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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要食物的摄入量和能量平衡受肠道信号通路的动态解释控制；霍弗，这些过程中的分子基础和观察中的失调保持较差理解。内源性大麻素（ECB）是肠道脑信号的关键介体，对食物摄入很重要，并且是饮食诱导的观察力中的肠道上调（DIO）。肠道是一种在严重性和代谢条件下激活的神经性信号，可能会变成肥胖症的不足。但是，DIO中的途径未知。肠上皮抑制营养和饱食肽的释放，这会增加膳食大小和延迟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中起着至关重要的作用传感和肠道饱腹信号传导，在长期暴露于高能营养素之后进行了重塑并有助于Dio中的暴饮暴食确定肠道控制肠道中的CB1R是否基于预后数据。假设肠上皮控制中的CB1RS营养感应和肠道 - 脑 - 脑SAT-脑脑脑信号传导在DIO中变得失调以检验该假设，我们将检查CB1RS的作用通过评估养分和在体外释放的营养和体外释放的行为有条件地缺乏肠上皮中CB1R的鼠标与周围限制 CB1R拮抗剂和肠道分泌细胞系将提供以前未知的证据养分诱导的肠道信号的机制。系统重塑DIO，以及饮食中的干预对这些途径的影响欧洲央行系统重塑的基础dio，驱动此过程的特定饮食成分以及我们假设饮食间隔对途径和行为结果的影响长期暴露于WD会导致肠道中欧洲央行系统的重塑，这促进了Overying和 dio。要检验此假设脂肪组学和高级UPLC/MS/MS基于欧洲央行系统功能的测定，以识别特定的饮食驱动欧洲央行系统Activim和暴饮暴食的组件以及重塑的机制发生在Dio中。暴饮暴食和肥胖；因此，我们将评估低热量饮食干预的能力 DIO中的欧洲央行信号传导。