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

项目摘要 减肥后，新的较低体重很难维持。许多研究表明 这是因为体重大幅减轻的人通常会出现“能量消耗” 体重减轻后的“间隙”（EEgap），在操作上定义为肥胖前状态下的总能量消耗（TEE）， 减去体重减轻后状态下的TEE，当体重相同时。最近的研究表明， 可能部分由基础能量消耗（BEE）的补偿性和持久性减少引起， 活动引起的能量消耗（AEE）增加。因此，一个体重明显减轻的人 与体重相当的人相比， 从来没有超重过。身体活动的范围从潜意识驱动移动（自发 身体活动，SPA）自愿，结构化，目标导向和高强度的身体活动（程序化 锻炼）。通过体力活动增加EE，结合热量限制是一种常见的治疗方法 方法减肥，但大多数人不坚持体育锻炼计划或保持足够的 强度以补偿体重减轻后TEE的降低。我们的实验室是少数几个研究中枢神经系统调节的实验室之一， SPA和集中在下丘脑神经肽食欲素A（OXA），它在促进食欲中起着核心作用。 保持清醒和能量平衡我们发现OXA注射和/或食欲素神经元激活逆转了 在动物模型中，BEE减少和增加NEAT和TEE，而不增加食物摄入量。 我们的合作者张博士是在开发新的小分子食欲素激动剂，激活 食欲素1（OX 1 R）和食欲素2（OX 2 R）受体，以及一种这样的OX激动剂，在腹膜内给药后， 增强SPA而不改变中年小鼠和5月龄肥胖倾向（OP）大鼠的食物摄入。在 此外，在新西兰，长期（5周）给予该激动剂可减少肥胖和体重增加。 肥胖（NZO）小鼠，支持食欲素激动剂作为预防减肥后体重复发的潜在疗法。 本项目的目标是测试这些食欲素激动剂在减少EEgap中的作用， 在啮齿动物肥胖模型中的减肥，并了解潜在的机制是否涉及改变 线粒体呼吸我们还将测试这些激动剂对睡眠/觉醒模式的副作用的影响。 为此，我们将使用间接测热法结合行为分析和外周给药 的食欲素激动剂，以确定食欲素系统的激活是否抑制体重恢复。远景目标 该项目的目的是使研究和开发使用增食欲素作为治疗肥胖，体重反弹， 相关合并症。

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.