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

摘要 强迫性暴饮暴食困扰着30%寻求治疗的肥胖症患者，并与 心血管疾病(CVD)危险因素。然而，目前的肥胖干预方法并不适用 专门针对导致强迫性暴饮暴食的机制。我对肥胖女性的研究表明 强迫性暴饮暴食与以恶心为指标的内源性阿片类药物活动的改变有关(和 阿片类拮抗剂纳曲酮(NX)给药后出现阿片能戒断症状。数据也 显示了强迫性暴饮暴食、非常可口的食物摄入量、冲动、奖赏敏感、 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的特征。这 K23奖将支持我专注于独立研究事业的发展，更加有效 肥胖患者强迫性暴食及其心血管并发症的干预。建议数 实验医学研究将通过调查强迫性暴饮暴食来推进这一研究计划 肥胖症的表型使用：(1)多方法评估组合(MAB)来评估行为，心理， 和肥胖的营养相关性，(2)与心血管疾病风险相关的肥胖指数(例如，血糖控制， 高血压)，和(3)我的新的NX方案来评估改变的内源性阿片活性(目标1)。我会评估 NX方案测试-重新测试可靠性，并在以下时间没有NX反应(恶心)的参与者子集中 初步测试，测试服用我们两周的含糖饮料后是否会产生NX反应 消费方案，因为糖影响内源性阿片类药物活动(目标2)。和我的导师们一起，我会认同 基于研究1结果和当前文献综述的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 在一项针对患有强迫性暴饮暴食和肥胖的女性的试点研究中，开发、提炼和测试这些成分 (目标3)。我将审查干预措施组成部分的可行性和可接受性，并收集关于 研究1中使用的措施的员额变化。先导数据将为R34临床试验先导研究提案I提供信息 将提交测试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，以获得阿片类药物鉴定方面的专业知识， 与强迫性暴饮暴食相关的心理、行为和营养指标；接受培训 需要独立设计和进行实验室研究并评估与肥胖相关的心血管疾病风险 并获得制定和测试肥胖干预措施所需的培训。这些培训 经验，再加上拟议的研究计划，将有助于我致力于发展 干预作用于肥胖患者强迫性暴饮暴食的机制。本次K23大奖将深化 当前对肥胖症强迫性暴食的认识和治疗，促进肥胖的发展 针对这一特殊人群的干预措施，我们目前缺乏对他们的有效干预措施。

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.