Gut-brain endocannabinoid signaling in feeding behavior and obesity

进食行为和肥胖中的肠脑内源性大麻素信号传导

• 批准号: 10375448
• 负责人: Nicholas Vincent DiPatrizio
• 金额: $ 34.05万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375448
• 关键词: Adult; Affect; Agonist; American; American Medical Association; Appetite Stimulants; Behavioral; Biological Assay; Body Weight decreased; Brain; CB1 knockout; CNR1 gene; Calories; Cannabinoids; Cannabis; Cell Line; Cells; Cholecystokinin; Cholecystokinin Receptor; Chronic; Consumption; Data; Development; Diet; Dietary Component; Dietary Fats; Dietary Intervention; Disease; Eating; Endocannabinoids; Enteroendocrine Cell; Enzymes; Exposure to; Fasting; Fat emulsion; Fatty Acids; Fatty acid glycerol esters; Feeding behaviors; Food Energy; Functional disorder; Gastrointestinal tract structure; Human; Hyperphagia; In Vitro; Intake; Intestinal Neuroendocrine Neoplasm; Intestines; Knockout Mice; Life Expectancy; Maps; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic Pathway; Molecular; Mus; Nutrient; Obese Mice; Obesity; Oral; Pathway interactions; Pattern; Peptides; Peripheral; Pharmacology; Physiology; Play; Process; Reporting; Rodent; Role; Satiation; Seminal; Signal Pathway; Signal Transduction; Signaling Molecule; Small Intestines; Sucrose; Testing; Thinness; Work; antagonist; base; behavioral outcome; detection of nutrient; diet-induced obesity; dieting; endocannabinoid signaling; endogenous cannabinoid system; energy balance; gut-brain axis; in vivo; inhibitor; intestinal epithelium; lipidomics; mouse model; novel; novel therapeutic intervention; obesity treatment; recidivism; response; sugar; tool; western diet

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.

项目总结/摘要 食物摄入和能量平衡是由肠-脑信号通路的动态相互作用控制的; 然而，这些过程的分子基础及其在肥胖症中的失调仍然很差 明白DiPatrizio实验室最近的研究表明，我们身体的大麻样信号分子， 内源性大麻素（eCB）是对食物摄入很重要的肠-脑信号传导的关键介质， 在饮食诱导的肥胖症（DIO）中在肠道中上调。这些开创性的研究表明，eCB信号在细胞中 肠道是一种食欲信号，在几种行为和代谢条件下被激活， 在肥胖症中失调。肠-脑eCB控制食物摄入的机制及其重组 DIO中的途径未知。然而，初步数据表明，在DIO中， 肠上皮抑制营养素诱导的饱足肽释放，饱足肽增加膳食量， 饱食我们提出了一个中心假设，即肠道中的eCB系统在营养方面起着关键作用。 感知和肠脑饱足信号，这是重塑后，慢性暴露于高能量营养素 并导致DIO患者暴饮暴食。我们提出了以下具体目标来检验这一假设：SA 1。到 确定肠道中的CB 1 R是否控制肠-脑饱足信号传导。根据初步数据，我们 假设肠上皮细胞中CB 1 R控制营养感受和肠-脑饱足信号传导， 在DIO中变得失调。为了验证这一假设，我们将研究CB 1 R在控制摄食中的作用。 行为通过评估营养素诱导的释放饱足肽在体内和体外使用我们的第一种 肠上皮中条件性缺乏CB 1 Rs并结合外周限制性的小鼠模型 CB 1 R拮抗剂和肠内分泌细胞系。这一目标将提供一个以前未被确认的证据， 营养素诱导的肠-脑饱足信号传导的控制机制。SA 2.确定eCB的作用机制 DIO中的系统重塑，以及饮食干预对这些途径的影响。分子 DIO中eCB系统重塑的基础，驱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 长期暴露于WD会导致肠道中eCB系统的重塑，这会促进暴饮暴食， DIO。为了验证这一假设，我们将使用我们的肠上皮CB 1 R-无效小鼠与靶向的 脂质组学和先进的基于UPLC/MS/MS的eCB系统功能测定，以确定特定的饮食 驱动增强eCB系统活性和暴饮暴食的成分，以及 发生在DIO。此外，节食后减肥往往会有很高的再犯率， 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。