Reducing the post weight-loss energy expenditure gap with orexin agonists

项目摘要 体重减轻后，新的较低体重极难维持。许多研究表明，现在 这是因为体重大幅下降的人通常会有一种“能量消耗” Gap“(EEgap)体重减轻后，在操作上定义为肥胖前期状态下的总能量消耗(TEE)， 减去T恤在减肥后的状态，当在相同的体重时。最近的研究表明，EEgap 可能部分是由于基础能量消耗(BEE)的补偿性和持久的减少所致 来自活动引起的能量消耗(AEE)的增加。因此，体重显著下降的人 与体重匹配的人相比，必须消耗更少的能量和更多的能量来保持体重稳定 他们从来没有超重过。身体活动的范围从潜意识的驱使到移动(自发的 体力活动(SPA)到自愿的、有组织的、以目标为导向的高强度体力活动(程序化 锻炼)。通过体力活动增加能量消耗，结合限制热量摄入是一种常见的治疗方法 减肥的方法，但大多数人不坚持体育锻炼计划或保持足够的 强度以补偿发球柱重量损失的减少。我们的实验室是为数不多的研究中枢神经系统调控的实验室之一 SpA和专注于下丘脑神经肽增食欲素A(OXA)，它在促进 清醒状态和能量平衡。我们发现注射OXA和/或增食欲素神经元激活逆转 在动物模型中，蜜蜂减少和增加整齐和TEE，而不会补偿性地增加食物摄入量。 我们的合作者张博士在开发新的小分子增食欲素激动剂方面走在了前列 增食欲素1(OX1R)和增食欲素2(OX2R)受体，以及一个这样的OX激动剂对I.P.强有力的行政管理 在不改变中年小鼠和5个月龄肥胖倾向(OP)大鼠食物摄入量的情况下提高SPA。在……里面 此外，在新西兰，长期(5wk)服用激动剂可以减少肥胖和体重增加 肥胖(NZO)小鼠，支持食欲素激动剂作为一种潜在的治疗方法，以防止减肥后体重复发。 目前项目的目标是测试这些增食欲素激动剂在减少EEgap方面的效果，如下 肥胖啮齿动物模型的体重减轻，并了解其潜在机制是否涉及 线粒体呼吸作用。我们还将测试这些激动剂对睡眠/醒来模式的影响，以确定副作用。 为此，我们将使用间接量热法与行为分析和外周给药相结合 食欲素激动剂(S)，以确定食欲素系统的激活是否抑制体重恢复。长期目标 这个项目的目的是使研究和开发将食欲素用作肥胖、体重回升和 相关的合并症。

Project Summary Following weight loss, the new lower body weight is extremely difficult to maintain. Many studies have now shown this is because individuals who lose a significant amount of body weight typically have an “Energy Expenditure Gap” (EEgap) post-weight loss, defined operationally as total energy expenditure (TEE) in the pre-obese state, minus TEE in the post-weight loss state, when at the same body weight. Recent studies suggest that the EEgap may be caused in part by compensatory and enduring reductions in basal energy expenditure (BEE) resulting from increases in activity-induced energy expenditure (AEE). Therefore, someone who has lost significant weight has to consume less and expend more energy to stay weight-stable compared to weight-matched individuals who have never been overweight. Physical activity ranges from a subconscious drive to move (spontaneous physical activity, SPA) to voluntary, structured, goal-oriented and high-intensity physical activity (programmed exercise). Increasing EE through physical activity, in combination with caloric restriction is a common therapeutic approach for weight loss, but most individuals do not adhere to physical exercise programs or maintain sufficient intensity to compensate for reductions in TEE post weight-loss. Our lab is one of few to study CNS regulation of SPA and have focused on the hypothalamic neuropeptide orexin A (OXA), which plays a central role in promoting wakefulness and energy homeostasis. We found that OXA injection and/or orexin neuron activation reverses BEE reductions and increases NEAT and TEE in animal models, without compensatory increases in food intake. Our collaborator Dr. Zhang is on the forefront of developing new small molecular orexin agonists that activate both orexin 1(OX1R) and orexin 2 (OX2R) receptors, and one such OX agonist upon i.p. administration robustly enhances SPA without changing food intake in middle aged mice and 5-mo old obesity prone (OP) rats. In addition, chronic (5wk) administration of the agonist reduced adiposity and weight gain in the New Zealand Obese (NZO) mice, supporting orexin agonists as a potential therapy to prevent weight relapse post weight-loss. The goal of the current project is to test the effects of these orexin agonists in reducing the EEgap, following weight-loss in rodent models of obesity, and to understand if the underlying mechanism involves alterations in mitochondrial respiration. We will also test the effect of these agonists on sleep/wake patterns for side effects. To do this, we will use indirect calorimetry in conjunction with behavioral analyses and peripheral administration of orexin agonist(s), to determine if activation of the orexin system suppresses weight regain. The long-term goal of this project is to enable research and development in using orexin as a therapy for obesity, weight regain and associated comorbidities.