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支链氨基酸（BCAA）代谢在肥胖和亮氨酸营养信号传导中的作用。多项研究结果表明，增加饮食中的膳食蛋白质对胰岛素敏感性、饱腹感、去脂体重和肥胖抵抗力具有有益影响。支链氨基酸（BCAA）或亮氨酸似乎是活性膳食成分。矛盾的是，BCAA 在肥胖症及其某些靶标（例如 PKC-？）中升高。和 mTOR 细胞信号通路似乎促进 IRS-1 的丝氨酸磷酸化，而 IRS-1 是胰岛素抵抗的原因之一。此外，mTOR 的底物、脂质、S6K1 和 4EBP1&2 也与肥胖或肥胖抵抗力有关。由于一些研究表明，在饮食中增加支链氨基酸对肥胖有益，而其他研究结果则预测肥胖并发症会恶化；目前尚不完全清楚通过提高饮食中的支链氨基酸或阻止外周支链氨基酸代谢会产生什么效果。拟议的研究将解决这个问题和以下问题。 BCAA 代谢在导致 PKC- 激活的营养信号传导中发挥什么作用？和 mTOR 通路？代谢缺陷是否在肥胖者观察到的 BCAA 升高中发挥作用？这是否可以通过减肥干预来逆转？在上一个资助期间，我们培育了一系列转基因小鼠（BCATm KO），这些小鼠在大多数外周（非神经元）组织中发现的线粒体支链转氨酶同工酶（BCATm）催化的支链氨基酸代谢的第一步中存在缺陷。支链氨基酸代谢的阻断将被用来帮助澄清这些与亮氨酸信号传导和代谢相关的不一致和问题。 BCATm KO 的 BCAA 持续升高，但这些可以通过饮食控制进行大范围调整。它还具有与肥胖相关的代谢表型：脂肪组织质量和脂肪细胞大小减少，胰岛素敏感性和葡萄糖耐量显着改善，与喂养相关的能量消耗增加以及对饮食引起的肥胖的强大抵抗力。值得注意的是，这些变化是在粮食消费增加的背景下发生的。改善胰岛素敏感性的机制尚不清楚，将在此进行研究。 BCAT2 KO 中发现的对饮食引起的肥胖的抵抗力和能量消耗增加似乎是由于我们将阐明的新的无效循环。解决这些问题的具体目标是：1) 阐明 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 BCAT2 KO 的胰岛素敏感性和对饮食诱导肥胖的抵抗力是由于 BCAA 升高或线粒体 BCAA 代谢丧失所致。 3) 确定心脏和骨骼肌中mTOR和PKC-5的激活是否需要亮氨酸代谢。 4) 确定肥胖患者血浆支链氨基酸升高的机制。 公共健康相关性：我们正在研究支链氨基酸 (BCAA) 代谢在营养信号传导和肥胖中的作用。一些人认为支链氨基酸是最近出现的高蛋白饮食（Akins，南海滩）、“蛋白质水”以及用于控制体重的补充支链氨基酸和乳清的零食棒的活性部分。我们正在进行的研究表明，用药物阻断支链氨基酸代谢的第一步，或者在较小程度上增加饮食中的支链氨基酸，将促进减肥。