The role of diet derived fatty acid ethanolamines on body weight control

脂肪酸乙醇酰胺（FAEs）是一类天然存在的生物活性脂质信号分子，来源于脂肪酸前体。据报道，FAEs在脂肪氧化、能量代谢和食欲控制中起着重要作用。从油酸（OA）中提取的FAE油基乙醇酰胺（OEA）在控制体重方面具有特别重要的意义。OEA在肠细胞中合成，是核转录因子过氧化物酶体增殖激活受体α (PPAR-α)的高亲和力激动剂。研究表明，富含OA的饮食会增加组织中OA的水平，从而刺激脂肪分解、FA β-氧化，并促进饱腹感。然而，对组织中不同浓度的FAE的下游代谢影响以及产生这些不同FAE水平的膳食FA组成的作用知之甚少。特别是，需要阐明循环和组织中OEA与其他FAEs的最佳比例。因此，长期目标是描述单个fae如何共同影响能量代谢，导致影响体重和组成的能量底物动员的变化。具体目标是：(i)评估富含传统和新型饲粮油混合物中单个前体脂肪酸的饲粮对十二指肠、空肠和回肠以及其他组织区域FA和FAE水平的影响，以及与能量调节相关的生理参数；（ii）检查选定比例的膳食脂肪酸（包括口服的OA和其他FA）和FAEs（包括口服的OA和其他FA）对血浆和组织FAE水平、基因表达以及与慢性和急性状态下能量消耗增强、体脂减少和抑制食物摄入相关的生理参数的影响；（iii）在FAE合成和分解敲除模型中评估不同膳食FA摄入量后FAE作用的脂质介质生物标志物效应。目标(i)和（ii）将通过仓鼠提供不同FA组成的饮食或通过短期和长期给药方案注射FAEs来实现。将评估FAE水平、PPAR-α和其他脂质介质的体成分和遗传调控。目的（iii）将使用FAE敲除小鼠模型来探讨FAE水平如何响应不同的膳食FA比例，以及由于控制FAE代谢的途径受到干扰而产生的下游代谢影响。最后，我们将探讨SNP频率、fae生理反应以及fae相关转录因子和参与脂质代谢的蛋白的表达/活性之间的关系。预计这些研究的结果将对饮食脂肪选择具有重要的实际意义，从而导致最佳FAE比率作为未来体重管理和肥胖治疗的治疗目标。

Fatty acid ethanolamides (FAEs) represent a class of naturally occurring bioactive lipid signaling molecules derived from FA precursors. Significant roles of FAEs have been reported in fat oxidation, energy metabolism and appetite control. The FAE oleoylethanolamide (OEA), from the oleic acid (OA), is of particular interest in body weight control. OEA, synthesized in enterocytes, is a high-affinity agonist of the nuclear transcription factor peroxisome proliferator-activated receptor α (PPAR-α). It has been demonstrated that diets high in OA rich oils increase tissue OEA levels which stimulate lipolysis, FA β-oxidation, and promote satiety. However, much less well understood is the downstream metabolic impact of varying concentrations of FAEs in tissues, and the role of dietary FA composition that generate these varying FAE levels. Particularly, identification of optimal ratios of OEA vs other FAEs in circulation and tissues need to be elucidated. Accordingly, the long-term goal is to characterize how individual FAEs work in combination to impact energy metabolism, leading to shifts in energy substrate mobilization which impact body weight and composition. Specific objectives are to (i) assess the impact of diets enriched in individual precursor FAs from conventional and novel dietary oil blends on FA and FAE levels across regions of duodenum, jejunum and ileum, as well as other tissues, and physiological parameters related to energy regulation; (ii) examine the impact of selected ratios of dietary FAs, including OA and other FA given orally, and FAEs, including OEA and others given iv, on plasma and tissue FAE levels, gene expression, and physiological parameters related to enhancement of energy expenditure, body fat reduction, and suppression of food intake in chronic and acute states; and (iii) assess lipid mediator biomarker effects of FAE actions subsequent to varying dietary FA intakes in FAE synthesis and breakdown knockout models. Objectives (i) and (ii) will be addressed using hamsters provided diets varying in FA composition or injected with FAEs using short and long term administration regimens. FAE levels and body composition and genetic regulation of PPAR-α and other lipid mediators will be assessed. Objective (iii) will be addressed using FAE knockout mouse models to explore how FAE levels respond to different dietary FA ratios, and what downstream metabolic effects occur as a result of perturbations in pathways controlling FAE metabolism. Lastly, relationships between SNP frequency, physiological response to FAEs, and expression/activity of FAE-associated transcription factors and proteins involved in lipid metabolism will be explored. It is anticipated that results from these studies will have significant practical implications for diet fat selection leading to optimal FAE ratios as a future therapeutic target for weight management and obesity treatment.