Mechanisms for differential effects of dietary fatty acids on metabolism

项目摘要。在年轻、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)降低日常非休息的能量消耗，减缓通常运动后能量的上升 支出，并降低脂肪酸(FA)氧化，而增加饮食油酸(OA)提高FA 氧化。然而，饲料中PA和OA对FA氧化的不同影响被大大夸大了 在雌性中，饮食对非静息能量消耗的影响主要限于雄性。 来自骨骼肌细胞研究的初步数据表明，OA优先增强过氧化物体 增殖物激活受体(PPAR)介导的p-氧化基因的诱导和高PA饮食 抑制肌肉PPAR X共激活蛋白(PGC-1a)的表达，PGC-1a是PPAR X-1a的转录共激活因子 PPAR也是线粒体功能的主要分子调节器。PPAR也是 不饱和脂肪酸对硬脂酰辅酶A去饱和酶1表达的抑制作用 (Scd1)，一种催化内源性合成维生素A的酶。SCD1基因敲除小鼠的显示增加 全身和肌肉的脂肪酸氧化，防止肥胖。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 心肌细胞内脂质的积累(例如二酰甘油)，这会抑制胰岛素信号转导。以下是 AIMS将在28名18-40岁的健康、非肥胖的成年人中进行双面交叉喂养试验。 YR年龄，随机顺序饲喂高PA饮食和高OA饮食(每种饮食3周)： 1.研究高油酸对骨骼肌转录重编程的影响 饮食(HIOA)与高棕榈酸饮食(HI PA)的比较，重点是PPAR的基因靶点 核激素受体与转录共激活因子PGC-1a 2.将饮食诱导的全身脂肪氧化变化与转录重编程联系起来 全身和肌肉内水平的各种脂质和线粒体衍生的代谢物。 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基因转录和代谢反应中的作用 膳食FA。 关联性。该项目将提供有关线粒体功能障碍的重要新信息， 经膳食FA修饰，在2型肥胖、代谢综合征的发生发展中起核心作用 糖尿病以及遗传性和与年龄相关的代谢性疾病

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-activatora (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 (HIOA)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