Motivational Changes for Nutritionally Relevant Tastes after Gastric Bypass

描述(申请人提供)：Roux-en-Y胃分流术(RYGB)被许多人认为是最有效的减肥维持治疗方法。患者术后长期平均减重25%，并伴随着食欲减弱导致热量摄入减少。重要的是，有报道称食物选择发生了变化。事实上，有一些证据表明，患者减少了他们对高甜度和高脂肪食物的偏好和摄入量，并可能增加了他们对水果和蔬菜的偏好。此外，有许多来自患者的轶事报道称，他们经历了味觉的变化。无可争议的味道指导着食物的选择，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加。然而，以饮食回忆等口头报告指标为主的文献喜忧参半，一些研究发现了变化，另一些研究则没有。我们研究RYGB诱导的味觉和动机变化的策略是采取协调一致的方法来解决这个问题，方法是在我们建立的大鼠模型和伦敦帝国理工学院的人类减肥临床研究项目中进行平行实验。我们的观点是，通过用更直接的人类靶向行为测量来补充现有发现的收集，可以更有效地解决文献中的差异，这些测量也可以应用于我们的动物模型。因此，我们的第一个目标是利用我们的动物模型来跟进我们有希望的初步发现，即RYGB在人类中降低了为食物奖励而工作的动机，这体现在累进比例任务中断点(动物停止为奖励工作的点)的减少(在该任务中，随后的每一次奖励传递都需要逐渐增加的反应数量)。我们希望确定RYGB后大鼠是否会表现出类似的断点调制，更重要的是，这种影响是否取决于奖赏的感官特征。递进比例任务是一种纯粹的食欲行为衡量标准，是为需要限制增强剂输送以消除饱足感的应用而设计的。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，同时使消化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潜在生理机制。RYGB治疗后，关键的厌氧性胃肠激素，如YY肽和胰升糖素样肽-1的循环水平增加。全身注射生长抑素类似物奥曲肽，阻止这些和其他胃肠激素的释放，使RYGB后大鼠的短期食物摄入量增加一倍，但对假手术对照组没有影响。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赏价值的变化，为未来工作中更具选择性的机械操作铺平道路。

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.