Mechanisms for differential effects of dietary fatty acids on metabolism

描述(由申请人提供)：项目摘要：在年轻的、非肥胖的人类受试者中的初步数据表明，增加饮食棕榈酸(PA)可以降低日常非静息能量消耗，减缓通常运动后能量消耗的上升，并降低脂肪酸(FA)的氧化，同时增加饮食油酸(OA)加强FA的氧化。然而，在雌性中，PA和OA对FA氧化的差异效应被大大夸大了，并且这两种食物对非静息能量消耗的影响大多局限于雄性。来自骨骼肌细胞研究的初步数据表明，OA优先增强过氧化体增殖物激活受体(PPAR)介导的p-氧化基因的诱导，高PA饮食抑制肌肉PPAR X共激活因子a(PGC-1a)的表达，PPAR X共激活因子a是PPAR的转录辅助激活因子，也是线粒体功能的主要分子调节因子。PPAR还被认为介导了不饱和脂肪酸对硬脂酰辅酶A去饱和酶1(SCD1)表达的抑制作用，SCD1是一种催化内源性合成OA的酶。SCD1基因敲除小鼠表现出全身和肌肉脂肪酸氧化增加，并对肥胖有保护作用。初步数据显示，OA下调SCD1mRNA的表达。线粒体FA氧化效率较低可能导致心肌细胞内脂质(如二酰甘油)的积累，从而抑制胰岛素信号转导。将在28名健康、非肥胖、成年、18-40岁的健康、非肥胖成年人中评估以下目标：1)研究高油酸饮食(HI OA)和高棕榈酸饮食(HI PA)对骨骼肌转录重编程的影响，重点关注PPAR核激素受体和转录辅助激活因子PGC-1a的基因靶点。2)将饮食诱导的全身脂肪氧化和转录重编程的变化与全身和肌肉中各种脂质和线粒体衍生代谢物的水平相关联。3)检测饮食诱导的肌肉SCD1mRNA和蛋白表达的变化，以及相应的肌脂减饱和指数的变化。4)评价性别在调节特定膳食FA的转录和代谢反应中的作用。相关性：该项目将提供重要的新信息，说明由膳食FA修饰的线粒体功能障碍如何在肥胖、代谢综合征、2型糖尿病以及遗传性和年龄相关代谢性疾病的发生中发挥核心作用。

DESCRIPTION (provided by applicant): Project Summary: Preliminary Data in young, non-obese, human subjects suggest that increasing dietary palmitic acid (PA) lowers daily non-resting energy expenditure, blunts the usual post-exercise rise in energy expenditure, and lowers fatty acid (FA) oxidation, while increasing dietary oleic acid (OA) enhances FA oxidation. However, the differential effects of dietary PA and OA on FA oxidation were greatly exaggerated in females, and the effects of the diets on non-resting energy expenditure were mostly confined to males. Preliminary data from studies in skeletal myocytes indicate that OA preferentially enhances peroxisomal proliferator-activated receptor (PPAR)-mediated induction of p-oxidative genes and that a high PA diet suppresses muscle expression of PPAR X co-activator a (PGC-1a), a transcriptional co-activator of the PPARs that also functions as a master molecular regulator of mitochondrial function. The PPARs are also thought to mediate the repressive effects of unsaturated FA on the expression of stearoyl-CoA desaturase 1 (SCD1), an enzyme that catalyzes endogenous synthesis of OA. SCD1 knockout mice display increased whole-body and muscle fatty acid oxidation and are protected against obesity. Preliminary data show that OA down-regulates mRNA expression of SCD1. Less efficient mitochondrial FA oxidation may cause accumulation of intramyocellular lipids (e.g. diacylglycerol), which inhibits insulin signaling. The following Aims will be assessed in a double-masked, cross-over, feeding trial in 28 healthy, non-obese, adults, 18-40 yr of age, who will be fed in random order both a high PA diet and a high OA diet (each for 3 wk): 1) To investigate transcriptional reprogramming of skeletal muscle in response to a high oleic acid diet (HI OA) compared to a high palmitic acid diet (HI PA), with a focus on gene targets of the PPAR nuclear hormone receptors and the transcriptional co-activator, PGC-1a. 2) To correlate diet-induced changes in whole-body fat oxidation and transcriptional reprogramming with systemic and intramuscular levels of various lipid- and mitochondrial-derived metabolites. 3) To measure diet-induced changes in muscle mRNA and protein expression of SCD1, as well as corresponding changes in the desaturation index of muscle lipids. 4) To evaluate the role of gender in modulating transcriptional and metabolic responses to specific dietary FA. Relevance: This project will provide important new information regarding how mitochondrial malfunction, modified by dietary FA, plays a central role in the development of obesity, the metabolic syndrome, type 2 diabetes, and both heritable and age-related metabolic diseases