Role of oleoylethanolamide in the control of food intake

描述（由申请人提供）：这是第三份RO1拨款申请，旨在研究内源性脂酰胺油基乙醇酰胺（OEA）在控制食物摄入中的功能。肥胖在工业化国家的日益流行强调了了解控制能量稳态的生理机制和开发有效的抗肥胖疗法的必要性。我们已经证明内源性脂质酰胺OEA可以减少啮齿动物的食物摄入量。这种效果需要完整的外周感觉纤维，并且由于OEA能够延长进食潜伏期和餐间间隔，而不会改变餐量或引起内脏疾病。我们还发现，禁食会降低肠道OEA水平，而喂食会增加它们。基于这些结果，我们假设进食依赖性小肠近端OEA动员有助于生理诱导饱腹感。目前的提议有两个目标与这一假设的检验有关：1。识别控制摄食诱导的OEA动员的生理信号。如果我们的假设是正确的，那么参与诱导饱腹感的生理信号应该启动小肠中的OEA动员。我们将采用手术和药理学相结合的方法来确定控制肠道OEA动员的机制。具体来说，我们将研究四个候选信号的贡献：（/）头侧刺激；（//）肠道脂肪消化吸收；（///）内源性和外源性神经支配；（四）吸收后过程。2. 目的：探讨进食诱导OEA动员在饱腹感控制中的作用。我们假设的另一个推论是，改变肠道OEA动员的实验干预应该影响摄食行为。为了验证这一预测，我们将进行两个互补系列的实验。在Aim 2.1中，我们将测试增强肠道OEA动员的遗传和药物干预是否也能诱导饱腹感。我们将利用三种互补策略：（/）病毒介导的oea合成酶NAPE-PLD （A/-磷脂酰乙醇胺特异性磷脂酶D）的过表达；（如果）oea降解酶FAAH（脂肪酸酰胺水解酶）的选择性药理抑制；（iii） FAAH基因的构成性基因缺失。在Aim 2.2中，我们将测试减少肠道OEA动员的基因干预是否也会降低饱腹感。我们将采用两种策略：（/）NAPE-PLD基因的构成性基因缺失；（如果）局部NAPE-PLD被病毒介导的RNA干扰敲低。通过确定OEA是一种新的饱腹感因子，我们的研究将为摄食行为的调节提供新的见解，并促进治疗肥胖和其他摄食障碍的新治疗策略的发展。

DESCRIPTION (provided by applicant): This is the third submission of an RO1 grant application to study the functions of the endogenous lipid amide oleoylethanolamide (OEA) in the control of food intake. The increasing prevalence of obesity in industrialized countries underscores the need to understand the physiological mechanisms that control energy homeostasis and to develop effective anti-obesity therapies. We have shown that the endogenous lipid amide OEA reduces food intake in rodents. This effect requires intact peripheral sensory fibers and results from the ability of OEA to prolong feeding latency and intermeal interval without altering meal size or causing visceral illness. We have also found that fasting decreases intestinal OEA levels, while feeding increases them. Based on these results, we hypothesize that feeding-dependent OEA mobilization in the proximal small intestine contributes to the physiological induction of satiety. The present proposal has two goals pertinent to a test of this hypothesis: 1. To identify physiological signals that control feeding-induced OEA mobilization. If our hypothesis is correct, then physiological signals involved in the induction of satiety should initiate OEA mobilization in the small intestine. We will use a combination of surgical and pharmacological approaches to identify the mechanisms governing intestinal OEA mobilization. Specifically, we will examine the contribution of four candidate signals: (/) cephalic stimuli; (//) intestinal fat digestion and absorption; (///) intrinsic and extrinsic neural innervation; and (iv) post-absorptive processes. 2. To determine the role of feeding-induced OEA mobilization in the control of satiety. Another corollary of our hypothesis is that experimental interventions that alter intestinal OEA mobilization should influence feeding behavior. To test this prediction, we will conduct two complementary series of experiments. In Aim 2.1 we will test whether genetic and pharmacological interventions that enhance intestinal OEA mobilization also induce satiety. We will utilize three complementary strategies: (/) viral- mediated overexpression of the OEA-synthesizing enzyme NAPE-PLD (A/-phosphatidylethanolamine- specific phospholipase D); (if) selective pharmacological inhibition of the OEA-degrading enzyme FAAH (fatty-acid amide hydrolase); (iii) constitutive genetic deletion of the FAAH gene. In Aim 2.2 we will test whether genetic interventions that decrease intestinal OEA mobilization also reduce satiety. We will use two strategies: (/) constitutive genetic deletion of the NAPE-PLD gene; (if) local NAPE-PLD knockdown by viral- mediated RNA interference. By identifying OEA as a novel satiety factor, our studies will provide new insights into the regulation of feeding behavior and facilitate the development of novel therapeutic strategies for the treatment of obesity and other feeding disorders.