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.