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: 7587388
• 负责人: Craig Lawrence Kien
• 金额: $ 54.54万
• 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/7587388
• 关键词: 1,2-diacylglycerol; Adult; Age; American Heart Association; Automobile Driving; Biochemical Pathway; Bioenergetics; Biogenesis; Biological Markers; Biopsy; Body Composition; Body fat; Candidate Disease Gene; Catabolism; Cholesterol; Chronic; Collaborations; Complement; Consumption; DNA Microarray Chip; Data; Development; Diet; Dietary Fatty Acid; Diglycerides; Education; Energy Metabolism; Enzymes; Exercise; Faculty; Family; Fasting; Fatty Acids; Female; Food; Gender Role; Gene Expression; Gene Targeting; Genes; Genetic Crossing Over; Genomics; Goals; Homeostasis; Human; Insulin Resistance; Intramuscular; Knockout Mice; Laboratories; Lead; Ligands; Lipids; Masks; Mass Spectrum Analysis; Measures; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Monounsaturated Fatty Acids; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nuclear Hormone Receptors; Obesity; Oleic Acids; Oligonucleotide Microarrays; Palmitic Acids; Pattern; Performance; Peripheral; Phenotype; Phospholipids; Play; Polymerase Chain Reaction; Property; Randomized; Receptor Activation; Recommendation; Reporting; Research Personnel; Resources; Respiratory Chain; Rest; Role; Saturated Fatty Acids; Serum; Site; Skeletal Muscle; Solid; Specimen; Spottings; Stearoyl-CoA Desaturase; Supplementation; Testing; Time; Tissues; Triglycerides; Universities; Unsaturated Fatty Acids; Urine; Western Blotting; acylcarnitine; age related; animal data; base; fatty acid oxidation; feeding; gene induction; human subject; indexing; insulin sensitivity; insulin signaling; mRNA Expression; male; member; metabolomics; nutrition; organic acid; oxidation; programs; protein expression; receptor; respiratory; response; tool; uptake

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：针对年轻、非肥胖人类受试者的初步数据表明，增加饮食中的棕榈酸 (PA) 可以降低每日非静息能量消耗，减缓运动后能量消耗的通常上升，并降低脂肪酸 (FA) 氧化，而增加饮食中的油酸 (OA) 可以增强 FA 氧化。然而，膳食 PA 和 OA 对 FA 氧化的差异影响在女性中被大大夸大，而饮食对非静息能量消耗的影响主要局限于男性。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，而高 PA 饮食会抑制 PPAR X 辅激活因子 a (PGC-1a) 的肌肉表达，PGC-1a 是 PPAR 的转录辅激活因子，同时也是 PPAR 的主要分子调节因子。 线粒体功能。 PPAR 还被认为介导不饱和 FA 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 OA 内源性合成的酶。 SCD1 敲除小鼠表现出全身和肌肉脂肪酸氧化增加，并且可以预防肥胖。初步数据显示 OA 下调 SCD1 mRNA 表达。线粒体 FA 氧化效率较低可能会导致肌细胞内脂质（例如二酰甘油）积累，从而抑制胰岛素信号传导。以下目标将在 28 名 18-40 岁健康、非肥胖成年人中进行双盲、交叉喂养试验中进行评估，这些人将按随机顺序喂养高 PA 饮食和高 OA 饮食（各 3 周）： 1) 与高棕榈酸饮食 (HI PA) 相比，研究骨骼肌对高油酸饮食 (HI OA) 的转录重编程反应，重点关注 PPAR 核激素受体和转录共激活因子 PGC-1a 的基因靶标。 2) 将饮食引起的全身脂肪氧化和转录重编程的变化与各种脂质和线粒体衍生代谢物的全身和肌内水平相关联。 3）测量饮食引起的肌肉SCD1 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，说明经膳食 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疾病的发展中发挥核心作用