Gastric bypass surgery alters the regulation of food reward

描述(申请人提供)：胃旁路手术(GBS)是一种非常成功的治疗病态肥胖和2型糖尿病的方法。GBS患者通常会减去总体重的25%-35%，表现出医疗合并症的改善，并在15年内持续减肥。鉴于肥胖症在美国的流行，更好地了解GBS导致和维持减肥的机制是一个重要的研究领域。虽然GBS机械地限制食物的摄入量，但它似乎也降低了食欲和对美味食物的吸引力。然而，目前尚不清楚为什么激励系统未能促使患者通过增加食物摄入量和偏爱美味、高卡路里的食物来补偿这种大规模的体重减轻--这是正常的体内平衡反应。阐明这一悖论将极大地提高我们对饮食和体重调节机制的理解。基于GBS的动物模型，我们处于一个独特的位置来解决这个问题，该模型展示了我们实验室开发的调节食物奖励功能的中枢神经机制的变化。目前的研究提出了在高能量/高脂肪饮食诱导的肥胖大鼠模型中进行行为、药理学、神经化学和组织学研究，以检验GBS改变食欲和食物偏好功能从而改变食物奖励系统的假设。这些实验的目标是伏隔核，这是奖励的关键结构，重点是两个主要的递质：多巴胺和乙酰胆碱。我们提出了四个具体目标来检验这一假设的不同组成部分。第一个目标将建立针对食物奖励的特定方面的行为影响(即激励、强化和享乐价值)，并比较不同减肥方法(即限制卡路里和GBS)中这些行为中的多巴胺参与。第二个和第三个目标将机械地分别解决潜在的动态和静态(即神经适应)信号机制。目标4将调查增加的肠脑肽信号是否有助于改善GBS后的食物奖励功能。我们相信，这项拟议的研究具有巨大的潜力来影响患者的护理，因为它将提高我们对可能对长期体重维持有积极或消极影响的因素的理解，并可能阐明开发侵入性较小的肥胖治疗方法的新目标。初步数据表明，GBS有益于调节食欲和食物选择，导致比节食更显著、更持久的减肥效果。目前的研究考察了与节食相比，GBS如何影响饮食肥胖大鼠大脑中美味食物的回报效果。关于GBS产生的动机行为和潜在神经底物的基本变化的信息可以帮助开发有效的非手术治疗肥胖症的方法。

DESCRIPTION (provided by applicant): Gastric bypass surgery (GBS) is an exceptionally successful therapy for morbid obesity and type 2 diabetes. GBS patients typically lose 25-35% of total body weight, demonstrate improvements in medical co- morbidities, and sustained weight loss over fifteen years. Given the epidemic of obesity in the United States, an improved understanding of the mechanisms by which GBS causes and maintains weight loss represents an important area of research. Although GBS mechanically restricts food intake, it also appears to reduce appetite and the appeal of savory meals. However, it is unclear why the motivational system fails to drive patients to compensate for this massive weight loss with increased food intake and preference for palatable, calorie-dense foods - the normal homeostatic response. Elucidating this paradox would substantially improve our understanding of the regulatory mechanisms for eating and body weight. We are in a unique position to address this question based on an animal model of GBS demonstrating alterations in the central neural mechanisms regulating food reward functions developed in our laboratory. The current study proposes behavioral, pharmacological, neurochemical and histological studies in high energy/high fat diet- induced obesity rat models to test the hypothesis that GBS alters appetite and food preference functions resulting in changes to the food reward system. The experiments target the nucleus accumbens, a critical structure for reward, with focus on two major transmitters: dopamine and acetylcholine. We propose four specific aims to test different components of this hypothesis. The first aim will establish the behavioral effects addressing specific aspects of food reward (i.e., incentive, reinforcement and hedonic value), and compare dopamine involvement in these behaviors across weight reduction methods (i.e. caloric restriction vs. GBS). The second and third aims will mechanistically address the underlying dynamic and static (i.e. neuroadaptive) signaling mechanisms, respectively. Aim 4 will investigate if increased gut-brain peptide signaling contributes to improved food reward functions following GBS. We believe the proposed research has significant potential to impact patient care as it will improve our understanding of factors that could positively or negatively contribute to long-term weight maintenance and could elucidate new targets for developing less invasive treatments for obesity. Preliminary data suggest GBS beneficially impacts the regulation of appetite and food choice resulting in more dramatic, sustained weight loss than dieting. The current study examines how GBS, in contrast to dieting, influences the rewarding effects of palatable food in the brains of dietary obese rats. Information concerning essential changes in motivated behavior and underlying neural substrates produced by GBS could assist in the development of effective non-surgical approaches to obesity treatment.