Oxytocin and Weight Loss in Humans

催产素与人类减肥

• 批准号: 9309526
• 负责人: Elizabeth Austen Lawson
• 金额: $ 63.68万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9309526
• 关键词: Address; Adult; Adverse effects; Affect; Age; Animal Model; Anterior; Basal Ganglia; Body Composition; Body Weight decreased; Body fat; Brain region; Comorbidity; Data; Desire for food; Diet; Dose; Double-Blind Method; Eating; Energy Intake; Energy Metabolism; Fasting; Fatty acid glycerol esters; Food; Food Energy; Functional Magnetic Resonance Imaging; Gender; Human; Hypothalamic Hormones; Impulsive Behavior; Impulsivity; Investigation; Knowledge; Leptin; Lipolysis; Liver; Mediating; Modeling; Monkeys; Motivation; Neural Pathways; Neurons; Neurosecretory Systems; Obese Mice; Obesity; Overweight; Oxytocin; Oxytocin Receptor; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Physiological; Placebo Control; Placebos; Prefrontal Cortex; Premature Mortality; Public Health; Randomized; Rattus; Rest; Rewards; Rodent; Safety; Serum; Stimulus; Testing; Translating; Translations; Triglycerides; Ventral Tegmental Area; Visceral; Visit; Visual; Weight; Weight Gain; Weight-Loss Drugs; Woman; alpha-Melanocyte stimulating hormone; behavior measurement; cingulate cortex; clinically relevant; feeding; follow-up; food consumption; men; mind control; neuroimaging; neuroregulation; nonhuman primate; novel therapeutics; obesity management; oxidation; placebo controlled study; pre-clinical; preclinical study; prevent; randomized placebo controlled trial; reduced food intake; relating to nervous system; respiratory; response

Project Summary / Abstract Meaningful weight reduction in obesity is difficult to achieve and sustain, and available therapies have significant limitations. Oxytocin (OXT), a hypothalamic hormone that regulates food intake and energy metabolism, is an exciting potential novel therapeutic in obesity management. A small study of obese adults demonstrated weight loss of nearly 20 lbs with 8 weeks of intranasal (IN) OXT at the proposed dose. Data in rodent and nonhuman primate models indicate that OXT drives weight loss by (1) increasing energy expenditure, (2) inducing lipolysis, and (3) reducing food consumption. We propose a randomized, placebo- controlled study of sustained IN OXT to determine whether OXT reduces body weight, increases energy expenditure and reduces total, visceral and liver fat in obese humans, as it does in animal models. We will also characterize the effects of sustained OXT on caloric intake and relevant neural pathways using cutting-edge neuroendocrine, neuroimaging, and behavioral measures. In a study of 60 obese men and women, we hypothesize that eight weeks of IN OXT (24 IU qid) compared to placebo will result in (a) weight loss, (b) increased resting energy expenditure; and (c) reduced total body, visceral and liver fat. Building on our prior findings indicating that OXT may achieve weight reduction in part by modulating reward and impulse control neural pathways to curb eating, we further hypothesize that OXT will result in reduced caloric intake at a test meal, independent of change in weight, compared to placebo, mediated by (a) reduced fasting and post- prandial fMRI activation of reward-related food motivation brain regions (ventral tegmental area, basal ganglia) using a visual food stimuli paradigm; and (b) increased impulse control accompanied by increased fMRI activation and functional connectivity of impulse control brain regions (anterior cingulate, dorsolateral prefrontal cortex) during a validated task requiring the engagement of impulse control to suppress impulsive responses. This study will demonstrate the efficacy and increase our understanding of the underlying mechanisms of IN OXT as a potential weight loss drug -- critical steps in the translation of preclinical findings to humans and optimizing therapies for patients with obesity.

项目总结/摘要 肥胖症患者的有意义的体重减轻难以实现和维持，现有的治疗方法 重大限制。催产素（OXT），一种调节食物摄入和能量的下丘脑激素 代谢，是一个令人兴奋的潜在的新的治疗肥胖管理。一项针对肥胖成年人的小型研究 经8周鼻内（IN）OXT治疗，在拟定剂量下体重减轻近20磅。数据 啮齿动物和非人类灵长类动物模型表明，OXT通过（1）增加能量 支出，（2）诱导脂肪分解，和（3）减少食物消耗。我们提出一个随机的安慰剂- 持续IN OXT的对照研究，以确定OXT是否减轻体重、增加能量 在动物模型中，它可以减少肥胖人群的总脂肪、内脏脂肪和肝脏脂肪。我们还将 使用最先进的技术来表征持续OXT对热量摄入和相关神经通路的影响。 神经内分泌、神经影像和行为测量。在一项针对60名肥胖男女的研究中， 假设与安慰剂相比，8周IN OXT（24 IU qid）将导致（a）体重减轻，（B） 增加静息能量消耗;和（c）减少全身、内脏和肝脏脂肪。根据我们之前 研究结果表明，OXT可能通过调节奖励和冲动控制来减轻体重 神经通路抑制进食，我们进一步假设OXT将导致在测试中减少热量摄入 与安慰剂相比，与体重变化无关，通过（a）减少空腹和餐后 进食时fMRI激活奖励相关食物动机脑区（腹侧被盖区，基底神经节） 使用视觉食物刺激范例;和（B）增加的冲动控制伴随增加的fMRI 冲动控制脑区（前扣带回、背外侧前额叶）的激活和功能连接 皮层）在需要参与脉冲控制以抑制脉冲反应的有效任务期间。 这项研究将证明其有效性，并增加我们对IN潜在机制的理解 OXT作为一种潜在的减肥药物-临床前研究结果转化为人类的关键步骤， 优化肥胖患者的治疗方案。