Branched chain amino acid metabolism

该提案的目的是确定不可缺少的支链氨基酸(BCAA)的作用。 在能量代谢和营养分配方面。有证据表明，增加膳食蛋白质对 有益于胰岛素敏感性、饱腹感、瘦体重和抵抗肥胖。亮氨酸是主要的 蛋白质来源的营养信号。矛盾的是，肥胖者血浆支链氨基酸水平升高，而且有证据表明 肥胖状态下支链氨基酸代谢紊乱。确定亮氨酸与其代谢物的作用 在营养信号方面，支链氨基酸分解代谢途径中第一种酶的全局缺失的小鼠 产生线粒体支链氨基转移酶(BCATm KO)。这种动物已经长期 血浆和组织支链氨基酸升高，未表现出枫糖尿的神经症状 疾病。BCATm KO小鼠能量消耗增加，对胰岛素更敏感，更瘦，而且 抵抗饮食引起的肥胖。一项新的研究部分解释了这种动物能量消耗的增加。 蛋白质无用循环(蛋白质合成和降解速度加快)。蛋白质无用的概念 骑自行车有助于增加能源消耗是一种新的、新颖的方式。在这项提案中，机制 肌肉蛋白分解增加的基础将被调查，并假设脂肪减少 (瘦肉型)BCATm KO脂肪生成减少和/或脂肪生成减少的结果将是 也做了测试。我们将确定在肝脏中表达BCATm的新小鼠(BCATm LivTg)是否是 适合人类的模型，因为人类在肝脏表达BCAT。最后，第一次发现 支链氨基酸分解代谢中的两种酶结合形成一个超分子复合体(支链氨基酸代谢)，该超分子复合体也 含有在碳水化合物、脂肪酸和氨基酸代谢中起关键作用的酶，提供了一种新的 支链氨基酸和其他营养途径之间的串扰机制。这一规定独立于 已知的由亮氨酸和胰岛素激活的信号通路。假设支链氨基酸/亮氨酸 通过这种新陈代谢与其他常量营养素的沟通将在分子水平上进行测试。 代谢功能在体外，在培养细胞中，最后在从转基因动物分离的线粒体中 支链氨基酸发生改变或被阻断时，将确定其分解代谢。这项研究的结果将提供新的见解 研究支链氨基酸和高蛋白饮食在减肥和能量消耗中所起的作用(S)。

The goals of this proposal are to determine the role of the indispensable branched-chain amino acids (BCAAs) in energy metabolism and nutrient partitioning. There is evidence that increasing dietary protein has a beneficial effect on insulin sensitivity, satiety, lean body mass, and resistance to obesity. Leucine is the primary protein-derived nutrient signal. Paradoxically, plasma BCAAs are elevated in obesity, and there is evidence for dysregulation of BCAA metabolism in the obese state. To determine the role of leucine versus its metabolites in nutrient signaling, a mouse with a global deletion of the first enzyme in the BCAA catabolic pathway, the mitochondrial branched-chain aminotransferase, was generated (BCATm KO). This animal has chronically elevated plasma and tissue BCAAs and does not exhibit the neurologic symptoms of Maple Syrup Urine Disease. The BCATm KO mouse has enhanced energy expenditure, is more insulin-sensitive, is lean, and is resistant to diet-induced obesity. Elevated energy expenditure in this animal is explained in part by a novel protein futile cycle (enhanced rates of protein synthesis and degradation). The concept that protein futile cycling contributes to enhanced energy expenditure is new and novel. In this proposal, the mechanisms underlying the increased muscle proteolysis will be investigated and the hypothesis that the reduced adiposity (lean phenotype) results from reduced lipogenesis and/or reduced adipogenesis in the BCATm KO will be tested as well. We will determine whether a new mouse that expresses BCATm in liver (BCATm LivTg) is an appropriate model for humans, because humans express BCAT in the liver. Finally, the discovery that the first two enzymes in BCAA catabolism associate to form a supramolecular complex (BCAA metabolon) that also contains enzymes that are key players in carbohydrate, fatty acid, and amino acid metabolism provides a new mechanism for cross-talk between the BCAAs and other nutrient pathways. This regulation is independent of known signaling pathways activated by leucine and insulin. The hypothesis that the BCAAs/leucine communicate with the other macronutrients through this metabolon will be tested at the molecular level. Metabolon function in vitro, in cultured cells and finally in mitochondria isolated from the transgenic animals with altered or blocked BCAA catabolism will be determined. Results from this study will provide new insights into the role(s) played by BCAAs and high protein diets in weight loss and energy expenditure.