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，增加饮食棕榈酸（PA）降低了每日的非长期能量消耗，钝化能量后的运动后能量增加，而脂肪酸（FA）的氧化降低，同时降低了饮食中的饮食氧酸（OAA）氧气酸（OAA）。然而，饮食PA和OA对FA氧化的不同影响在女性中被大大夸张，饮食对非饲养能量消耗的影响大部分局限于男性。 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线粒体功能。 PPAR还被认为可以介导不饱和FA对stearoyl-COA去饱和酶1（SCD1）表达的抑制作用，该酶是催化OA内源性合成的酶。 SCD1基因敲除小鼠表现出增加的全身和肌肉脂肪酸氧化，并受到保护。初步数据表明，OA下调SCD1的mRNA表达。效率较低的线粒体FA氧化可能会导致细胞内脂质（例如二酰基甘油）的积累，从而抑制胰岛素信号传导。 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 PPAR核激素受体的基因靶标和转录共激活因子PGC-1A。 2）将饮食诱导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的代谢物的全身和肌内水平的变化相关联。 3）测量饮食诱导的肌肉mRNA和SCD1的蛋白质表达的变化，以及肌肉脂质的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：该项目将提供有关线粒体故障如何通过饮食FA修饰的重要新信息，在肥胖，代谢综合征，2型糖尿病以及可遗传和年龄有关的代谢性疾病中起着核心作用