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：
10435539
负责人：
Miriam Antoinette Bredella
金额：
$ 72.13万
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 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10435539
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 Body mass index 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 Life Lipids Lipoproteins Magnetic Resonance Imaging Measures Mediating Medical Metabolic Monkeys Motor Activity Neuroendocrine Therapy Neurosecretory Systems Obesity Overweight Oxytocin Pharmaceutical Preparations Physical activity Physiological Physiology Placebo Control 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 Triglycerides Visceral Weight Weight Gain Youth adult obesity cardiometabolic risk comorbidity critical period developmental plasticity diet-induced obesity efficacy study energy balance food consumption improved intrahepatic lifestyle intervention mortality muscle form neuroinflammation nonhuman primate novel novel therapeutics obese patients obesity treatment peptide hormone preservation prevent randomized placebo controlled study reduced food intake systemic inflammatory response therapeutically effective 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早期的肥胖很流行，导致晚年代谢风险增加。这通过生活方式干预的减肥程度各不相同且难以维持。现有医疗针对成人的疗法通常未获得 FDA 批准用于儿童，可能会导致适度的体重减轻，但效果难以维持，并且这些药物因其耐受性而受到限制。催产素 (OXT) 是一种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疗法人口。一项为期 8 周的小型研究显示，鼻内 (IN) OXT 可显着减轻体重，且耐受性良好患有肥胖症的成年人。我们的初步数据显示 BMI SDS 降低，并且 6 个月的耐受性良好 IN OXT 针对不同 BMI 的 5-18 岁儿童。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量消耗来减轻体重。重要的是，OXT 还具有通过减少内脏和肝脏脂肪来降低代谢风险的潜力，减少炎症，改善血脂。事实上，OXT 最近被证明可以减少神经炎症，并且肥胖啮齿动物模型中的下丘脑炎症。我们提出一项随机、安慰剂对照研究为期 12 周的 IN OXT 与安慰剂对比，以确定 OXT 是否可以减轻体重和代谢风险标志物在肥胖青少年中，就像在饮食引起的肥胖动物模型中一样。我们还将调查底层使用尖端成像和代谢评估驱动 OXT 效应的机制。在一项针对 75 人的研究中对于患有肥胖症的青少年，我们假设与安慰剂相比，12 周的 IN OXT 会导致 (1) BMI SDS 的降低源自 (a) 禁食状态和不饥饿状态下食物摄入量的减少，以及 (b) 增加静息能量消耗和饮食诱导的生热作用，由减少措施介导下丘脑炎症； (2) 减少内脏和肝内脂肪，并相对保存瘦肉/肌肉质量，与减少全身炎症和改善血脂状况相关。这项研究将成为第一个系统研究 OXT 作为新型治疗剂的功效和安全性的人减肥并改善肥胖青少年的代谢风险指标。