Glucagon-like peptide-1 agonist effects on energy balance in hypothalamic obesity

胰高血糖素样肽-1 激动剂对下丘脑肥胖能量平衡的影响

• 批准号: 9324973
• 负责人: M. Jennifer Abuzzahab
• 金额: $ 49.15万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-24 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324973
• 关键词: Adipose tissue; Adolescent obesity; Adult; Affect; Agonist; Anti-Obesity Agents; Appetitive Behavior; Area; Behavioral; Biological Factors; Blood Glucose; Body Composition; Body Weight; Body Weight decreased; Body fat; Body mass index; Brain; Brain Neoplasms; Brain region; Cardiovascular system; Cell Nucleus; Cerebral Infarction; Cerebrovascular Disorders; Cessation of life; Child; Childhood Brain Neoplasm; Clinical; Clinical Research; Clinical Trials; Controlled Clinical Trials; Craniopharyngioma; Data; Desire for food; Development; Diet; Disease; Double-Blind Method; Energy Intake; Energy Metabolism; Fasting; Functional disorder; GLP-I receptor; Gastrointestinal tract structure; General Population; Glucose; Goals; Homeostasis; Hormonal; Human; Hyperinsulinism; Hyperphagia; Hypothalamic Neoplasms; Hypothalamic dysfunction; Hypothalamic structure; Injection of therapeutic agent; Insulin Resistance; Intervention; Intervention Studies; Lead; Leptin; Leptin resistance; Lesion; Light; Lipids; Magnetic Resonance Imaging; Measures; Medial; Metabolic; Metabolic syndrome; Morbid Obesity; Multicenter Studies; Multicenter Trials; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Outcome; Outcome Measure; Patients; Peripheral; Pharmaceutical Preparations; Physical activity; Physiology; Pilot Projects; Placebo Control; Placebos; Population; Population Study; Quality of life; Randomized; Randomized Clinical Trials; Regulation; Reporting; Resistance; Risk; Risk Factors; Rodent; Safety; Satiation; Secondary to; Serum; Severities; Signal Pathway; Signal Transduction; Site; Survival Rate; Sweden; Testing; Treatment outcome; Vagus nerve structure; Weight Gain; Work; actigraphy; base; brain size; cardiometabolic risk; cardiovascular disorder risk; cohort; cost effective; design; doubly-labeled water; effective therapy; energy balance; exenatide; glucagon-like peptide 1; glucose tolerance; hindbrain; improved; inflammatory marker; innovation; insight; insulin secretion; mortality; neuroimaging; novel; novel therapeutics; obesity management; open label; predictive of treatment response; prospective; public health relevance; randomized placebo controlled trial; randomized trial; response; success; successful intervention; total energy expenditure; treatment response; tumor

