A Role for Endocannabinoids in the Control of Dietary Fat Intake

项目摘要/摘要。哺乳动物在寻找美味的富含脂肪的食物方面具有适应性优势，这 在营养上是必不可少的，但在大多数自然栖息地是稀缺的。在现代社会，富含脂肪的食物很容易 而且找到它们所需的能量很少，这种与生俱来的动力可能会变得不适应，并且是 被认为是肥胖、心血管疾病和糖尿病的主要促成因素。尽管它的 控制脂肪偏好和强迫进食的神经机制的理论和实践意义 在很大程度上是未知的。尤其是内源性大麻素(ECB)系统，因其在 天然(如食品)和非天然(如滥用药物)增强剂的获取和感官评价。 ECB是内源性脂类，结合并激活与精神活性物质∆9-THC相同的受体 大麻中的成分。来自我们实验室的最新数据表明，口服摄入膳食脂肪会刺激 ECB在大鼠小肠的动员，并局部阻断这一信号事件抑制脂肪假象 喂食。这些结果表明，肠道ECB系统对脂肪具有强大的调控作用。 摄入量，并对控制脂肪偏好的生理机制提供了新的见解，这些机制是 假定具有令人上瘾的特性。这项研究计划的长期目标是利用国家 最先进的实验工具，探索食物摄取和奖励的界面，从而阐明生物 脂肪偏爱和强迫性进食的基础。这项提议的中心假设是 由富含脂肪的食物刺激味觉刺激引起的小肠内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。我们有三个具体目标 与这一假说的检验相关的独特方法：(I)识别刺激肠道的脂类 ECB动员和促进膳食脂肪摄取通过利用外科手术、生化和 用于识别负责驱动肠道ECB信号及其作用的特定脂类的药理学工具 脂肪偏好；(Ii)定义与头相脂肪有关的肠道ECB代谢酶的变化 通过表征肠道基因转录本和参与ECB代谢的蛋白质的修饰来摄取； (Iii)确定维持肠道ECB动员和脂肪的口服脂肪酸受体和神经通路 通过研究假脂肪喂养增强缺乏肠道ECB信号的动物的摄入量 推测的脂肪受体，并确定正常情况下将这些信息传递到肠道的神经路径。 总的来说，提议的计划将确定控制正反馈的生理机制 根据其感官特性从脂肪餐中获得。此外，这项建议非常新颖 因为它关注的是欧洲央行在肠道中的一个信号，这是在我们的初步工作中发现的，它推动了脂肪的摄入。因此， 这些研究将为开发针对欧洲央行系统的减肥药物提供支持 而不会扰乱可能导致精神副作用的中枢机制。

Project Summary/Abstract. 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 and 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 and 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.