A Role for Endocannabinoids in the Control of Dietary Fat Intake

项目概要/摘要。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， 是营养必需品，但在大多数自然栖息地稀缺。在现代社会，高脂肪食物很容易 如果你没有足够的能量来找到它们，而且找到它们所需的能量是最小的，这种先天的驱动力可能会变得适应不良， 被认为是肥胖、心血管疾病和糖尿病的主要促成因素。尽管 理论和实践意义，控制脂肪偏好和强迫进食的神经机制， 大部分都是未知的。特别是内源性大麻素（eCB）系统因其在以下方面的关键作用而受到关注： 天然（例如，食物）和非天然（例如，滥用药物）的人。 eCB是内源性脂质，其结合并激活与精神活性物质β 9-THC相同的受体。 大麻的成分。我们实验室的最新数据表明， eCB在大鼠小肠中的动员，以及该信号传导事件的局部阻断抑制脂肪假手术 喂食这些结果表明，肠道eCB系统对脂肪施加了强大的调节控制， 摄入量，并提供了新的见解的生理机制，支配偏好的脂肪， 被认为具有类似成瘾的特性。这项研究计划的长期目标是利用国家的- 最先进的实验工具，以探索食物摄入和奖励的界面，从而阐明生物学 脂肪偏好和强迫性进食的基质。这一建议的核心假设是， 通过富含脂肪的食物引起的口腔感觉刺激引起的小肠中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。我们有三个具体目标 和与该假设的测试相关的独特方法：（i）鉴定刺激肠刺激的脂质类， eCB动员和促进膳食脂肪的摄入，通过利用手术，生化和 药理学工具，以确定负责驱动肠道eCB信号传导的选定脂质类别及其作用 在脂肪偏好;（ii）定义在肠eCB代谢酶的变化参与头相脂肪 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来摄入; (iii)确定维持肠道eCB动员和脂肪代谢的口服脂肪酸受体和神经通路， 通过研究脂肪假喂食增强缺乏ECB的动物的肠道eCB信号传导的能力， 假定的脂肪受体，并确定通常将此信息传递到肠道的神经通路。 总的来说，拟议的计划将确定控制积极反馈的生理机制， 基于其口腔感觉特性从脂肪膳食中获得。此外，这项建议非常新颖， 因为它关注的是肠道中的eCB信号，这是我们在前期工作中发现的，它驱动着脂肪的摄入。因此，在本发明中， 这些研究将为靶向eCB系统的抗肥胖药物的开发提供支持， 外围，而不会破坏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.