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减肥最有效的治疗方法。术后患者平均体重会长期下降25%，这伴随着食欲减弱，导致热量摄入减少。据报道，食物选择发生了重要变化。事实上，有一些证据表明，患者减少了对高甜和高脂肪食物的偏好和摄入，并可能增加对水果和蔬菜的偏好。此外，有许多来自患者的轶事报道，他们经历了味觉的变化。味道无可争议地指导食物选择，RYGB对味觉过程的影响可能会促进向较低血糖指数饮食的转变，并可能有助于减肥和健康增益。然而，以口头报告（如饮食回忆）为主导的文献是混合的，一些研究发现了变化，另一些则没有。我们研究RYGB诱导的味觉和动机变化的策略是通过在我们建立的大鼠模型和我们在伦敦帝国理工学院的人类肥胖临床研究项目中进行平行实验来采取协调的方法来解决问题。我们的观点是，文献中的差异可以更有效地解决，通过补充现有的研究结果，更直接地测量人类的目标行为，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踪我们有希望的初步发现，这些发现表明人类的RYGB降低了为食物奖励而工作的动机，如在渐进比率任务（其中每个随后的奖励传递需要越来越多的响应）中断点（动物停止为奖励而工作的点）的减少所证明的。我们希望建立大鼠是否会显示类似的调制断点后RYGB，重要的是，这种效果是否取决于orosensory奖励的特点。渐进比率任务是对食欲行为的一种纯粹的测量，并且被设计用于需要将食欲传递限制在食欲满足的应用。因此，它非常适合于评估RYGB后简单和复杂味觉刺激的奖励值的变化，同时使摄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，循环中关键的促胃肠激素如肽YY和胰高血糖素样肽-1的水平增加。全身给药生长抑素类似物奥曲肽，阻断这些和其他肠道激素的释放，使RYGB后大鼠的短期食物摄入量增加一倍，但对SHAM操作的对照组没有影响。因此，我们将测试特定营养相关刺激的奖励值的变化是否可能被奥曲肽逆转，为未来工作中更具选择性的机械操作铺平道路。 公共卫生相关性：每年在美国进行近10万例胃旁路手术，许多人认为这是长期减肥最有效的治疗方法之一。促进和维持体重减轻的机制还不清楚。这项拟议中的研究将客观地检查胃旁路手术是否会改变特定类型食物的味道适口性，从而有助于促进更健康的饮食，并开始测试肠道激素在这些预期效果中的作用。最终，我们的长期目标是促进开发微创干预措施，以治疗和预防肥胖及其相关疾病。

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.