Motivational Changes for Nutritionally Relevant Tastes after Gastric Bypass

描述（由申请人提供）：Roux-en-Y胃旁路术（RYGB）被许多人认为是维持体重最有效的治疗方法。长期来看，术后患者体重平均减少25%，同时伴有食欲减退，导致热量摄入减少。据报道，食物选择发生了重大变化。确实，有一些证据表明，患者减少了对高甜高脂食物的偏好和摄入，可能增加了对水果和蔬菜的偏好。此外，有许多患者的轶事报告说，他们经历了味觉敏感性的变化。味觉无可争议地指导着食物的选择，RYGB对味觉过程的影响可能会促进向低血糖指数饮食的转变，并可能有助于减肥和健康。然而，以口头报告（如饮食回忆）为主的文献是混杂的，有些研究发现了变化，有些则没有。我们研究rygb诱导的味觉和动机变化的策略是采取一种协调的方法，在我们建立的大鼠模型和帝国理工学院的人类肥胖临床研究项目中进行平行实验。我们的观点是，通过对人类目标行为的更直接的测量来补充现有的研究结果，可以更有效地解决文献中的差异，这也可以应用于我们的动物模型。因此，我们的第一个目标是使用我们的动物模型来跟进我们有希望的初步发现，表明人类的RYGB降低了为食物奖励而工作的动机，这可以通过在递进比例任务（其中每个后续奖励交付需要逐步增加的响应数量）中断点（动物停止为奖励而工作的点）的减少来证明。我们希望确定大鼠在RYGB后是否会表现出类似的断点调节，重要的是，这种影响是否取决于奖励的感官特征。递进比例任务是对食欲行为的一种纯粹的测量，是为需要限制强化物的传递以避免满足的应用而设计的。因此，它非常适合评估RYGB后简单和复杂味觉刺激的奖励值变化，同时使进食后负荷的潜在影响可以忽略不计。我们的第二个目标是开始研究潜在的生理机制。RYGB后，循环中的关键厌食性胃肠激素如肽YY和胰高血糖素样肽-1水平升高。全身给予生长抑素类似物奥曲肽（octreotide），阻断这些和其他肠道激素的释放，RYGB后大鼠的短期食物摄入量增加一倍，但对sham手术的对照组没有影响。因此，我们将测试奥曲肽是否可以逆转特定营养相关刺激的奖励值变化，为未来工作中更有选择性的机制操作铺平道路。

DESCRIPTION (provided by applicant): Roux-en-Y gastric bypass (RYGB) is considered by many to be the most effective treatment available for weight loss maintenance. Patients lose, on average, 25% of their body weight postoperatively for the long term, and this is accompanied by an attenuation of appetite leading to decreased caloric intake. Importantly alterations in food selection have been reported. Indeed, there is some evidence that patients decrease their preference for and intake of high sweet and high fat foods and possibly increase their preference for fruits and vegetables. Moreover, there are many anecdotal reports from patients that they experience changes in taste sensibility. Taste indisputedlty guides food choices and the effect of RYGB on gustatory processes may promote a shift to a lower glycemic index diet and potentially contribute to the weight loss and health gain. However, the literature, which is dominated by measures of verbal report such as dietary recall, is mixed, with some studies finding changes and others not. Our strategy to studying RYGB-induced taste and motivational changes has been to take a coordinated approach to the problem by conducting parallel experiments in both our established rat model and our human bariatric clinical research program at Imperial College London. Our view is that disparities in the literature could be more effectivel resolved by complementing the collection of existing findings with more direct measures of target behaviors in humans that can also be applied to our animal model. Accordingly, our first objective is to use our animal model to follow up our promising preliminary findings suggesting that RYGB in humans decreases the motivation to work for food reward as demonstrated by a decrease in breakpoint (the point at which animals cease working for reward) in a progressive ratio task (in which each subsequent reward delivery requires a progressively greater number of responses). We wish to establish whether rats will display similar modulation of breakpoint after RYGB and, importantly, whether this effect depends on the orosensory characteristics of the reward. The progressive ratio task is a pure measure of appetitive behavior and is designed for applications in which the reinforcer delivery needs to be limited to obviate satiation. As such, itis well suited for assessing changes in the reward value of simple and complex taste stimuli after RYGB, while rendering the potential effects of the postingestive load negligible. Our second objective is to begin to study potential underlying physiological mechanisms. After RYGB, circulating levels of key anorexogenic gastrointestinal hormones such as peptide YY and glucagon-like peptide-1 increase. Systemic administration of the somatostatin analog, octreotide, which blocks the release of these and other gut hormones, doubles short-term chow intake in rats after RYGB, but has no effects in SHAM-operated controls. Thus, we will test whether changes in the reward value of specific nutritionally relevant stimuli might be reversed by octreotide, paving the way for more selective mechanistic manipulations in future work. PUBLIC HEALTH RELEVANCE: Close to 100,000 gastric bypass operations are performed in the US every year, and it is considered by many to be one of the most effective treatments available for long-term body weight loss. The mechanisms promoting and maintaining the weight loss are not well understood. The proposed research will objectively examine whether gastric bypass changes the taste palatability of specific types of foods helping to promote a more healthy diet and begin to test the role of gut hormones in these anticipated effects. Ultimately, our long-range goal is to contribute to the development of less invasive interventions to treat and prevent obesity and its associated disorders.