Oxytocin as a Neuroendocrine Therapy for Obesity in Youth

项目摘要 青春期和青年期的肥胖是流行病，导致以后生活中代谢风险增加。的 通过生活方式干预减轻体重的程度是可变的，难以维持。现有医疗 用于成人的治疗，通常没有FDA批准用于儿童，可能会导致适度的体重减轻，但效果 很难维持，这些药物的耐受性有限。催产素（OXT），下丘脑 调节食物摄入和能量代谢激素，是一种令人兴奋的潜在新型治疗药物， 人口在一项为期8周的小型研究中，鼻内（IN）OXT诱导了显著的体重减轻，并且耐受性良好。 肥胖的成年人。我们的初步数据显示，6个月的BMI SDS降低，耐受性极佳。 在一系列BMI的5-18岁儿童中，啮齿动物和非人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肥。重要的是，OXT 也有可能通过减少内脏和肝脏脂肪， 炎症和改善的脂质。事实上，OXT最近被证明可以减少神经炎症， 肥胖啮齿动物模型中的下丘脑炎症。我们建议进行一项随机、安慰剂对照研究 12周IN OXT与安慰剂的比较，以确定OXT是否降低了体重和代谢风险标志物 在肥胖青少年中的作用与在饮食诱导的肥胖动物模型中的作用相同。我们还将调查潜在的 使用先进的成像和代谢评估驱动OXT效应的机制。在一项研究中，75 对于肥胖青少年，我们假设与安慰剂相比，12周IN OXT将导致（1） BMI SDS降低，源于（a）空腹状态和无饥饿时摄食量减少，和（B） 增加静息能量消耗和饮食诱导的产热作用，通过降低 下丘脑炎症;（2）内脏和肝内脂肪减少， 瘦/肌肉质量，与减少全身炎症和改善血脂相关。本研究将 成为第一个系统地研究OXT作为一种新型治疗药物的有效性和安全性， 减肥和改善肥胖青少年的代谢风险指标。

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.