DIFFERENTIAL METABOLISM OF DIETARY FATTY ACIDS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。我们在年轻的、非肥胖的人类受试者中的初步数据表明，在28天的时间里增加饮食棕榈酸(PA)可以降低日常非静息能量消耗，钝化通常运动后能量消耗的上升，并降低美联储状态下的脂肪酸(FA)氧化。相反，我们发现，增加饮食油酸(OA)会增强FA的氧化，并增加非静息能量消耗。然而，重要的是要确定这种影响是否可以在饮食后几天内看到，或者是否需要显著改变膜脂成分。这个问题与未来研究的设计有关，受试者可以自己控制。此外，由于PA和OA对脂肪氧化的相反作用，它们可能反过来对心肌细胞内的脂质浓度产生相反的影响，这可能会影响该组织中的胰岛素信号。Muoio博士和其他人最近在杜克大学Stedman中心所做的工作(1)表明，代谢筛选(酰肉碱和酰辅酶A图谱)如何既可以用来解决假设的机制，也可以用来揭示意外的关系，从而引发新的和/或替代的假设。特别是，这项工作表明，以前用于推测诊断FA代谢的先天错误的技术，可以用于提供特定生化途径的数据，这些生化途径可能会因FA氧化能力的变化而改变。作为为NIH相关申请收集初步数据的总体计划的一部分，我们将于2005年2月1日提交，我们将收集肌肉组织，供Stedman中心的Muoio博士分析酰基-肉碱和酰基-CoA。为了探索这些问题，在24名18-40岁的健康、非肥胖成年人中进行了一项双盲、随机、平行分组的受控喂养试验(7d)，以考察两种真实食物饮食的影响，两种饮食中PA和OA的相对浓度不同。将实现两个特定的目标：1.确定与低PA和高OA的饮食相比，增加饮食中PA含量是否可以减少摄食状态下的脂肪氧化。2.确定提高日粮PA含量是否会增加肌肉的三酰甘油(TAG)和二酰甘油(DAG)的含量，改变肌肉的心磷脂含量、肌肉和脂肪组织中磷脂的脂肪酸组成以及骨骼肌酰肉碱和酰辅酶A的组成。该项目将在非肥胖、非糖尿病的人类中提供有关PA和OA对脂肪氧化和肌肉脂肪影响的新数据。PA和OA是饮食中最常见的两种脂肪酸。这项研究将对预防胰岛素抵抗、糖尿病和肥胖症具有特别的相关性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our Preliminary Data in young, non-obese, human subjects suggest that increasing dietary palmitic acid (PA) over a period of 28-d lowers daily non-resting energy expenditure, blunts the usual post-exercise rise in energy expenditure, and lowers fatty acid (FA) oxidation in the fed state. Conversely, we found that increasing dietary oleic acid (OA) enhances FA oxidation and increases non-resting energy expenditure. However, it is important to determine if this effect can be seen within days of the diet or whether marked changes in membrane lipid composition are required. This question has relevance to the design of future studies, where subjects could be their own control. Also, as a consequence of their opposite effects on fat oxidation, PA and OA may in turn have contrasting effects on intramyocyte lipid concentration, which could affect insulin signaling in that tissue. Recent work at the Duke University Stedman Center by Dr. Muoio and others (1) has shown how metabolic screening (acyl-carnitine and acyl-CoA profiling) can be used both to address hypothesized mechanisms, and to reveal unexpected relationships that prompt new and/or alternative hypotheses. In particular, this work has demonstrated that techniques, previously used to presumptively diagnose inborn errors of FA metabolism, can be used to provide data on particular biochemical pathways that can be altered by changes in the capacity for FA oxidation. As part of an overall plan to gather preliminary data for a related NIH application, submitted on 2/1/05, we will collect muscle tissue for analysis of acyl-carnitine and acyl-CoA by Dr. Muoio at the Stedman Center. To explore these issues, a double-masked randomized, parallel groups, controlled feeding trial (7d) is proposed in 24 healthy, non-obese, adults, 18-40 yr of age examining the effects of two real food diets, differing in the relative concentrations of PA and OA. Two Specific Aims will be carried out: 1. To determine if increasing the PA content of the diet decreases fat oxidation in the fed state compared to a diet with lower PA and much higher OA. 2. To determine if raising the PA content of the diet increases the triacylglycerol (TAG) and diacylglycerol (DAG) content of muscle and alters the cardiolipin content of muscle, the fatty acid composition of phospholipids in muscle and adipose tissue, and the acyl-carnitine and acyl-CoA profile of skeletal muscle. This project will provide novel data in non-obese, non-diabetic humans on the effects of PA and OA, the two most common FA in the diet, on fat oxidation and muscle lipids. This study will have particular relevance to the prevention of insulin resistance, diabetes, and obesity.