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Remodeling of Lipid Metabolism by Dietary Methionine Restriction

通过饮食蛋氨酸限制重塑脂质代谢

基本信息

批准号：
8354428
负责人：
Eric Paul Plaisance
金额：
$ 11.23万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8354428
关键词：
Accounting Address Adipocytes Adipose tissue Adult Age Amino Acids Behavior Therapy Biological Markers Blood Body Weight decreased Body fat Brown Fat Cell Culture Techniques Cells Clinical Comorbidity Custom Data Deposition Detection Development Diet Disease Eating Energy Intake Energy Metabolism Essential Amino Acids Eukaryotic Initiation Factor-2 Evaluation Fatty Liver Fatty acid glycerol esters Feeding behaviors Fructose Gene Deletion Gene Expression Genes Genetic Goals Hepatic Hepatocyte Human In Vitro Insulin Resistance Intake Knockout Mice Knowledge Laboratories Lead Link Lipids Lipolysis Liver Longevity Mediating Metabolic Diseases Metabolic syndrome Metabolism Methionine Modeling Mus Nutrient Nutritional Obesity Obesity associated disease Pathology Pathway interactions Phenotype Phosphorylation Phosphotransferases Prevalence Production Proteins Regulation Research Rodent Role Series Serum Solutions Stearoyl-CoA Desaturase System Testing Therapeutic Tissues Transfer RNA Translating Triglycerides United States Weight Gain Work carbohydrate metabolism cohort coping deprivation detection of nutrient dietary restriction drinking water energy balance improved in vivo insight insulin sensitivity lipid biosynthesis lipid metabolism loss of function novel oxidation programs recidivism response

项目摘要

DESCRIPTION (provided by applicant): Metabolic syndrome is a clinical condition characterized by a cluster of pathologies that includes obesity and impaired regulation of carbohydrate and fat metabolism. Lifestyle modifications producing weight loss improves biomarkers of metabolic syndrome, but the high rate of recidivism with these strategies has prompted evaluation of alternative nutritional approaches. Dietary restriction of the essential amino acid methionine by 80% (MR) in rodents limits the accumulation of body fat despite an increase in food intake. A significant increase in energy expenditure compensates for increased food intake and accounts for the reduced accumulation of body fat. A number of studies conducted by our lab and others show that dietary MR also improves carbohydrate and fat metabolism. Preliminary data underscored in the current application suggest that MR may activate general control non-derepressible 2 (GCN2) kinase, a protein which is activated when any one of the 9-10 essential amino acids (EAAs) in the diet are removed. However, there are a number of fundamental differences between studies which completely remove EAAs (100%) and our studies with 80% MR suggesting that GCN2 may not explain all of the responses. Our hypothesis is that GCN2 activation reduces the expression of genes for fat synthesis in the liver and increases the expression of genes related to fat synthesis and oxidation in adipose tissue, and that these changes are responsible for at least part of the increase in energy expenditure following MR. The objective of the proposed studies will be to determine 1) which components of the overall responses to MR require GCN2, 2) if changes in carbohydrate and fat metabolism in liver and adipose tissue are necessary for increasing metabolism and 3) if MR decreases pre- existing obesity, fatty liver and insulin resistance in adult mice. In our first series of studies,we will use mice which have a genetic deletion of GCN2 to determine the role of this protein on the response to MR. We will then treat fat and liver cells isolated from a different group of wild-type and GCN2 null mice with media containing the amino acid levels found in blood after a prior MR study. These studies will allow us to determine if the different responses to MR for fat-producing genes in liver and adipose tissue are direct and if these effects are caused by GCN2. In our second series of studies, we will place mice with an adipose tissue-specific deletion of the gene for stearoyl CoA desaturase 1 (SCD1) on MR to determine if an inhibition of the synthesis of fats reduces metabolism in adipose tissue and decreases overall energy expenditure. In our final study, we will determine if MR reverses pre-existing obesity, fatty liver and insulin resistance in mice after a high fructose diet. These studies will help us to determine how MR is detected and generates its effects and will refine our approach to accomplish my long-term goal of conducting these studies in humans as a therapeutic strategy for obesity and other metabolic disease-related conditions. PUBLIC HEALTH RELEVANCE: The results of the proposed studies will lead to a more thorough understanding of the integrated responses of the liver and adipose tissue to the intake of specific nutrients such as amino acids in the diet. These studies will also provide insight into the capacity of nutrients to functionally remodel the storage and production capacity of fat in adipose tissue. These studies have the potential to enhance our understanding of the causes of obesity and could lead to the development of dietary or pharmacological strategies to reduce the progression of weight-gain and the burden of obesity-related diseases in the United States and throughout the world.

描述（由申请人提供）：代谢综合征是一种临床病症，其特征在于包括肥胖和碳水化合物和脂肪代谢调节受损的一系列病理。生活方式的改变导致体重减轻，改善了代谢综合征的生物标志物，但这些策略的高复发率促使人们对替代营养方法进行评估。尽管食物摄入量增加，但啮齿动物对必需氨基酸甲硫氨酸的饮食限制80%（MR）仍会限制体脂的积累。能量消耗的显著增加弥补了食物摄入的增加，并减少了体内脂肪的积累。我们实验室和其他人进行的一些研究表明，饮食MR还可以改善碳水化合物和脂肪代谢。在本申请中强调的初步数据表明，MR可以激活一般控制非去阻遏2（GCN 2）激酶，当饮食中的9-10种必需氨基酸（EAA）中的任何一种被去除时，该蛋白被激活。然而，完全去除EAA（100%）的研究与我们80% MR的研究之间存在许多根本差异，这表明GCN 2可能无法解释所有反应。我们的假设是，GCN 2激活降低了肝脏中脂肪合成基因的表达，并增加了脂肪组织中与脂肪合成和氧化相关的基因的表达，并且这些变化是MR后能量消耗增加的至少一部分原因。所提出的研究的目的是确定1）对MR的总体响应的哪些组分需要GCN 2，2）如果肝脏和脂肪组织中碳水化合物和脂肪代谢的变化对于增加代谢是必要的，以及3）如果MR降低成年小鼠中预先存在的肥胖、脂肪肝和胰岛素抵抗。在我们的第一系列研究中，我们将使用GCN 2基因缺失的小鼠来确定这种蛋白质对MR反应的作用。和GCN 2缺失小鼠，其培养基含有在先前MR研究后在血液中发现的氨基酸水平。这些研究将使我们能够确定肝脏和脂肪组织中脂肪产生基因对MR的不同反应是否是直接的，以及这些影响是否由GCN 2引起。在我们的第二系列研究中，我们将把脂肪组织特异性缺失硬脂酰辅酶A去饱和酶1（SCD 1）基因的小鼠置于MR上，以确定抑制脂肪合成是否会降低脂肪组织的代谢并降低总体能量消耗。在我们的最后研究中，我们将确定MR是否逆转先前存在的肥胖，脂肪肝和胰岛素抵抗。高果糖饮食后的小鼠。这些研究将帮助我们确定MR是如何被检测到并产生其影响的，并将完善我们的方法，以实现我在人类中进行这些研究的长期目标，作为肥胖和其他代谢疾病相关疾病的治疗策略。公共卫生关系：拟议研究的结果将导致更全面地了解肝脏和脂肪组织对饮食中特定营养素（如氨基酸）摄入的综合反应。这些研究还将提供深入了解营养素在功能上重塑脂肪组织中脂肪储存和生产能力的能力。这些研究有可能提高我们对肥胖原因的理解，并可能导致饮食或药理学策略的发展，以减少美国和世界各地体重增加的进展和肥胖相关疾病的负担。