的长期目标是利用SPA和NEAT调控途径的知识来指导肥胖人群对这些机制的治疗干预。我们计划三个目标：目标1)表征对SPA重要的促食欲素神经元亚群。A)在促食素神经元亚群中，促食素信息和肽是否存在品系差异？B)食欲素神经元亚群的破坏是否影响SPA？目的2)确定oxa介导的SPA对体重增加的重要性。A) OR大鼠rLH中OxA作用的降低是否会降低对体重增加的抵抗力？B)大剂量OxA刺激rLH诱导的SPA是否会减少OP大鼠的体重增加？目的3)验证OR大鼠食欲素敏感性增加是由于食欲素受体表达增加所致。A)与OP大鼠相比，OR大鼠的食欲素受体数量是否增加？B) OR大鼠中携带rLH食欲素受体的神经元中c-fos的激活是否高于OP大鼠？C) OR大鼠rLH中携带食欲素受体的神经元减少是否会增加体重？进一步了解脑促食欲素及其与肥胖中SPA的关系，将填补对中枢介导的SPA和NEAT及其对肥胖抵抗的重要性的认识空白。目前的建议旨在了解控制身体活动的特定大脑通路的作用，这对体重调节很重要。肥胖是影响至少三分之一美国人口的主要健康问题，也是心脏病、糖尿病和几种癌症等多种疾病的风险因素。问题的潜在部分是身体活动的失调，更好地了解与此相关的大脑通路对于开发肥胖治疗方法是必要的。

DESCRIPTION (provided by applicant): Obesity and overweight affects most Americans, but there are some who resist obesity, just as some animals resist obesity. Animal and human studies indicate that spontaneous physical activity (SPA), which generates nonexercise activity thermogenesis (NEAT), is an important defense against weight gain. Brain mechanisms control the level SPA, and the NEAT so generated, but the specifics are undefined. We propose that hypothalamic orexin A (OxA) is an important part of the SPA regulatory pathway, and that sensitivity to OxA signals enhancing SPA and NEAT helps determine propensity for obesity. The objectives of this application are to test the following hypotheses: (1) elevated OxA mediated SPA protects against weight gain and (2) increased OxA-mediated SPA in obesity resistant (OR) rats results from increased orexin receptor expression. Our long-range goal is to use knowledge of SPA and NEAT regulatory pathways to guide therapeutic interventions on these mechanisms among obese humans. We plan 3 aims: Aim 1) Characterize orexin neuron subpopulations important to SPA. A) Are there strain differences in orexin message and peptide in subpopulations of orexin neurons? B) Does destruction of subpopulations of orexin neurons affect SPA? Aim 2) Determine importance of OxA-mediated SPA to weight gain. A) Does reduced OxA action in rLH of OR rats reduce resistance to weight gain? B) Does SPA induced by high dose OxA stimulation of rLH reduce weight gain in OP rats? Aim 3) Verify that increased orexin sensitivity in OR rats is due to increased orexin receptor expression. A) Is orexin receptor number increased in OR compared to OP rats? B) Is c-fos activation in rLH orexin receptor bearing neurons higher in OR than OP rats? C) Does reducing orexin receptor bearing neurons in rLH of OR rats enhance weight gain? A greater understanding of brain orexin and its relationship to SPA in obesity will fill a large gap in knowledge of centrally mediated SPA and NEAT, and its importance to obesity resistance. PUBLIC HEALTH RELEVANCE The current proposal is aimed at understanding the role of a specific brain pathway that controls physical activity, which is important to body weight regulation. Obesity is a major health problem affecting at least one third of the U.S. population, and is a risk factor for several diseases, including heart disease, diabetes and several types of cancer. Underlying part of the problem is disordered regulation of physical activity, and a better understanding of the brain pathways important to this is necessary in developing treatments for obesity.