A Role for Endocannabinoids in the Control of Dietary Fat Intake

描述(申请人提供)：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，这些食物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……里面 在现代社会，高脂肪食物随处可得，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不适应，被认为是肥胖、心血管疾病和糖尿病的主要促成因素。尽管它具有理论和实践意义，但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。尤其是内源性大麻素(ECB)系统，由于其在天然(如食品)和非天然(如滥用药物)增强剂的获取和感官评价中的关键作用而受到关注。ECB是内源性脂类，与9-THC(大麻中的精神活性成分)结合并激活相同的受体。我们实验室的最新数据表明，口服膳食脂肪可以刺激大鼠小肠ECB的动员，并且局部阻断这一信号事件可以抑制脂肪的假喂养。这些结果表明，肠道ECB系统对脂肪摄取实施了强大的调节控制，并为控制对脂肪的偏好的生理机制提供了新的见解，脂肪被认为具有成瘾样特性。这项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取和奖励的界面，从而阐明脂肪偏好和强迫进食的生物底物。这一建议的中心假设是，在富含脂肪的食物的味觉刺激下，小肠内ECB的动员有助于脂肪摄入量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来检验这一假说：(I)识别刺激肠道ECB的脂质类别 通过综合利用外科、生化和药理学工具来确定特定的脂类负责驱动肠道ECB信号及其在脂肪偏好中的作用，以动员和促进膳食脂肪摄入量；(Ii)通过表征对肠道基因转录本和参与ECB代谢的蛋白质的修饰来确定参与头部阶段脂肪摄取的肠道ECB代谢酶的变化；(Iii)通过研究假喂脂来增强缺乏可能的脂肪受体的动物的肠道ECB信号的能力，确定维持肠道ECB动员和脂肪摄入的神经通路的口服脂肪酸受体，并确定通常将这一信息传递到肠道的神经通路。 总而言之，拟议的计划将根据脂肪餐的口感特性确定控制其正反馈的生理机制。此外，这项提议非常新颖，因为它关注的是欧洲央行在肠道中发出的信号，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外围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央机制。

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.