Mechanisms for differential effects of dietary fatty acids on metabolism

项目简介：在年轻、非肥胖的人类受试者中，初步数据表明，增加膳食棕榈酸（PA）可降低每日非静息能量消耗，减弱运动后能量消耗的增加，降低脂肪酸（FA）氧化，而增加膳食油酸（OA）可增强FA氧化。然而，饮食中PA和OA对FA氧化的差异影响在雌性中被大大夸大了，而饮食对非静息能量消耗的影响主要局限于雄性。骨骼肌细胞研究的初步数据表明，OA优先增强过氧化物酶体增殖因子激活受体（PPAR）介导的p-氧化基因诱导，高PA饮食抑制PPAR X共激活因子a （PGC-1a）的肌肉表达，PPAR X共激活因子a是PPAR的转录共激活因子，也是线粒体功能的主要分子调节剂。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OA合成的酶。SCD1基因敲除小鼠显示出全身和肌肉脂肪酸氧化增加，防止肥胖。初步数据显示OA下调SCD1 mRNA表达。较低效率的线粒体FA氧化可能导致细胞内脂质（如二酰基甘油）的积累，从而抑制胰岛素信号传导。下面的目的将评估在一个双盲,交叉,喂养试验在28个健康,非肥胖,成年人,18-40年年龄,谁将成为美联储以随机的顺序高PA饮食和高OA饮食(每3周):1)探讨转录改变骨骼肌的反应高油酸饮食(嗨OA)相比,高棕榈酸饮食(嗨PA),重点是基因目标PPAR核激素受体和转录co-activator PGC-1a。2)将饮食引起的全身脂肪氧化和转录重编程的变化与全身和肌肉内各种脂质和线粒体衍生代谢物的水平联系起来。3)测定饮食诱导的肌肉SCD1 mRNA和蛋白表达的变化，以及相应的肌脂去饱和指数的变化。4)评估性别在调节特定饲粮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，了解线粒体功能障碍如何被膳食FA改变，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疾病的发展中发挥核心作用

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