Gut-brain endocannabinoid signaling in feeding behavior and obesity

项目摘要/摘要 食物摄入量和能量平衡由肠道-大脑信号通路的动态相互作用控制； 然而，这些过程中的分子基础及其在肥胖症中的失调仍然很差。 明白了。迪帕特里齐奥实验室最近的研究表明，我们身体中类似大麻的信号分子， 内源性大麻素(ECB)是肠道-大脑信号传递的关键介质，对食物摄取至关重要，并且 在饮食诱导的肥胖(DIO)中，肠道中表达上调。这些开创性的研究表明，欧洲央行在 肠道是一种食欲信号，在几种行为和代谢条件下被激活，并可能成为 肥胖症的失调。肠-脑欧洲央行控制摄食量的机制(S)及其重组 DIO中的通路未知。然而，初步数据表明，在DIO中，欧洲央行在 肠上皮抑制了营养诱导的饱腹肽的释放，从而增加了食物的大小和延迟 满足感。我们提出了一个中心假设，即肠道中的欧洲央行系统在营养方面起着关键作用 感觉和肠脑饱足信号，在长期暴露于高能营养后被重塑 并导致酒后驾车人员暴饮暴食。我们提出以下具体目标来检验这一假说：SA1。至 确定肠道中的CB1Rs是否控制肠道-大脑饱足信号。根据初步数据，我们 假设肠上皮细胞中的CB1Rs控制营养感知和肠脑饱和信号 在DIO中变得不受监管。为了验证这一假设，我们将检验CB1Rs在控制摄食中的作用 用我们的第一台机器评估营养诱导的饱腹肽在体内和体外的释放行为 肠上皮有条件缺乏CB1Rs并外周受限的小鼠模型 CB1R拮抗剂和肠内分泌细胞系。这一目标将提供以前未被确认的证据 营养诱导的肠脑饱足信号的调控机制。SA2.确定欧洲央行的机制 DIO的系统重构，以及饮食干预对这些通路的影响。分子 DIO中欧洲央行系统重塑的基础，推动这一过程的特定饮食成分，以及 饮食干预对这些途径和行为结果的影响尚不清楚。我们假设 长期接触WD会导致欧洲央行肠道系统的重塑，这会促进暴饮暴食和 我的天。为了验证这一假设，我们将使用我们的肠道上皮细胞CB1R缺失的小鼠与靶向 脂类组学和先进的基于UPLC/MS/MS的ECB系统功能分析用于识别特定的膳食 推动欧洲央行系统活动增加和暴饮暴食的组件，以及重塑这一系统的机制 发生在DIO中。此外，节食后的减肥经常会遇到高水平的再犯罪率 暴饮暴食和肥胖；因此，我们将评估低热量饮食干预使肠脑正常化的能力。 DIO中的ECB信令。

PROJECT SUMMARY/ABSTRACT Food intake and energy balance are controlled by a dynamic interplay of gut-brain signaling pathways; however, the molecular underpinnings in these processes and their dysregulation in obesity remain poorly understood. Recent work from the DiPatrizio lab suggests that our bodies’ cannabis-like signaling molecules, the endocannabinoids (eCBs), are critical mediators of gut-brain signaling important for food intake, and are upregulated in the gut in diet-induced obesity (DIO). These seminal studies suggest that eCB signaling in the gut is an orexigenic signal that is activated under several behavioral and metabolic conditions, and may become dysregulated in obesity. The mechanism(s) of gut-brain eCB control of food intake and reorganization of these pathways in DIO is unknown. Preliminary data, however, suggests that in DIO, increased eCB signaling in the intestinal epithelium inhibits nutrient-induced release of satiation peptides, which increases meal size and delays satiation. We propose the central hypothesis that the eCB system in the gut plays a critical role in nutrient sensing and gut-brain satiation signaling, which is remodeled after chronic exposure to high-energy nutrients and contributes to overeating in DIO. We propose the following specific aims to test this hypothesis: SA1. To determine if CB1Rs in the gut control gut-brain satiation signaling. Based on preliminary data, we hypothesize that CB1Rs in the intestinal epithelium control nutrient sensing and gut-brain satiation signaling that become dysregulated in DIO. To test this hypothesis, we will examine the role for CB1Rs in controlling feeding behavior by evaluating nutrient-induced release of satiation peptides in vivo and in vitro using our first-of-kind mouse model that conditionally lacks CB1Rs in intestinal epithelium in combination with peripherally-restricted CB1R antagonists, and enteroendocrine cell lines. This aim will provide evidence of a previously unidentified control mechanism of nutrient-induced gut-brain satiation signaling. SA2. To determine the mechanism of eCB system remodeling in DIO, and impact of dietary intervention on these pathways. The molecular underpinnings of eCB system remodeling in DIO, specific dietary components that drive this process, as well as the impact of dietary intervention on these pathways and behavioral outcomes are unknown. We hypothesize that chronic exposure to WD leads to remodeling of the eCB system in the gut, which promotes overeating and DIO. To test this hypothesis, we will use our intestinal epithelial CB1R-null mice in combination with targeted lipidomics and advanced UPLC/MS/MS-based assays of eCB system function to identify specific dietary components that drive heightened eCB system activity and overeating, and the mechanism of remodeling that occurs in DIO. Furthermore, weight loss following dieting is all-too-often met with high levels of recidivism to overeating and obesity; thus, we will assess the ability for low-calorie dietary intervention to normalize gut-brain eCB signaling in DIO.