An experimental medicine approach toward the identification of a compulsive overeating phenotype in obesity

摘要 强迫性暴饮暴食折磨着30%的肥胖寻求治疗的个体， 心血管疾病（CVD）的危险因素。然而，目前的肥胖干预方法并不 专门针对强迫性暴饮暴食的机制。我对肥胖女性的研究表明， 强迫性暴饮暴食与内源性阿片样物质活性的改变有关， 阿片样物质能戒断症状）。数据还 显示出强迫性暴饮暴食，高可口食物摄入，冲动，奖励敏感， 以及其他因素，这些因素加在一起，可能是肥胖症中强迫性暴饮暴食表型的特征。这 K23奖将支持我的独立研究事业的发展更加有效地集中 肥胖症及其心血管并发症中强迫性暴饮暴食的干预措施。拟议 实验医学研究将通过调查强迫性暴饮暴食来推进这项研究计划。 肥胖症的表型，使用：（1）多方法评估组合（MAB），以评估行为，心理， 和肥胖的营养相关性，（2）CVD风险的肥胖相关指数（例如，血糖控制， 高血压），和（3）我的新NX协议，以评估改变内源性阿片活性（目的1）。我将评估 NX方案的重测可靠性，并且，在一个没有NX反应（恶心）的受试者子集中， 初步测试，测试在施用我们的2周糖饮料后是否可以诱导NX反应 消费协议，因为糖影响内源性阿片活性（目标2）。和我的导师们一起，我会确定 根据研究1的结果和当前的文献综述，确定了强迫性暴饮暴食的干预目标。我 然后，将选择在先前研究中对这些目标产生变化的干预成分，并将 在一项针对强迫性暴饮暴食和肥胖妇女的试点研究中，开发、完善和测试这些成分 (Aim 3）。我将研究干预措施的可行性和可接受性，并收集预 在研究1中使用的措施的变化后。初步数据将告知R34临床试验初步研究提案I 将提交测试一种针对肥胖症患者强迫性暴饮暴食的优化干预措施。拟议的培训计划 将为我提供必要的支持和指导，以获得识别阿片类药物的专业知识， 与强迫性暴饮暴食相关的心理、行为和营养目标;获得培训 需要独立设计和进行实验室研究，并评估肥胖相关的CVD风险 因素;并获得开发和测试肥胖干预措施所需的培训。这些培训 经验，加上拟议的研究计划，将有助于我的职业生涯致力于发展 对肥胖症强迫性暴饮暴食机制的干预措施。此次K23奖将深化 了解和治疗强迫性暴饮暴食的现状，促进肥胖症的发展， 针对这一特殊人群的干预措施，我们目前缺乏有效的干预措施。

ABSTRACT Compulsive overeating afflicts 30% of treatment-seeking individuals with obesity and correlates with cardiovascular disease (CVD) risk factors. Current obesity intervention approaches, however, do not specifically target mechanisms that underlie compulsive overeating. My research on obese women shows that compulsive overeating is associated with alterations in endogenous opioid activity as indexed by nausea (an opioidergic withdrawal symptom) following administration of the opioid antagonist naltrexone (NX). Data also show associations between compulsive overeating, highly palatable food intake, impulsivity, reward-sensitivity, and other factors, which, taken together, may characterize a compulsive overeating phenotype in obesity. This K23 Award will support the development of my independent research career focused on more effective interventions for compulsive overeating in obesity and its cardiovascular comorbidities. The proposed experimental medicine studies will advance this research program by investigating a compulsive overeating phenotype in obesity using: (1) a multimethod assessment battery (MAB) to assess behavioral, psychological, and nutritional correlates of obesity, (2) obesity-related indices of CVD risk (e.g., glycemic control, hypertension), and (3) my novel NX protocol to assess altered endogenous opioid activity (Aim 1). I will assess NX protocol test-retest reliability and, in a subset of participants who do not have a NX response (nausea) at initial testing, test whether NX response can be induced after administering our 2-week sugar-beverage consumption protocol, as sugar impacts endogenous opioid activity (Aim 2). With my mentors, I will identify intervention targets in compulsive overeating based on Study 1 results and a current review of the literature. I will then select intervention components that have produced change in these targets in prior research, and will develop, refine, and test these components in a pilot study of women with compulsive overeating and obesity (Aim 3). I will examine feasibility and acceptability of the intervention components and collect pilot data on pre- post change in the measures used in Study 1. Pilot data will inform the R34 Clinical Trial Pilot Study proposal I will submit to test an optimized intervention for compulsive overeating in obesity. The proposed training plan will provide me with the support and mentorship necessary to gain expertise in the identification of opioidergic, psychological, behavioral, and nutritional targets associated with compulsive overeating; to obtain the training needed to independently design and conduct laboratory research and to assess obesity-related CVD risk factors; and to obtain the training necessary to develop and test obesity interventions. These training experiences, coupled with the proposed research plan, will facilitate my career devoted to the development of interventions that act on mechanisms underlying compulsive overeating in obesity. This K23 Award will deepen current understanding and treatment of compulsive overeating in obesity and promote development of interventions for this distinct subset of individuals, for whom we currently lack effective interventions.