Promoting metabolic health through the reduction of dietary branched chain amino acids

通过减少膳食支链氨基酸促进代谢健康

• 批准号: 10266012
• 负责人: Dudley William Lamming
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266012
• 关键词: Adult; Affect; Age; Alzheimer' s Disease; American; Amino Acids; Area; Biological Assay; Blood Glucose; Body Weight; Body Weight decreased; Branched-Chain Amino Acids; Calories; Cardiovascular Diseases; Cause of Death; Cell Culture System; Cell Culture Techniques; Cells; Chromosome Mapping; Clinic; Clinical Trials; Consumption; Data; Diabetes Mellitus; Diet; Dietary Component; Dietary Intervention; Dietary Proteins; Dietary intake; Disease; Eating; Energy Intake; Energy Metabolism; Environment; FDA approved; Fatty acid glycerol esters; Financial Hardship; Future; GCN2 protein kinase; General Population; Genetic; Genetic Variation; Glucose Clamp; Glucose Intolerance; Goals; Health; Health Care Costs; Healthcare; Healthcare Systems; Hepatic; Hepatocyte; Human; In Vitro; Inbred Strain; Inbreeding; Intake; Intervention; Isoleucine; Knowledge; Lead; Leucine; Liver; Macronutrients Nutrition; Mediating; Mediator of activation protein; Metabolic; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pharmacologic Substance; Pharmacology; Phosphotransferases; Physiological; Population; Prediabetes syndrome; Prevalence; Prevention; Process; Protein-Restricted Diet; Proteins; Proteomics; Quality of life; Rattus; Recommendation; Regulation; Research Personnel; Research Priority; Resources; Risk; Risk Factors; Rodent; Role; Signal Transduction; Speed; Sucrose; Testing; Therapeutic; Thinness; Translating; Translations; United States; Valine; Veterans; Work; base; combat; cost; design; diabetic; diabetic patient; diet-induced obesity; dietary; dieting; feeding; genetic variant; glucose metabolism; glucose production; glucose tolerance; glycemic control; hepatic gluconeogenesis; improved; in vivo; individual response; innovation; insight; insulin sensitivity; medical food; metabolic phenotype; metabolomics; military veteran; mouse model; nutrition; obesity treatment; overtreatment; personalized medicine; preclinical study; prevent; protein intake; response; western diet

Type 2 diabetes affects over 29 million Americans (12.3% of adults over the age of 20). The prevalence of diabetes in Veterans is approximately double that in the general population and continues to rise. Dietary interventions to control or prevent type 2 diabetes could be highly effective and affordable, but reduced calorie diets have proven to be unsustainable over the long term. Diet plans without a decrease in caloric consumption that instead alter the level of specific macronutrients have therefore been seen as more sustainable by both researchers and the public. Intriguingly, recent studies in mice and humans have found that low dietary protein intake is positively associated with health and insulin sensitivity; however, the physiological and molecular mechanisms by which a low protein diet promotes metabolic health is not fully understood. We recently determined that decreased dietary intake of the three branched chain amino acids (BCAAs; leucine, isoleucine, and valine) recapitulates many metabolic benefits of a low protein diet, promoting leanness and glycemic control even in mice with pre-existing diet-induced obesity and type 2 diabetes. Our preliminary data suggests that a low BCAA diet promotes glucose tolerance in part by reducing hepatic gluconeogenesis and increasing hepatic insulin sensitivity, an effect that may be mediated by the AA-sensing kinase, GCN2. The central hypothesis examined here is that reducing levels of one or more dietary BCAAs alters signaling through the amino acid-sensing kinase GCN2 or other mediators, leading to favorable physiological changes that promote metabolic health in both inbred and genetically heterogeneous mice as well as in humans. Our long-term goal is to gain mechanistic insight into how reducing dietary BCAAs promotes metabolic health, identifying new points of intervention that may be targeted with pharmaceutical interventions or dietary strategies and enabling better therapeutic options to prevent and treat obesity and type 2 diabetes in Veterans. In this proposal, we will determine the specific contribution of each of the three BCAAs on metabolic health in the context of a Western diet, performing metabolic phenotyping and quantitatively determining the effect of altered BCAAs on the liver in vivo using hyperinsulinemic-euglycemic clamps and ex vivo in primary hepatocytes. We will test if our findings are applicable beyond inbred C57BL/6J mice by determining if reducing BCAAs promotes metabolic health in genetically heterogeneous mice. Finally, we will undertake a two-pronged approach to gain mechanistic insight into the molecular mechanisms by which reduced BCAAs promote metabolic health. First, we will test the role of GCN2 using a genetic mouse model lacking hepatic Gcn2. Second, we will identify candidate molecular mediators by proteomic and metabolomics profiling of the livers of mice fed a reduced BCAA diet, and test the role of these candidate mediators in the regulation of hepatocyte glucose metabolism in a cell culture system. The innovative preclinical studies described in this proposal will significantly advance our understanding of how specific dietary BCAAs regulate metabolic health in mice, filling an important gap in present knowledge. While the present studies will be conducted in mice, all of the questions are directly relevant to our current and ongoing efforts to translate our preliminary findings into humans, with the goal of improving preventative and therapeutic options for Veterans who are obese or who have type 2 diabetes.

