A Role for Endocannabinoids in the Control of Dietary Fat Intake

内源性大麻素在控制膳食脂肪摄入中的作用

基本信息

批准号：
8509542
负责人：
Nicholas Vincent DiPatrizio
金额：
$ 12.63万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8509542
关键词：
Address Adverse effects Anabolism Animals Anti-Obesity Agents Attention Automobile Driving Binge Eating Biochemical Biological Biology Brain Brain Stem Calories Cannabis Carbohydrates Cardiovascular Diseases Cells Cephalic Data Detection Development Diabetes Mellitus Dietary Fats Drug Targeting Eating Endocannabinoids Environment Enzymes Evaluation Event Exposure to Fatty Acids Fatty acid glycerol esters Feedback Feeding behaviors Food Genes Genetic Goals Habitats Health Hormones Human Intake Intervention Intestines Laboratories Lead Lipid Binding Lipids Mammals Mediating Metabolic Metabolism Methodology Modification Molecular Nature Neural Pathways Neurobiology Obesity Operative Surgical Procedures Oral Oral cavity Pharmaceutical Preparations Phase Physiological Positioning Attribute Property Proteins Rattus Research Rewards Role Satiation Sensory Signal Transduction Small Intestines Societies System Taste Perception Testing Transcript Work base drug of abuse innovation insight neuromechanism novel novel therapeutics obesity treatment preference programs public health relevance receptor reinforcer sham feeding therapeutic development tool

项目摘要

DESCRIPTION (provided by applicant): Mammals have an adaptive advantage in seeking palatable fat-rich foods, which are nutritionally essential but scarce in most natural habitats. In modern societies, where fatty foods are readily available and the energy necessary to find them is minimal, this innate drive can become maladaptive and is considered a primary contributing factor for obesity, cardiovascular disease, and diabetes. Despite its theoretical and practical significance, the neural mechanisms controlling fat preference and compulsive eating are largely unknown. The endocannabinoid (eCB) system, in particular, has gained attention for its key roles in the acquisition and sensory evaluation of natural (e.g., food) and non-natural (e.g., drugs of abuse) reinforcers. The eCBs are endogenous lipids that bind to and activate the same receptors as 9-THC, the psychoactive component in cannabis. Recent data from our laboratory indicate that oral exposure to dietary fat stimulates eCB mobilization in the rat small intestine, and localized blockade of this signaling event suppresses fat sham feeding. These results suggest that the intestinal eCB system exerts a powerful regulatory control over fat intake, and provide novel insights into physiological mechanisms that govern preference for fats, which are posited to possess addictive-like properties. The long-term goal of this research program is to utilize state-of- the-art experimental tools to probe the interface of food intake and reward, and thus, elucidate the biological substrates of fat preference and compulsive eating. The central hypothesis of this proposal is that the mobilization of eCBs in the small intestine, elicited by orosensory stimulation by fat-rich foods, contributes to the physiological control of fat intake an the pathophysiological state of obesity. We have three specific aims and unique approaches pertinent to a test of this hypothesis: (i) to identify lipid classes that stimulate intestinal eCB mobilization and promote dietary fat intake by utilizing a combination of surgical, biochemical, and pharmacological tools to identify select lipid classes responsible for driving intestinal eCB signaling and its role in fat preference; (ii) to define changes in intestinal eCB-metabolizing enzymes involved in cephalic-phase fat intake by characterizing modifications to intestinal gene transcripts and proteins involved in eCB metabolism; (iii) to identify oral fatty-acid receptors an neural pathways that maintain intestinal eCB mobilization and fat intake by investigating the ability for fat sham feeding to enhance intestinal eCB signaling in animals that lack the putative fat receptors, and identify the neural pathways that normally transmit this information to the gut. Collectively, the proposed plan will identify physiological mechanisms that control the positive feedback obtained from a fatty meal based on its orosensory properties. Furthermore, the proposal is highly novel because it focuses on an eCB signal in the gut, discovered in our preliminary work that drives fat intake. Thus, these studies will provide support for the development of anti-obesity drugs that target the eCB system in the periphery, without disrupting central mechanisms that may lead to psychiatric side effects.

描述（由申请人提供）：哺乳动物在寻找可口的富含脂肪的食物方面具有适应性优势，这些食物在营养上是必需的，但在大多数自然栖息地中都很稀缺。在现代社会，脂肪食物很容易获得，而找到它们所需的能量却很少，这种与生俱来的驱动力可能会变得适应不良，并被认为是导致肥胖、心血管疾病和糖尿病的主要因素。尽管具有理论和实践意义，但控制脂肪偏好和强迫性饮食的神经机制在很大程度上还是未知的。尤其是内源性大麻素（eCB）系统，因其在天然（例如食物）和非天然（例如滥用药物）强化物的获取和感官评估中的关键作用而受到关注。 eCB 是内源性脂质，与大麻中的精神活性成分 9-THC 结合并激活相同的受体。我们实验室的最新数据表明，口服膳食脂肪会刺激大鼠小肠中的 eCB 动员，而局部阻断该信号事件会抑制脂肪假喂养。这些结果表明，肠道 eCB 系统对脂肪摄入发挥强大的调节控制作用，并为控制脂肪偏好的生理机制提供了新的见解，脂肪被认为具有类似成瘾的特性。该研究计划的长期目标是利用最先进的实验工具来探索食物摄入和奖励的界面，从而阐明脂肪偏好和强迫性饮食的生物学基础。该提议的中心假设是，富含脂肪食物的口腔感觉刺激引起小肠中 eCB 的动员，有助于对脂肪摄入的生理控制和肥胖的病理生理状态。我们有与检验这一假设相关的三个具体目标和独特方法：（i）确定刺激肠道 eCB 的脂质类别通过结合手术、生化和药理学工具来识别负责驱动肠道 eCB 信号传导及其在脂肪偏好中的作用的选定脂质类别，动员并促进膳食脂肪摄入； (ii) 通过表征参与 eCB 代谢的肠道基因转录本和蛋白质的修饰，定义参与头相脂肪摄入的肠道 eCB 代谢酶的变化； (iii) 通过研究假脂肪喂养增强缺乏推定脂肪受体的动物肠道 eCB 信号传导的能力，确定口腔脂肪酸受体和维持肠道 eCB 动员和脂肪摄入的神经通路，并确定正常情况下维持肠道 eCB 动员和脂肪摄入的神经通路。将这些信息传输到肠道。总的来说，拟议的计划将确定根据其口感特性控制从脂肪餐中获得的正反馈的生理机制。此外，该提案非常新颖，因为它关注肠道中的 eCB 信号，这是我们在前期工作中发现的驱动脂肪摄入的信号。因此，这些研究将为开发针对外周 eCB 系统的抗肥胖药物提供支持，而不会破坏可能导致精神副作用的中枢机制。