Role of oleoylethanolamide in the control of food intake

描述(由申请人提供)：这是第三次提交RO1拨款申请，研究内源性脂酰胺油酰乙醇酰胺(OEA)在控制食物摄入量中的作用。工业化国家日益普遍的肥胖症凸显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，内源性脂酰胺OEA减少了啮齿类动物的食物摄入量。这种效果需要完整的外周感觉纤维，这是由于OEA能够延长进食潜伏期和进食间隔，而不改变进食大小或导致内脏疾病。我们还发现，禁食降低了肠道中的OEA水平，而进食则增加了它们。基于这些结果，我们假设近端小肠中依赖喂食的OEA动员有助于生理上诱导饱足感。目前的建议有两个与检验这一假说相关的目标：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，那么诱导饱腹感的生理信号应该会在小肠中启动OEA动员。我们将结合手术和药理学方法来确定控制肠道OEA动员的机制。具体地说，我们将研究四个候选信号的贡献：(/)头部刺激；(//)肠道脂肪消化和吸收；(/)内在和外在神经支配；以及(Iv)吸收后过程。2.确定摄食诱导的OEA动员在控制饱足感中的作用。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喂养行为。为了验证这一预测，我们将进行两个互补的系列实验。在目标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会导致饱腹感。我们将利用三种互补的策略：(1)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；(2)选择性药物抑制OEA降解酶FAAH(脂肪酸酰胺水解酶)；(3)结构性遗传缺失FAAH基因。在目标2.2中，我们将测试减少肠道OEA动员的基因干预是否也会减少饱腹感。我们将使用两种策略：(1)结构性遗传缺失NAPE-PLD基因；(IF)通过病毒介导的RNA干扰局部击倒NAPE-PLD基因。通过将OEA确定为一种新的饱腹感因子，我们的研究将为调节喂养行为提供新的见解，并促进开发治疗肥胖症和其他喂养障碍的新治疗策略。

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.