Role of Leucine Metabolism in Leucine Signaling

亮氨酸代谢在亮氨酸信号转导中的作用

• 批准号: 7677993
• 负责人: CHRISTOPHER JOHN LYNCH
• 金额: $ 31.26万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-20 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677993
• 关键词: Address; Adipocytes; Adipose tissue; Animals; Automobile Driving; Biochemical; Blood Circulation; Body Weight; Body Weight decreased; Branched-Chain Amino Acids; Cell Size; Cells; Clinical; Complex; Cytosol; Data; Deoxyglucose; Diet; Dietary Component; Dietary Proteins; Energy Metabolism; Euglycemic Clamping; Fatty acid glycerol esters; Funding; Futile Cycling; Glucose Clamp; Goals; Hand; Heart; Hormones; In Vitro; Insulin; Insulin Resistance; Isoenzymes; Keto Acids; Leucine; Liver; Medicine; Metabolic; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Mus; Muscle; Neurons; Nutrient; Obesity; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physiological; Plasma; Play; Protein Biosynthesis; Proteins; Recommendation; Research; Resistance; Role; Satiation; Signal Pathway; Signal Transduction; Sirolimus; Skeletal Muscle; Supplementation; Testing; Tissues; Transgenic Mice; Universities; Water; Weight maintenance regimen; base; branched-chain-amino-acid transaminase; college; feeding; food consumption; forest; glucose tolerance; glucose uptake; human FRAP1 protein; improved; in vivo; inhibitor/antagonist; insulin sensitivity; insulin sensitivity/resistance; lipine; mTOR Signaling Pathway; mTOR protein; medical schools; novel; oxidation; prevent; protein kinase C epsilon; public health relevance; response; weight loss intervention

DESCRIPTION (provided by applicant): The long-term goal of these studies is to determine the role of branched chain amino acid (BCAA) metabolism in obesity and nutrient signaling from leucine. Results from a number of studies indicate that increasing dietary protein in the diet has a beneficial effect on insulin sensitivity, satiety, lean body mass and resistance to obesity. Branched chain amino acids (BCAAs) or leucine appear to be the active dietary component. Paradoxically, BCAAs are elevated in obesity and their some of their targets, such PKC-? and the mTOR cell signaling pathway, appear to promote Ser-phosphorylation of IRS-1, a cause of insulin resistance. Further, substrates of mTOR, lipin, S6K1 and 4EBP1&2, have been alternatively implicated in either obesity or resistance to obesity. Since some studies suggest that raising BCAAs in the diet would be beneficial for obesity whereas other findings predict a worsening of obesity co-morbidities; it is not entirely clear what might be expected from raising BCAAs in the diet or preventing peripheral BCAA metabolism. The proposed research will address that and the following questions. What is the role of BCAA metabolism in nutrient signaling leading to the activation of PKC-? and the mTOR pathway? Does defective metabolism play a role in the elevations of BCAAs observed in obesity and can this be reversed by weight loss intervention? In the last funding period, we generated a line of transgenic mice (BCATm KO) deficient in the first step in BCAA metabolism catalyzed by the mitochondrial branched chain aminotransferase isozyme (BCATm) found in most peripheral (non-neuronal) tissues. The block in BCAA metabolism will be exploited to help clarify these inconsistencies and questions related to leucine signaling and metabolism. The BCATm KO has persistently elevated BCAAs, but these can be adjusted over a wide range by dietary manipulation. It also has an obesity- related metabolic phenotype: decreased adipose tissue mass and fat cell size, markedly improved insulin sensitivity and glucose tolerance, increased feeding-related energy expenditure and robust resistance to diet- induced obesity. Remarkably, these changes occur in the context of increased food consumption. The mechanisms underlying the improved insulin sensitivity are not understood and will be investigated here. The resistance to diet-induced obesity and increased energy expenditure found in the BCAT2 KO appear to be due to novel futile cycle that we will elucidate. The specific aims to address these questions are to: 1) Elucidate the mechanisms involved in the increased energy expenditure observed in the BCAT2 KO mouse. 2) Test the alternate hypotheses that the insulin sensitivity and resistance to diet-induced obesity of the BCAT2 KO is due to either elevated BCAAs or the loss of mitochondrial BCAA metabolism. 3) To determine whether leucine metabolism is needed for mTOR and PKC-5 activation in heart and skeletal muscle. 4) Determine the mechanism through which plasma BCAAs are elevated in obesity. PUBLIC HEALTH RELEVANCE: We are examining the role of branched chain amino acid (BCAA) metabolism in nutrient signaling and obesity. BCAAs are believed by some to be the active portion of recently emerging high protein diets (Akins, South Beach), "protein water" as well as BCAA- and Whey-supplemented snack bars for body weight control. The implication of our ongoing research is that blocking the first step in BCAA metabolism with a drug, or to a less extent increasing dietary BCAAs, will promote weight loss.

