Orexin agonists as novel obesity therapeutics

食欲素激动剂作为新型肥胖疗法

• 批准号: 10655285
• 负责人: CATHERINE M KOTZ
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655285
• 关键词: Address; Adult; Affect; Affinity; Age; Agonist; Anti-Obesity Agents; Automobile Driving; Behavior; Behavioral; Biological Availability; Body Weight; Body Weight decreased; Brain; Calories; Caring; Chronic Disease; Cognition; Data; Desire for food; Development; Diet; Eating; Effectiveness; Energy Metabolism; Environment; Evaluation; Exercise; Exposure to; Feeding behaviors; Future; General Population; Goals; Health; Health Care Costs; Healthcare Systems; High Fat Diet; Home; Homeostasis; Human; Hypothalamic structure; Indirect Calorimetry; Individual; Lateral; Measures; Medical; Metabolic; Metabolic Diseases; Methods; Modeling; Moderate Exercise; Molecular Weight; Morbidity - disease rate; Movement; Mus; Narcolepsy; Neurodegenerative Disorders; Neurons; Neuropeptides; Obese Mice; Obesity; Outcome; Overweight; Pattern; Peptide Hydrolases; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Physical Exercise; Physical activity; Physiological; Population; Predisposition; Prevention; Property; Quality of life; Receptor Activation; Research; Rodent; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Structure; Subconscious; System; Testing; Therapeutic; Thermogenesis; Treatment outcome; Vertebral column; Veterans; Veterans Health Administration; Weight Gain; blood-brain barrier crossing; blood-brain barrier permeabilization; comorbidity; diet-induced obesity; effective therapy; efficacy testing; exercise program; feeding; good diet; healthspan; hypocretin; improved; improvement on sleep; in vivo; interest; military veteran; novel; obese person; obesity development; obesity prevention; obesity treatment; obesogenic; orexin A; pre-clinical; prevent; receptor; reduced food intake; research and development; scale up; side effect; small molecule; success; therapeutic target; tool; total energy expenditure; weight maintenance; wireless

Overweight and obesity are common among Veterans served by the Veterans Health Administration (VHA). Obesity and the chronic diseases associated with obesity place a tremendous burden on our healthcare system and reduce quality of life for the general population as well as for Veterans. As our Veteran population ages over the next decades, this burden will only increase. In addition to few effective pharmacotherapies for obesity prevention, there are no effective therapies for long-term weight maintenance after weight loss in obese subjects. Therapeutically targeting fundamental mechanisms that drive energy expenditure has a larger dividend in terms of improving the health of the overweight Veteran population than would treating individual co-morbidities associated with obesity. One of the possible mechanisms for the development of obesity is decreased availability of the hypothalamic neuropeptide orexin. The orexin neuropeptide, produced in the lateral hypothalamus, are key regulators of physiological functions, including energy homeostasis, sleep/wake stabilization and cognition. A defective orexin system results in weight gain despite reduced food intake, and complete absence of orexin neurons results in the sleep disorder narcolepsy, which is also characterized by weight gain, despite reduced food intake. We and others have consistently demonstrated that orexin enhances physical activity and energy expenditure, and improves sleep/wake patterns. Despite this demonstration that the orexin system can be targeted for weight loss, it’s not feasible to peripherally administer the orexin peptide itself due to its lack of blood- brain barrier permeability. Therefore, to achieve obesity therapies based on orexin, the development and testing of small molecular weight orexin agonists is needed. The overarching hypothesis of this proposal is that small molecular weight agonists for orexin will prevent and reverse diet-induced obesity, through increasing energy expenditure and improving sleep/wake patterns. The goals are to systematically test the efficacy of two small molecule orexin agonists in preventing and reversing high-fat diet-induced obesity by enhancing energy expenditure and improving sleep/wake behavior. To this end, we will expose mice to high-fat diet and use indirect calorimetry in conjunction with wireless radio-telemetric sleep/wake behavioral analyses, to determine if activation of orexin receptors using peripheral novel small molecule orexin agonists prevents and/or reverses obesity, and improves behavioral sleep/wake patterns. The immediate goal is to generate sufficient preclinical data to support use of small molecular-weight orexin agonists to prevent adverse body weight outcomes associated with exposure to obesogenic environments. The long-term goal is to enable research and development of orexin agonists as therapies for obesity and associated comorbidities commonly observed in the Veteran population.

在退伍军人卫生管理局（VHA）服务的退伍军人中，超重和肥胖很常见。 肥胖和与肥胖相关的慢性疾病在我们的医疗保健系统上占有巨大的伯宁 并降低普通人群以及退伍军人的生活质量。随着我们的资深人口的年龄 接下来的几十年，这种燃烧只会增加。除了几乎没有有效的肥胖药物治疗 预防，肥胖受试者体重减轻后没有有效的长期体重维持疗法。 在治疗上瞄准驱动能量消耗的基本机制的股息更大 改善超重退伍军人人口的健康，而不是治疗个人合并症 与肥胖有关。肥胖发展的可能机制之一是降低可用性 下丘脑神经肽OREXIN。下丘脑中产生的Orexin神经肽是 身体功能的关键调节剂，包括能量体内稳态，睡眠/唤醒稳定和认知。 奥列生酸蛋白系统有缺陷导致体重增加目的地减少食物摄入量，并且完全没有奥列生酸蛋白 神经元导致睡眠障碍性疾病，也以体重增加，dospite的特征减少 食物摄入量。我们和其他人一贯证明奥列海素可以增强体育锻炼和能量 支出并改善睡眠/唤醒方式。尽管证明了Orexin System可以是 针对体重减轻的针对性，由于缺乏血液 - 脑屏障渗透性。因此，为了基于Orexin的肥胖疗法，开发和测试 需要小分子量或需要小分子激动剂。 该提案的总体假设是，小分子量的小动物会阻止 通过增加能量消耗和改善睡眠/唤醒方式，逆转饮食引起的肥胖症。 目标是系统地测试两个小分子奥列生酸蛋白激动剂在预防和逆转方面的效率 高脂饮食引起的肥胖，通过增强能量消耗并改善睡眠/唤醒行为。为此， 我们将使小鼠暴露于高脂饮食中，并与无线无线电量表结合使用间接量热法 睡眠/唤醒行为分析，以确定使用外周种新颖的小型Orexin受体的激活 分子或/或反向肥胖症分子或/或反向肥胖，并改善行为睡眠/唤醒模式。 直接目标是生成足够的临床前数据，以支持使用小分子量的OREXIN激动剂的使用 为了防止体重不利的结果与肥胖环境相关。长期 目标是使Orexin激动剂的研究和开发作为肥胖和相关的疗法 在退伍军人人口中通常观察到合并症。