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.

项目概要 减肥后，新的下体重很难维持。现在许多研究表明 这是因为体重大幅减轻的人通常会出现“能量消耗” 减肥后的“差距”（EEgap），操作上定义为肥胖前状态下的总能量消耗（TEE）， 体重相同时，减去减肥后状态下的 TEE。最近的研究表明，EEgap 可能部分是由于基础能量消耗（BEE）的补偿性和持久性减少造成的 来自活动引起的能量消耗（AEE）的增加。因此，体重明显减轻的人 与体重匹配的人相比，必须消耗更少并消耗更多能量才能保持体重稳定 从未超重的人。身体活动的范围从潜意识驱动的运动（自发的 身体活动（SPA）到自愿的、结构化的、目标导向的和高强度的身体活动（有计划的） 锻炼）。通过体力活动结合热量限制来增加能量效率是一种常见的治疗方法 减肥的方法，但大多数人没有坚持体育锻炼计划或保持足够的身体锻炼 强度以补偿减肥后 TEE 的减少。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 并专注于下丘脑神经肽食欲素 A (OXA)，它在促进 觉醒和能量稳态。我们发现 OXA 注射和/或食欲素神经元激活可逆转 BEE 在动物模型中减少和增加 NEAT 和 TEE，但食物摄入量不会补偿性增加。 我们的合作者张博士处于开发新型小分子食欲素激动剂的最前沿，该激动剂可激活 食欲素 1 (OX1R) 和食欲素 2 (OX2R) 受体，以及腹膜内注射一种此类 OX 激动剂。强有力的管理 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增强 SPA。在 此外，在新西兰，长期（5周）服用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。 当前项目的目标是测试这些食欲素激动剂在减少 EEgap 方面的效果，如下 肥胖啮齿动物模型中的体重减轻，并了解其潜在机制是否涉及体重的改变 线粒体呼吸。我们还将测试这些激动剂对睡眠/觉醒模式的影响是否有副作用。 为此，我们将使用间接量热法结合行为分析和外周给药 食欲素激动剂，以确定食欲素系统的激活是否抑制体重反弹。长期目标 该项目的目的是促进研究和开发使用食欲素治疗肥胖、体重反弹和 相关的合并症。