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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要许多研究表明，减肥后，新的较低体重很难维持。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），最近的研究表明，在减肥后的状态下，当体重相同时，EEgap 会减少。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由于活动引起的能量消耗（AEE）增加，因此，体重显着减轻的人。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的体力活动包括潜意识的运动（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）通过体力活动结合热量限制来增加能量消耗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前沿，该激动剂可激活食欲素 1 (OX1R) 和食欲素 2 (OX2R) 受体，以及一种此类 OX 激动剂，可在腹膜内强力给药。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。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。