 DESCRIPTION (provided by applicant): Hypothalamic obesity (HO) occurs in patients with tumors and lesions in the medial hypothalamic region. Hypothalamic dysfunction can lead to hyperinsulinemia and leptin resistance. This study is focused on HO caused by craniopharyngiomas (CP), which are the most common childhood brain tumors of nonglial origin. Despite excellent overall survival rates, CP patients have substantially reduced quality of life because of significant long-term sequelae, notably severe obesity in about 50% of patients, leading to a high rate of cardiovascular mortality. Recent studies reported that both hyperphagia and decreased energy expenditure can contribute to severe obesity in HO patients. Previous drug intervention studies were either too small or showed only moderate effects, and it is not clear which biological factors are responsible for successful intervention. Some anti-obesity drugs that require intact hypothalamic signaling pathways for appetite inhibition show poor efficacy in patients with HO. Based on promising results using a glucagon-like-peptide-1 receptor agonist (GLP1RA) in obese adolescents with and without HO, as well as in rodents with HO, the proposed multicenter study will test the effect of the GLP1RA exenatide once weekly extended-release (ExQW) on clinical outcomes and metabolic function in a 36 week double-blind, placebo-controlled randomized trial followed by a 18 week open label extension. Forty-eight subjects will be randomized to GLP1RA (24) or placebo (24). The overall hypothesis is that in severely obese HO subjects with extended hypothalamic damage, drugs causing weight loss via hindbrain signaling, such as GLP1RAs, will reduce body weight, providing a desperately needed non-surgical option for treatment of HO. We recognize that there may be variability of treatment response and will therefore also test potential behavioral, metabolic, and neuroradiological predictors of treatment response. The primary endpoint is to test long-term efficacy of GLP1RA treatment on body mass index reduction after 36 weeks. Secondary endpoints include changes in body composition, parameters of metabolic syndrome, free-living total energy expenditure, appetitive behavior, physical activity, hormonal parameters of energy homeostasis and insulin resistance. Specific Aim (SA) 1 will test if GLP1RA treatment will lead to reduced BMI. SA 2 will test if GLP1RA improves adiposity, cardiometabolic risk factors, glucose tolerance and hyperinsulinemia. SA 3 will include exploratory studies in order to test if GLP1RA will lead to changes in energy intake and expenditure. SA 3 will also test innovative predictors of GLP1RA treatment outcomes such as pretreatment hyperphagia, energy expenditure, serum leptin and the severity of the hypothalamic lesion assessed by a novel neuroimaging score obtained prior to study intervention. The study is guided by an integrated transdisciplinary team. The goals are to implement cost-effective treatments to improve HO outcomes, and to get fundamental mechanistic insights into GLP-1 physiology and factors that determine treatment success, which are also relevant for other forms of obesity.

 描述（由适用提供）：下丘脑肥胖症（HO）发生在内侧下丘脑区域的肿瘤和病变患者中。下丘脑功能障碍会导致高胰岛素血症和瘦素耐药性。这项研究的重点是由颅咽管瘤（CP）引起的HO，这是非乳腺癌起源的最常见的儿童脑肿瘤。尽管总体生存率出色，但CP患者的质量大大降低了 生命是由于长期后遗症的明显，尤其是大约50％的患者肥胖，导致心血管死亡率高。最近的研究报告说，倍率和能量消耗降低都会导致HO患者严重的肥胖症。先前的药物干预研究要么太小，要么仅显示中等影响，尚不清楚哪些生物学因素是成功干预的原因。一些需要完整的下丘脑信号传导途径以抑制食欲的抗肥胖药物在HO患者中效率较差。基于有希望的结果，使用有或没有HO的肥胖青少年以及HO的啮齿动物中使用胰高血糖素样肽1受体激动剂（GLP1RA），拟议的多中心研究将测试GLP1RA EnceNaTide每周一次的GLP1RA ENCENATIDE每周一次延长释放（EXQW）对临床和周期的延长次数的延长，并在36周进行了三个周的次数，并在36周中进行了新的综合函数标签扩展。 48名受试者将被随机分为GLP1RA（24）或安慰剂（24）。总体假设是，在严重的肥胖HO受试者中，下丘脑损伤的受试者，通过后脑信号传导（例如GLP1RAS）导致体重减轻的药物将减轻体重，从而为HO治疗急需的非手术选择。我们认识到治疗反应可能存在差异，因此还将测试潜在的行为，代谢和 治疗反应的神经放射学预测指标。主要终点是测试36周后GLP1RA处理对体重指数降低的长期有效性。次要终点包括身体成分的变化，代谢综合征的参数，自由生活的总能量消耗，食欲，体育锻炼，能量稳态的马匹参数和胰岛素抵抗。具体目标（SA）1将测试GLP1RA治疗SA 2是否会测试GLP1RA是否会提高肥胖，心脏代谢危险因素，葡萄糖耐受性和高胰岛素血症。 SA 3将包括探索性研究，以测试GLP1RA是否会导致能量摄入和支出变化。 SA 3还将测试GLP1RA治疗结果的创新预测指标，例如预处理食管，能量消耗，血清瘦素以及通过在研究干预之前获得的新神经影像学评分评估的下丘脑病变的严重程度。该研究由综合跨学科团队指导。目标是实施具有成本效益的治疗方法，以改善HO结果，并获得对GLP-1生理学的基本机理见解和确定治疗成功的因素，这也与其他形式的肥胖有关。