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

• 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
• 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

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）：哺乳动物在寻求美味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是稀缺的。在 在现代社会，高脂肪食物随处可得，而寻找它们所需的能量却微乎其微，这种先天的驱动力可能变得适应不良，并被认为是肥胖、心血管疾病和糖尿病的主要促成因素。尽管其理论和实践意义，控制脂肪偏好和强迫性进食的神经机制在很大程度上是未知的。特别是内源性大麻素（eCB）系统，由于其在天然大麻（例如，食物）和非天然（例如，滥用药物）的人。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，口服暴露于膳食脂肪刺激eCB动员在大鼠小肠，和局部阻断这种信号传导事件抑制脂肪假喂养。这些结果表明，肠道eCB系统对脂肪摄入施加了强大的调节控制，并提供了新的见解，控制对脂肪的偏好的生理机制，这被认为具有成瘾性。本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进食的生物学基础。该建议的中心假设是，由富含脂肪的食物引起的orosensory刺激引起的小肠中eCB的动员有助于脂肪摄入的生理控制和肥胖的病理生理状态。我们有三个具体的目标和独特的方法相关的测试这一假设：（i）确定脂质类刺激肠道eCB 动员和促进膳食脂肪摄入，通过利用手术，生物化学和药理学工具的组合，以确定负责驱动肠道eCB信号传导的选择脂质类及其在脂肪偏好中的作用;（ii）通过表征对参与eCB代谢的肠道基因转录物和蛋白质的修饰，确定参与头相脂肪摄入的肠道eCB代谢酶的变化;（iii）通过研究脂肪假喂养增强缺乏推定脂肪受体的动物中的肠eCB信号传导的能力，鉴定维持肠eCB动员和脂肪摄入的口服脂肪酸受体神经通路，并鉴定通常将该信息传递至肠道的神经通路。 总的来说，拟议的计划将确定生理机制，控制从脂肪餐获得的正反馈的基础上，其orosensory属性。此外，该提案非常新颖，因为它关注的是肠道中的eCB信号，这是我们在初步工作中发现的，可以驱动脂肪摄入。因此，这些研究将为开发靶向外周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。