Oxytocin as a Neuroendocrine Therapy for Obesity in Youth

催产素作为青少年肥胖症的神经内分泌疗法

基本信息

批准号：
10118294
负责人：
Miriam Antoinette Bredella
金额：
$ 73.38万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-17 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10118294
关键词：
18 year old Adolescence Adolescent Adolescent obesity Adult Animal Model Anti-Inflammatory Agents Automobile Driving Behavior Body Composition Body Weight Body Weight decreased Child Data Diet Dose Dual-Energy X-Ray Absorptiometry Dyslipidemias Early treatment Eating Eating Behavior Elderly Energy Intake Energy Metabolism Epidemic Executive Dysfunction Fasting Fatty acid glycerol esters Food Energy Heart Diseases Hepatic Hunger Hypothalamic Hormones Hypothalamic structure Image Indirect Calorimetry Individual Inflammation Interleukin-6 Intervention Investigation Lead Life Lipids Lipoproteins Measures Mediating Medical Metabolic Monkeys Motor Activity Neuroendocrine Therapy Neurosecretory Systems Obesity Overweight Oxytocin Patients Pharmaceutical Preparations Physical activity Physiological Physiology Placebos Population Property Quality of life Randomized Randomized Controlled Trials Rattus Rest Risk Risk Marker Rodent Rodent Model Safety Serum Single-Blind Study TNF gene Taste Perception Testing Therapeutic Therapeutic Agents Thermogenesis Thinness Time Treatment Efficacy Triglycerides Visceral Weight Weight Gain Youth adult obesity cardiometabolic risk comorbidity critical period developmental plasticity efficacy study energy balance food consumption improved intrahepatic lifestyle intervention mortality muscle form neuroinflammation nonhuman primate novel novel therapeutics peptide hormone preservation prevent randomized placebo controlled study reduced food intake young adult

项目摘要

PROJECT ABSTRACT Obesity in adolescence and young adulthood is epidemic, leading to increased metabolic risk later in life. The extent of weight loss through lifestyle interventions is variable and difficult to sustain. Existing medical therapies for adults, which are often not FDA-approved in children, may lead to modest weight loss, but effects are difficult to sustain, and these medications are limited by their tolerability. Oxytocin (OXT), a hypothalamic hormone that regulates food intake and energy metabolism, is an exciting potential novel therapeutic in this population. Intranasal (IN) OXT induced marked weight loss and was well tolerated in a small 8-week study of adults with obesity. Our preliminary data show reduction in BMI SDS with excellent tolerability with 6-months of IN OXT in 5-18-year-old children across a range of BMIs. Data in rodent and nonhuman primates indicate that OXT drives weight loss by reducing food consumption and increasing energy expenditure. Importantly, OXT also has the potential to reduce metabolic risk through reduction in visceral and hepatic fat, reduced inflammation, and improved lipids. In fact, OXT has recently been shown to reduce neuroinflammation, and hypothalamic inflammation in rodent models with obesity. We propose a randomized, placebo-controlled study of twelve weeks of IN OXT vs. placebo to determine whether OXT reduces weight and metabolic risk markers in adolescents with obesity as it does in diet-induced obese animal models. We will also investigate underlying mechanisms driving OXT effects using cutting-edge imaging and metabolic assessments. In a study of 75 adolescents with obesity, we hypothesize that twelve weeks of IN OXT compared to placebo will result in (1) reduced BMI SDS from (a) decreased food intake in the fasting state and in the absence of hunger, and (b) increased resting energy expenditure and diet-induced thermogenesis, mediated by reduced measures of hypothalamic inflammation; and (2) reduced visceral and intrahepatic fat with relative preservation of lean/muscle mass, associated with reduced systemic inflammation and an improved lipid profile. This study will be the first to systematically investigate the efficacy and safety of OXT as a novel therapeutic agent to induce weight loss and improve indicators of metabolic risk in adolescents with obesity.

项目摘要青春期和成年年轻人的肥胖症是流行病，导致生命之后的代谢风险增加。这通过生活方式干预措施减肥的程度是可变的，难以维持。现有医疗成人的疗法通常不受FDA批准的儿童批准，可能会导致体重减轻，但影响难以维持，这些药物受到其耐受性的限制。催产素（OXT），下丘脑调节食物摄入和能量代谢的激素是一种令人兴奋的潜在新型治疗方法人口。鼻内（IN）OXT诱导了显着的体重减轻，并在一项为期8周的小研究中耐受肥胖的成年人。我们的初步数据显示，BMI SD的降低，具有出色的耐受性，6个月在一系列BMI的5-18岁儿童中，在OXT中。啮齿动物和非人类灵长类动物的数据表明 OXT通过减少食物消耗和增加能源消耗来促进体重减轻。重要的是，牛还有可能通过减少内脏和肝脂肪来降低代谢风险，减少炎症和改善的脂质。实际上，最近已显示OXT可以减少神经炎症，并且肥胖的啮齿动物模型中的下丘脑炎症。我们提出了一项随机，安慰剂控制的研究在OXT中与安慰剂的十二周，以确定OXT是否减少体重和代谢风险标记在肥胖的青少年中，就像在饮食引起的肥胖动物模型中一样。我们还将调查基础使用最先进的成像和代谢评估来驱动OXT效应的机制。在研究75 肥胖症的青少年，我们假设OXT与安慰剂相比将在OXT中进行十二周，将导致（1）（a）减少了在禁食状态和没有饥饿状态下食物摄入量的BMI SDS，并且（b）增加的静息能量消耗和饮食引起的热发生，这是通过减少的措施介导的下丘脑炎症；（2）减少内脏和肝内脂肪，并相对保留瘦/肌肉质量，与系统性炎症减少和脂质谱的改善有关。这项研究会成为第一个系统地研究OXT作为新型治疗剂的疗效和安全性的人体重减轻并改善肥胖青少年代谢风险的指标。