Translational Analyses of Ingestive Behavior After Gastric Bypass

 描述(申请人提供)：Roux-en-Y胃分流术(RYGB)后，患者的食欲、卡路里摄入量、体重和血糖下降，所有这些都得到长期维持。这就是为什么它成为一种流行的治疗病态肥胖症和2型糖尿病(T2 DM)的一大原因。然而，一个尚未解决的主要问题是，在RYGB之后，患者是否会选择少吃高脂肪和高糖的食物，转而选择能量密度较低的替代品，如蔬菜。如果这是真的，可以想象这有助于改善体重和血糖。关于食物选择和摄入量的研究之间的差异可能是由于几乎完全依赖于自我报告的食物摄入量，这很容易出现不准确的情况。这一争议最好的解决办法是用对人类靶标行为的直接测量来补充现有的发现，这种测量也可以应用于动物模型，反之亦然。拟议的实验将扩展已发表的和初步的发现，即RYGB改变了食物的偏好，而不会表面上改变食物的适口性。仅在食物选择上的这种改变就被认为有利于肥胖症和/或T2 DM患者，这可能是RYGB改善体重维持和血糖控制的一种未被研究的方法。在RYGB之后，老鼠和人类的直接测量将被用来检验这样一个假设，即对脂肪含量和血糖指数不同的食物的选择和摄入，以及餐内和餐间的摄入模式，以导致有益于体重的结果的方式发生变化。虽然在大鼠模型中，RYGB后食物偏好的明显渐进变化强烈表明学习，但这种基于经验的变化可能是由食物厌恶(适口性改变)或食物回避(适口性不变)驱动的。缺乏消除这些学习过程的歧义的证据，拟议的实验旨在明确区分这些重要的和概念上不同的行为机制。对RYGB的夸大的多效性胃肠激素反应是导致进食、体重减轻和血糖控制变化的最有希望的生理机制。尤其是一种胃肠激素，即胰高血糖素样肽-1(GLP-1)，已成为治疗T2 DM的药物干预的靶点，并与喂养饱足感有关。因此，在翻译实验中，生长抑素类似物奥曲肽将被用来阻断RYGB的多效性胃肠激素反应，以询问这些内分泌过程在观察到的进行性消化行为变化中的作用。在其他实验中，GLP-1受体将被拮抗剂Exendin-9选择性地作为靶点。这一科学联盟是通过美国-爱尔兰研发伙伴计划实现的，该计划使这个老牌的国际研究团队能够继续应用他们的互补专业知识来解决基本问题，这些问题可以帮助指导未来肥胖和T2 DM的治疗和管理研究。

 DESCRIPTION (provided by applicant): After Roux-en-Y gastric bypass (RYGB), patients decrease: appetite, caloric intake, body weight, and glycemia, all of which are maintained long-term. This is a large reason why it has become a popular treatment for morbid obesity and Type 2 diabetes mellitus (T2DM). However, a major unresolved issue is whether, after RYGB, patients choose to eat less foods that are high in fat and sugar in favor of lower energy dense alternatives such as vegetables. If true, this could conceivably contribute to improved body weight and glycemia. Disparities among studies on food selection and intake are likely due to the almost complete reliance on self- reported food intake which is vulnerable to inaccuracy. This controversy can best be resolved by complementing existing findings with direct measures of target behaviors in humans that can also be applied to animal models and vice-versa. The proposed experiments will extend the published and preliminary findings suggesting that RYGB alters food preferences without ostensibly changing food palatability. Such changes in food selection alone have been postulated to benefit patients with obesity and/or T2DM and this may be an under-investigated means by which RYGB improves maintenance of body weight and glycemic control. Direct measures in both rats and humans after RYGB will be used to test the hypothesis that the selection and intake of foods varying in fat content and glycemic index, as well as the pattern of ingestion within and across meals, changes in a manner that leads to beneficial outcomes on body weight. While the apparent progressive changes in food preference after RYGB in the rat model strongly suggest learning, such experience-based changes could be driven by either food aversion (changed palatability) or food avoidance (unchanged palatability). Evidence disambiguating these learning processes is lacking, and the proposed experiments are designed to explicitly distinguish between these important and conceptually distinct behavioral mechanisms. The exaggerated pleiotropic gut hormone response to RYGB has been the most promising lead to a physiologic mechanism underlying the changes in feeding, weight loss, and glycemic control. One gut hormone in particular, glucagon like peptide-1 (GLP-1) has been a target in pharmacological interventions in the management of T2DM and is implicated in feeding satiation. Accordingly, the somatostatin analogue Octreotide will be used to block the pleiotropic gut hormone response to RYGB in translational experiments to interrogate the role of these endocrine processes in the progressive changes in ingestive behavior observed. In other experiments, the GLP-1 receptor will be selectively targeted by the antagonist Exendin-9. This scientific alliance is made possible through the US-Ireland R&D Partnership Program which is allowing this established international research team to continue to apply their complementary expertise in the service of addressing fundamental questions that can help guide future research in the treatment and management of obesity and T2DM.