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

脂肪酸乙醇酰胺(FAE)是一类源于脂肪酸前体的天然生物活性脂质信号分子。FAE在脂肪氧化、能量代谢和食欲控制中的重要作用已被报道。FAE油酰乙醇胺(OEA)是从油酸(OA)中提取的，在控制体重方面特别有价值。肠毒素A是一种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，富含维生素A的饮食会增加组织中的氧化产物水平，从而刺激脂肪分解、FA-β氧化，并促进饱腹感。然而，对于组织中不同浓度的FAE对下游代谢的影响，以及产生这些不同FAE水平的膳食FA组成的作用，人们了解得要少得多。特别是，确定OEA与其他FAE在循环和组织中的最佳比例需要阐明。因此，长期目标是表征单个FAE是如何结合在一起影响能量代谢的，从而导致能量底物动员的变化，从而影响体重和组成。具体目标是：(I)评估从传统和新型混合膳食油中富含个别前体FAs的日粮对十二指肠、空肠和回肠以及其他组织的FA和FAE水平以及与能量调节相关的生理参数的影响；(Ii)研究选定的FAs比例，包括口服的OA和其他FA，以及FAE，包括OEA和其他静脉注射的FAE，对血浆和组织FAE水平、基因表达和与增加能量消耗、身体脂肪减少和抑制慢性和急性状态的食物摄入有关的生理参数的影响；以及(Iii)在FAE合成和分解基因敲除模型中，评估不同膳食FA摄入量后FAE作用的脂质介体生物标记物效应。目标(I)和(Ii)将通过提供脂肪酸组成不同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水平和身体成分以及PPAR-α和其他脂质介体的遗传调节。目的(Iii)利用FAE基因敲除小鼠模型，探讨FAE水平对不同膳食FA比例的响应，以及FAE代谢调控途径的扰动对下游代谢的影响。最后，将探讨SNP频率、对FAE的生理反应以及FAE相关转录因子和参与脂类代谢的蛋白质的表达/活性之间的关系。预计这些研究的结果将对饮食脂肪的选择具有重要的实际意义，从而使FAE比率成为未来体重管理和肥胖症治疗的治疗目标。

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.