MECHANISMS FOR DIFFERENTIAL EFFECTS OF DIETARY FATTY ACIDS ON METABOLISM

膳食脂肪酸对代谢产生不同影响的机制

• 批准号: 7952115
• 负责人: Craig Lawrence Kien
• 金额: $ 82.25万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7952115
• 关键词: Adult; Affect; Age; Animals; Blood; Blood Glucose; Body Weight; Body fat; Burn injury; Carnitine; Cells; Ceramides; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Diet; Dietary Fats; Dietary Fatty Acid; Eligibility Determination; Epidemic; Exercise; Fat-Restricted Diet; Fatty acid glycerol esters; Female; Funding; Gender Role; Genes; Genetic Transcription; Glucose; Grant; Hormones; Human; Hydroxybutyrates; Inherited; Institution; Insulin; Insulin-Dependent Diabetes Mellitus; Intake; Lipids; Masks; Measurement; Metabolic Diseases; Metabolism; Muscle; Muscle Cells; Muscle function; Needle biopsy procedure; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oleic Acids; Oral Contraceptives; Palmitic Acids; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Play; Production; Research; Research Personnel; Resources; Rodent; Role; Series; Serum; Source; Testing; Thigh structure; United States National Institutes of Health; Universities; age related; cost; enzyme activity; feeding; human subject; insulin signaling; intravenous glucose tolerance test; male; monounsaturated fat; oxidation; prevent; response; saturated fat; sedentary

