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

脂肪酸乙醇酰胺（FAE）代表一类天然存在的衍生自FA前体的生物活性脂质信号传导分子。FAE在脂肪氧化、能量代谢和食欲控制中具有重要作用。来自油酸（OA）的FAE油酰乙醇酰胺（OEA）在体重控制中特别令人感兴趣。OEA在肠上皮细胞中合成，是核转录因子过氧化物酶体增殖物激活受体α（PPAR-α）的高亲和力激动剂。已经证明，富含OA的油的饮食增加了组织OEA水平，其刺激脂解、FA β-氧化并促进饱腹感。然而，不太清楚的是下游代谢的影响，不同浓度的FAE在组织中，和饮食FA组成的作用，产生这些不同的FAE水平。特别是，需要阐明OEA与循环和组织中其他FAE的最佳比例。因此，长期目标是表征单个FAE如何联合作用以影响能量代谢，从而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）评估富含来自常规和新型膳食油混合物的单独前体FA的膳食对十二指肠、空肠和回肠区域以及其他组织的FA和FAE水平以及与能量调节相关的生理参数的影响;（ii）检查选定比例的膳食FA（包括口服OA和其他FA）和FAE（包括静脉注射OEA和其他FA）的影响，对血浆和组织FAE水平、基因表达以及与慢性和急性状态下的能量消耗增强、体脂减少和食物摄入抑制相关的生理参数的影响;以及（iii）评估FAE合成和分解敲除模型中在改变饮食FA摄入后FAE作用的脂质介体生物标志物效应。目标（i）和（ii）将使用提供不同FA组成的饲料或使用短期和长期给药方案注射FAE的仓鼠来解决。将评估FAE水平和身体组成以及PPAR-α和其他脂质介质的遗传调节。目的（iii）将使用FAE基因敲除小鼠模型来探讨FAE水平如何响应于不同的膳食FA比率，以及由于控制FAE代谢的途径中的扰动而发生的下游代谢效应。最后，SNP频率之间的关系，生理反应FAE，FAE相关的转录因子和蛋白质参与脂质代谢的表达/活性将进行探讨。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比率作为体重管理和肥胖治疗的未来治疗靶点。

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.