Mechanisms for differential effects of dietary fatty acids on metabolism

膳食脂肪酸对代谢的不同影响机制

• 批准号: 7256631
• 负责人: Craig Lawrence Kien
• 金额: $ 43.13万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-13 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256631
• 关键词: Mechanisms; differential; effects; dietary; fatty

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

描述（由申请人提供）：项目摘要：年轻、非肥胖、人类受试者的初步数据表明，增加膳食棕榈酸（PA）可降低每日非静息能量消耗，减弱通常的运动后能量消耗上升，并降低脂肪酸（FA）氧化，而增加膳食油酸（OA）可增强FA氧化。然而，饲料PA和OA对FA氧化的差异性影响在雌性中被大大夸大，并且饲料对非静息能量消耗的影响主要限于雄性。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物激活受体（PPAR）介导的p-氧化基因的诱导，高PA饮食抑制了PPARX共激活因子a（PGC-1a）的肌肉表达，PGC-1a是PPARs的转录共激活因子，也是线粒体功能的主要分子调节因子。PPARs还被认为介导不饱和FA对硬脂酰辅酶A去饱和酶1（SCD 1）表达的抑制作用，SCD 1是一种催化OA内源性合成的酶。SCD 1基因敲除小鼠表现出全身和肌肉脂肪酸氧化增加，并可防止肥胖。初步数据表明，OA下调SCD 1的mRNA表达。较低效率的线粒体FA氧化可能导致肌细胞内脂质（例如二酰基甘油）的积累，这抑制胰岛素信号传导。在一项双盲、交叉、喂养试验中，将对28名18-40岁健康、非肥胖成年人进行以下目的评估，这些人将随机接受高PA饮食和高OA饮食（各3周）：1）为了研究与高棕榈酸饮食（HIPA）相比，响应于高油酸饮食（H10 A）的骨骼肌的转录重编程，重点是PPAR核激素受体和转录辅激活因子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变化与全身和肌内各种脂质和胆固醇衍生代谢物水平相关联。3)测量饮食诱导的肌肉SCD 1 mRNA和蛋白表达的变化，以及肌肉脂质去饱和指数的相应变化。4)评估性别在调节特定饮食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，说明线粒体功能障碍如何被膳食FA修饰，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