Orexin agonists as novel obesity therapeutics

食欲素激动剂作为新型肥胖疗法

• 批准号: 10369478
• 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/10369478
• 关键词: Address; Adult; Affect; Affinity; Age; Agonist; Anti-Obesity Agents; Automobile Driving; Behavior; Behavioral; Biological Availability; Blood - brain barrier anatomy; 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; Prevention; Property; Quality of life; Radio; Receptor Activation; Research; Rodent; Sleep; Sleep Disorders; Sleep Wake Cycle; Sleep disturbances; Structure; Subconscious; System; Telemetry; Testing; Therapeutic; Thermogenesis; Treatment outcome; Vertebral column; Veterans; Veterans Health Administration; Weight Gain; base; blood-brain barrier permeabilization; comorbidity; diet-induced obesity; effective therapy; efficacy testing; exercise program; good diet; healthspan; hypocretin; improved; 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.

超重和肥胖在退伍军人健康管理局（VHA）服务的退伍军人中很常见。 肥胖和与肥胖相关的慢性疾病给我们的医疗保健系统带来了巨大的负担 并降低普通人群和退伍军人的生活质量。随着我们的退伍军人年龄的增长， 在未来的几十年里，这种负担只会增加。除了少数有效的药物治疗肥胖外， 由于肥胖症的预防，没有有效的治疗方法用于肥胖受试者体重减轻后的长期体重维持。 针对驱动能量消耗的基本机制进行治疗， 改善超重退伍军人人群的健康，而不是治疗个体合并症， 与肥胖有关。其中一个可能的机制发展肥胖是减少可用性 下丘脑神经肽增食欲素。下丘脑外侧产生的食欲素神经肽， 生理功能的关键调节因子，包括能量稳态、睡眠/觉醒稳定和认知。 一个有缺陷的食欲素系统导致体重增加，尽管减少食物摄入量，并完全缺乏食欲素 神经元导致睡眠障碍发作性睡病，这也是以体重增加为特征，尽管减少 食物摄入量我们和其他人一直证明食欲素增强体力活动和能量 消耗，并改善睡眠/觉醒模式。尽管这表明食欲素系统可以被 作为减肥的目标，由于缺乏血液，外周施用食欲肽本身是不可行的， 脑屏障通透性因此，要实现基于食欲素的肥胖疗法， 需要小分子量的食欲素激动剂。 该建议的首要假设是，食欲素的小分子量激动剂将阻止食欲素的产生。 并通过增加能量消耗和改善睡眠/觉醒模式来逆转饮食引起的肥胖。 目的是系统地测试两种小分子食欲素激动剂在预防和逆转 通过增加能量消耗和改善睡眠/觉醒行为来治疗高脂饮食引起的肥胖。为此目的， 我们将小鼠暴露于高脂肪饮食中，并使用间接热量测定法结合无线电遥测技术， 睡眠/觉醒行为分析，以确定是否使用外周新的小分子 分子食欲素激动剂预防和/或逆转肥胖，并改善行为睡眠/觉醒模式。的 当前目标是产生足够的临床前数据以支持小分子量食欲素激动剂的使用 以防止与暴露于致肥胖环境相关的不良体重结果。长期 目标是能够研究和开发食欲素激动剂作为肥胖症和相关疾病的治疗方法， 在退伍军人人群中常见的合并症。