Gastric bypass surgery alters the regulation of food reward

描述（由申请人提供）：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患者通常减轻总体重的25-35%，显示出医疗合并症的改善，并持续体重减轻超过15年。鉴于肥胖在美国的流行，提高对GBS引起和维持体重减轻的机制的理解是一个重要的研究领域。虽然GBS机械地限制食物摄入，但它似乎也会降低食欲和美味食物的吸引力。然而，目前还不清楚为什么动机系统不能驱使患者通过增加食物摄入量和偏好美味的、高热量的食物来补偿这种巨大的体重减轻——这是正常的体内平衡反应。阐明这一悖论将大大提高我们对饮食和体重调节机制的理解。我们处于一个独特的位置来解决这个问题，基于GBS的动物模型，证明了在我们实验室开发的调节食物奖励功能的中枢神经机制的改变。目前的研究提出在高能/高脂肪饮食诱导的肥胖大鼠模型中进行行为学、药理学、神经化学和组织学研究，以验证GBS改变食欲和食物偏好功能从而导致食物奖励系统改变的假设。实验的目标是伏隔核，这是一个关键的奖励结构，重点关注两种主要的递质：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特定方面的行为影响（即激励，强化和享乐价值），并比较多巴胺在减肥方法（即热量限制与GBS）中对这些行为的参与。第二个和第三个目标将分别从机制上解决潜在的动态和静态（即神经适应性）信号机制。目的4将研究肠脑肽信号的增加是否有助于改善GBS后的食物奖励功能。我们相信这项研究对患者护理有重大的影响，因为它将提高我们对长期体重维持的积极或消极因素的理解，并可能阐明开发低侵入性肥胖治疗的新目标。初步数据表明，与节食相比，GBS对食欲和食物选择的调节产生了有益的影响，从而产生了更显著、更持久的体重减轻。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奖励效应。关于GBS产生的动机行为和潜在神经基质的基本变化的信息可以帮助开发有效的非手术方法来治疗肥胖。

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.