2 型糖尿病影响着超过 2900 万美国人（20 岁以上成年人的 12.3%）。患病率 退伍军人的糖尿病发病率大约是普通人群的两倍，并且还在持续上升。饮食 控制或预防 2 型糖尿病的干预措施可能非常有效且负担得起，但热量会减少 饮食已被证明从长远来看是不可持续的。不减少热量消耗的饮食计划 因此，这两种方法都认为改变特定常量营养素水平的方法更具可持续性 研究人员和公众。有趣的是，最近对小鼠和人类的研究发现，低膳食蛋白质 摄入量与健康和胰岛素敏感性呈正相关；然而，生理学和分子学 低蛋白饮食促进代谢健康的机制尚不完全清楚。 我们最近确定，三种支链氨基酸（BCAA； 亮氨酸、异亮氨酸和缬氨酸）概括了低蛋白饮食的许多代谢益处，促进瘦身 甚至对患有饮食诱发肥胖和 2 型糖尿病的小鼠也能进行血糖控制。我们的初步 数据表明，低支链氨基酸饮食可部分通过减少肝脏糖异生来促进葡萄糖耐量 增加肝脏胰岛素敏感性，这种作用可能是由 AA 感应激酶 GCN2 介导的。 这里检验的中心假设是，降低一种或多种膳食支链氨基酸的水平会改变信号传导 通过氨基酸感应激酶 GCN2 或其他介质，导致有利的生理变化 促进近交系和遗传异质小鼠以及人类的代谢健康。我们的 长期目标是深入了解减少膳食支链氨基酸如何促进代谢健康， 确定可能针对药物干预或饮食干预的新干预点 策略并提供更好的治疗方案来预防和治疗退伍军人的肥胖和 2 型糖尿病。 在本提案中，我们将确定三种支链氨基酸中的每一种对代谢健康的具体贡献 在西方饮食的背景下，进行代谢表型分析并定量确定 使用高胰岛素-正常血糖钳在体内改变肝脏上的支链氨基酸，并在体外进行原代实验 肝细胞。我们将通过确定是否可以测试我们的发现是否适用于近交 C57BL/6J 小鼠之外 减少支链氨基酸可促进遗传异质小鼠的代谢健康。最后，我们将进行一次 双管齐下的方法，深入了解减少支链氨基酸的分子机制 促进代谢健康。首先，我们将使用缺乏肝细胞的基因小鼠模型来测试 GCN2 的作用 GCN2。其次，我们将通过蛋白质组学和代谢组学分析来确定候选分子介质 饲喂减少 BCAA 饮食的小鼠肝脏，并测试这些候选介质在调节 细胞培养系统中的肝细胞葡萄糖代谢。 该提案中描述的创新临床前研究将显着增进我们对如何 特定的膳食支链氨基酸调节小鼠的代谢健康，填补了现有知识的一个重要空白。尽管 目前的研究将在小鼠中进行，所有问题都与我们当前和 不断努力将我们的初步发现转化为人类，目的是改善预防和 肥胖或患有 2 型糖尿病的退伍军人的治疗选择。