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

使用食欲素激动剂减少减肥后的能量消耗差距

• 批准号: 10745184
• 负责人: CATHERINE M KOTZ
• 金额: $ 73.1万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745184
• 关键词: Address; Affinity; Agonist; Animal Model; Animals; Automobile Driving; Behavioral; Body Weight; Body Weight decreased; Brain; Caloric Restriction; Calories; Chronic; Compensation; Consumption; Data; Drug Kinetics; Eating; Energy Metabolism; Evaluation; Excretory function; Exercise; Fatty acid glycerol esters; Goals; Homeostasis; Human; Hypothalamic structure; Indirect Calorimetry; Individual; Injections; Laboratories; Left; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mus; Neurons; Neuropeptides; New Zealand; Obese Mice; Obesity; Overweight; Pattern; Peptides; Peripheral; Physical Exercise; Physical activity; Play; Property; Public Health; Rattus; Regulation; Relapse; Reporting; Respiration; Rodent Model; Role; Sleep; Structure; Study models; Subconscious; System; Testing; Therapeutic; Toxic effect; Wakefulness; Weight; Weight Gain; absorption; abuse liability; analog; comorbidity; design; diet-induced obesity; exercise program; hypocretin; improved; improvement on sleep; interest; middle age; neurochemistry; obesity treatment; orexin A; prevent; receptor; research and development; side effect; small molecule; therapy development; total energy expenditure

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.

项目摘要 体重减轻后，新的下体重非常难以维持。现在已经显示了许多研究 这是因为失去大量体重的个人通常具有“能量消耗 差距”（EEGAP）重量后损失，在肥胖状态下在操作上定义为总能量支出（TEE）， 当体重相同时，在重量后损耗状态下减去T恤。最近的研究表明EEGAP 可能部分是由基本能量支出（BEE）的补偿性和持久减少引起的 从活动引起的能源消耗（AEE）的增加。因此，一个体重减轻的人 与体重匹配的个体相比 从未超重的人。体育锻炼范围从潜意识驱动到移动（自发） 体育锻炼，水疗）至自愿，结构化，面向目标和高强度的体育活动（编程 锻炼）。通过体育锻炼增加EE，结合热量限制是一种常见的疗法 减肥方法，但大多数人不遵守体育锻炼计划或保持足够 补偿T恤减肥后减少的强度。我们的实验室是研究CNS调节的少数 水疗中心，并专注于下丘脑神经肽OREXIN A（OXA），在促进中起着核心作用 清醒和能量稳态。我们发现OXA注射和/或Orexin神经元激活反向 在动物模型中，蜜蜂减少并增加了整洁和T恤，而食物摄入量没有补偿性增加。 我们的合作者张博士处于开发新的小分子或激活的小分子奥甲蛋白激动剂的最前沿 Orexin 1（OX1R）和Orexin 2（OX2R）受体，以及I.P.管理强大 在中年小鼠和5-MO旧肥胖症（OP）大鼠的情况下，可以增强水疗中心，而不会改变食物摄入量。 此外，激动剂的慢性（5WK）给药减少了新西兰的肥胖和体重增加 肥胖（NZO）小鼠，支持Orexin激动剂作为一种潜在的疗法，以防止减肥后减轻体重。 当前项目的目的是测试这些Orexin激动剂在减少EEGAP中的影响， 肥胖模型中的减肥模型，并了解基本机制是否涉及改变 线粒体呼吸。我们还将测试这些激动剂对副作用的睡眠/唤醒模式的影响。 为此，我们将使用间接量热法与行为分析和外围给药 OREXIN激动剂（S）确定Orexin System的激活是否再次抑制重量。长期目标 这个项目的是使使用Orexin作为肥胖症的疗法，体重仍然存在，并且 相关的合并症。