描述（由申请人提供）：这些研究的长期目标是确定分支链氨基酸（BCAA）代谢在亮氨酸的肥胖和营养信号传导中的作用。许多研究的结果表明，饮食中饮食蛋白的增加对胰岛素敏感性，饱腹感，瘦体重和对肥胖症的抗性具有有益的作用。分支链氨基酸（BCAA）或亮氨酸似乎是活跃的饮食成分。矛盾的是，肥胖症及其某些靶标的BCAA升高了这样的PKC-？ MTOR细胞信号通路似乎促进了IRS-1的磷酸化，IRS-1是胰岛素抵抗的原因。此外，MTOR，LIPIN，S6K1和4EBP1和2的底物已与肥胖或对肥胖症的抗性有关。由于一些研究表明，提高饮食中的BCAA会对肥胖有益，而其他发现预测肥胖症合并症会恶化。目前尚不清楚在饮食中提高​​BCAA或防止外周BCAA代谢会产生什么期望。拟议的研究将解决这一点以及以下问题。 BCAA代谢在养分信号传导中的作用是什么？还有mtor路径？有缺陷的新陈代谢在肥胖症中观察到的BCAA的海拔高度中是否起作用？是否可以通过减肥干预来逆转？在最后一个资金期间，我们在BCAA代谢中产生了一系列的转基因小鼠（BCATM KO），这是由在大多数外周（非神经神经元）组织中发现的线粒体分支链氨基转移酶（BCATM）催化的BCAA代谢中。 BCAA代谢中的阻滞将被利用，以帮助阐明与亮氨酸信号传导和代谢有关的这些不一致之处和问题。 BCATM KO持续升高BCAA，但可以通过饮食操纵在广泛的范围内进行调整。它还具有与肥胖相关的代谢表型：脂肪组织质量降低和脂肪细胞大小，显着提高了胰岛素敏感性和葡萄糖耐受性，增加了与喂养相关的能量消耗以及对饮食诱导的肥胖症的耐药性。值得注意的是，这些变化发生在粮食消费量增加的背景下。改善胰岛素敏感性的基础机制尚不清楚，并将在此处进行研究。在BCAT2 KO中发现的饮食引起的肥胖和增加的能量消耗的耐药性似乎是由于我们将阐明的新型徒劳循环所致。解决这些问题的具体目的是：1）阐明在BCAT2 KO小鼠中观察到的能量消耗增加所涉及的机制。 2）测试替代假设，即胰岛素敏感性和对饮食诱导的BCAT2 KO肥胖症的抗性是由于BCAA升高或线粒体BCAA代谢的丧失所致。 3）确定心脏和骨骼肌中MTOR和PKC-5激活是否需要亮氨酸代谢。 4）确定肥胖症中血浆BCAA升高的机制。 公共卫生相关性：我们正在研究分支链氨基酸（BCAA）代谢在营养信号和肥胖症中的作用。人们认为，BCAA是最近出现的高蛋白质饮食（Akins，South Beach），“蛋白质水”以及BCAA和乳清补充的小吃棒的活跃部分，以控制体重。我们正在进行的研究的含义是，通过药物阻止BCAA代谢的第一步，或者在较小程度上增加饮食BCAA，将促进体重减轻。