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: 8166977
• 负责人: Craig Lawrence Kien
• 金额: $ 59.39万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166977
• 关键词: Adult; Affect; Age; Animals; Blood; Blood Glucose; Body Weight; Body fat; Burn injury; Carnitine; Cells; Ceramides; 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 在世界范围内，肥胖和“2 型糖尿病”（与“1 型糖尿病”不同，“1 型糖尿病”通常在成年之前发生，且病因不同）确实是一种流行病。 虽然肥胖有许多并发症，但 2 型糖尿病是其中重要的一种，并非所有肥胖者都会患上，但某些不肥胖的人却会患上。 因此，了解饮食是否会促进 2 型糖尿病的发生非常重要。 人们认为，2 型糖尿病的发生部分是因为激素、胰岛素无法充分发挥作用，无法让血糖（葡萄糖）进入肌肉细胞。 胰岛素活性缺陷反过来被认为是由于脂肪在肌肉细胞中没有得到最佳燃烧，导致“有毒脂肪”在肌肉细胞中积聚，从而阻止胰岛素向肌肉细胞发出信号以允许更多葡萄糖进入其中。 “有毒脂肪”的一些例子是“DAG、神经酰胺、β-羟基丁酸酯和酰基肉碱”。 我们在年轻、非肥胖人类受试者中的初步数据表明，增加膳食饱和脂肪（棕榈酸，PA）可以降低脂肪燃烧率，尤其是女性，并且还可以通过降低运动的能量成本（特别是男性）来降低维持体重的每日能量成本。 我们还获得了杜克大学联合研究员黛博拉·穆奥 (Deborah Muoio) 的初步数据，她研究从啮齿动物和人类身上分离出的肌肉细胞。 她证明单不饱和脂肪（油酸，OA）会导致细胞内控制脂肪氧化的基因（“PPAR 基因”）活性增加。 她还表明，饱和脂肪会导致基因 PGC-1 的产生（“转录”）减少，该基因会激活刺激脂肪和能量燃烧的其他基因。这些基因还会抑制细胞中从饱和脂肪制造单不饱和脂肪的酶（称为 SCD1）的活性，该酶位于细胞的某些区室中，这些区室可能与储存膳食脂肪的区室不同。SCD1 活性较低的动物受到保护 免受肥胖的影响，并且能够以更高的速度燃烧脂肪和能量。 Muoio 博士的初步数据显示，OA 导致 SCD1 活性降低。 我们将对 28 名 18-40 岁的健康、非肥胖成年人进行喂养试验，他们将按随机顺序喂养实验饮食（脂肪含量中等）：高 OA/低 PA 饮食（称为 HI OA）和高 PA 饮食（称为 HI PA）（每种饮食 3 次） 周）。 受试者和研究人员将无法了解饮食顺序的身份，直到判断数据完整且充分。 每个受试者都将接受筛选以确定资格：健康且未服用药物（包括避孕药）；非肥胖；久坐且身体状况不佳；血液中的血糖和血脂正常。 然后，每位受试者将接受一周的低脂对照饮食，然后进行血液检查 将在早餐前和早餐后状态下通过大腿穿刺活检获得肌肉组织。然后受试者将被喂食两种实验饮食中的一种，为期三周。 将重复血液和肌肉测试，然后受试者将被喂食低脂饮食一周，然后是第二个实验饮食三周。将重复最后（第三）系列的血液和肌肉测试。 此外，在每个末尾 在实验性饮食中，受试者将接受脂肪和卡路里燃烧的测量（过夜）以及胰岛素作用和分泌的测试（静脉内葡萄糖耐量测试）。 将评估以下目标： 1. 与对照低脂饮食相比，研究肌肉中 PPAR 和 PGC 基因如何根据实验饮食进行调节。 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的摄入量是否会降低SCD1的活性。 4. 评估性别在影响 PA 和 OA 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 型糖尿病以及遗传性和年龄相关代谢疾病的发展中发挥核心作用的重要新信息。