Oxytocin and Weight Loss in Humans

项目摘要/摘要 在肥胖症中有意义的体重减轻是难以实现和持续的，而现有的治疗方法 明显的局限性。催产素(OXT)，一种调节食物摄入量和能量的下丘脑激素 新陈代谢，是一种令人兴奋的潜在的肥胖治疗新方法。一项针对肥胖成年人的小型研究 在建议剂量下，8周的鼻腔(IN)OXT显示体重减轻了近20磅。数据输入 啮齿动物和非人类灵长类动物模型表明，OXT通过(1)增加能量来推动体重减轻 支出，(2)导致脂肪分解，(3)减少食物消耗。我们提出了一种随机的安慰剂- OXT持续存在的对照研究，以确定OXT是否减轻体重，增加能量 并减少肥胖人类的总脂肪、内脏脂肪和肝脏脂肪，就像在动物模型中所做的那样。我们还将 用尖端技术表征持续OXT对卡路里摄入量和相关神经通路的影响 神经内分泌、神经成像和行为测量。在一项对60名肥胖男女的研究中，我们 假设与安慰剂相比，服用8周的INoxt(24IU Qid)将导致(A)体重减轻，(B) 增加静息能量消耗；以及(C)减少全身、内脏和肝脏脂肪。建立在我们之前的基础上 研究结果表明，OXT可能部分通过调节奖赏和冲动控制来实现减肥 抑制进食的神经通路，我们进一步假设OXT将导致测试中卡路里摄入量减少 与安慰剂相比，与体重变化无关的膳食，由以下因素调节：(A)空腹和餐后体重减少 食物刺激相关大脑区域(腹侧被盖区、基底节)的膳食fMRI激活 使用视觉食物刺激范式；和(B)增加冲动控制，同时增加功能磁共振 冲动控制脑区(前扣带回、前额背外侧区)的激活和功能连接 在需要使用脉冲控制来抑制脉冲反应的有效任务中。 这项研究将证明IN的有效性，并加深我们对IN潜在机制的理解 OXT作为一种潜在的减肥药--将临床前研究成果转化为人类和 优化肥胖患者的治疗方法。

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.