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Worldwide, there is truly an epidemic of obesity and "type 2 diabetes" (distinguished from "type 1 diabetes" which usually develops before adulthood and has a different cause). Although there are many complications of obesity, type 2 diabetes is an important one and does not develop in all obese people but does develop in some people who are not obese. It is thus important to understand whether diet may promote the development of type 2 diabetes. Type 2 diabetes is thought to develop, in part, because the hormone, insulin, does not function adequately in allowing blood sugar (glucose) to enter the muscle cells. Defective activity of insulin is in turn thought to develop because fat is not optimally burned in the muscle cell leading to the accumulation of "toxic fats" in the muscle cell which prevent insulin from signaling the muscle cell to allow more glucose to enter it. Some examples of "toxic fats" are "DAG, ceramide, -hydroxybutyrate, and acyl-carnitines". Our preliminary data in young, non-obese, human subjects suggest that increasing dietary saturated fat (palmitic acid, PA) lowers the rate of fat burning, especially in females and also lowers the daily energy cost for maintaining body weight by lowering the energy cost of performing exercise (especially in males). We also have preliminary data from our co-investigator at Duke University, Deborah Muoio, who studies isolated muscle cells from rodents and humans. She has shown that monounsaturated fat (oleic acid, OA) causes increased activity of genes which govern fat oxidation in the cell ("PPAR genes"). She also has shown that saturated fat causes less production ("transcription) of the gene, PGC-1, which activates other genes that stimulate both fat and energy burning. These genes also inhibit the activity of an enzyme which manufactures monounsaturated fat from saturated fat in the cell (called SCD1), within certain compartments of the cell which may be distinct from the compartments where dietary fat is stored. Animals which have lower activity of SCD1 are protected from obesity and are able to burn fat and energy at an increased rate. Dr. Muoio's preliminary data show that OA caused less activity of SCD1. We will conduct a feeding trial in 28 healthy, non-obese, adults, 18-40 yr of age, who will be fed experimental diets (moderately high in fat), in random order: both a high OA/low PA diet called HI OA and a high PA diet, called HI PA (each for 3 wk). The subjects and the investigators will be masked to the identity of the order of the diets until the data are judged to be complete and adequate. Each subject will be screened to determine eligibility: healthy and not on medication (including birth control pills); non-obese; sedentary and not exceptionally physically fit; normal serum glucose and lipids in blood. Then, each subject will be fed a low-fat, control diet for one week after which blood will be drawn and muscle tissue will be obtained by needle biopsy of the thigh in the pre-breakfast and post-breakfast state. Then the subject will be fed one of the two experimental diets for three weeks. The blood and muscle tests will be repeated and then the subject will be fed the low-fat diet for one week followed by the second experimental diet for three weeks. The final (third) series of blood and muscle tests will be repeated. In addition, at the end of each of the experimental diets, the subjects will undergo measurements of fat and calorie burning (overnight) and a test of insulin action and secretion (intravenous glucose tolerance test). The following Aims will be assessed: 1. To investigate how PPAR and PGC genes are regulated in muscle in response to the experimental diets in comparison to the control, low fat, diet. 2. To correlate changes in whole-body fat burning and gene activity with levels of various toxic lipids in muscle. 3. To assess whether increasing the intake of OA lowers the activity of SCD1. 4. To evaluate the role of gender in affecting responses to PA and OA. This project will provide important new information regarding how diet fat alters the functions of muscle and whether it plays a central role in the development of obesity, type 2 diabetes, and both inherited and age-related metabolic diseases.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 在全球范围内，确实存在肥胖和“ 2型糖尿病”的流行病（与通常在成年前发展的“ 1型糖尿病”区分开，并且有不同的原因）。 尽管肥胖存在很多并发症，但2型糖尿病是重要的，并且并非在所有肥胖者中发展，而是在某些不是肥胖的人中发展出来的。 因此，重要的是要了解饮食是否可以促进2型糖尿病的发展。 2型糖尿病被认为部分发展是因为激素，胰岛素，在允许血糖（葡萄糖）进入肌肉细胞方面无法充分发挥作用。 胰岛素活性有缺陷又被认为是由于脂肪在肌肉细胞中没有最佳燃烧而导致肌肉细胞中积累的脂肪的最佳燃烧，从而防止胰岛素向肌肉细胞发出信号，从而使更多的葡萄糖输入。 一些“有毒脂肪”的例子是“ DAG，神经酰胺， - 羟基丁酸和酰基肉碱”。 我们在年轻，非肥胖，人类受试者中的初步数据表明，增加饮食饱和脂肪（棕榈酸，宾夕法尼亚州）降低了脂肪燃烧的速度，尤其是在女性中，并且通过降低表现运动的能量成本（尤其是在男性中）来降低每日能量的能量成本。 我们还拥有杜克大学（Duke University）的共同投资者Deborah Muoio的初步数据，他研究了将肌肉细胞与啮齿动物和人类隔离的。 她表明，单不饱和脂肪（油酸，OA）会导致控制细胞中脂肪氧化的基因活性（“ PPAR基因”）。 她还表明，饱和脂肪会导致基因，PGC-1的产生（“转录）PGC-1，该基因激活了刺激脂肪和能量燃烧的其他基因。这些基因还抑制了在动物的某些销售中，这些酶在细胞中的某些障碍物较低，从而抑制了在细胞中较低的动物量较低的酶，该酶的生产的脂肪从细胞中较低，而该动物的活性较低。肥胖症能够以增加的速度燃烧脂肪和能量。 WK）。 将筛选每个受试者以确定资格：健康而不是药物（包括避孕药）；非肥胖；久坐不明的身体身体不适；血清葡萄糖正常和血液中的脂质。 然后，每个受试者将被喂入低脂饮食一周，然后吸收血液，并通过在早餐前和早餐后的大腿进行针头活检来获得肌肉组织。然后，该受试者将在三个星期中喂食两种实验饮食之一。 将重复血液和肌肉测试，然后将受试者喂入低脂饮食一周，然后进行第二次实验饮食三周。最终（第三）系列的血液和肌肉测试将重复。 此外，在每种实验饮食结束时，受试者将经过脂肪和卡路里燃烧的测量（过夜），并测试胰岛素作用和分泌（静脉内葡萄糖耐受性测试）。 将评估以下目标： 1。为了研究与对照，低脂肪，饮食相比，在肌肉中如何调节PPAR和PGC基因。 2。将全身脂肪燃烧和基因活性的变化与肌肉中各种有毒脂质的水平相关联。 3。评估增加OA摄入量是否降低了SCD1的活性。 4。评估性别在影响对PA和OA的反应中的作用。 该项目将提供有关饮食脂肪如何改变肌肉功能以及它是否在肥胖，2型糖尿病以及遗传和与年龄相关的代谢性疾病中起核心作用的重要新信息。