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: 10409708
• 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/10409708
• 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; translational potential; 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（占20岁以上成年人的12.3%）。之时尚 退伍军人的糖尿病发病率约为普通人群的两倍，并继续上升。膳食 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， 饮食已被证明是不可持续的长期。不减少热量消耗的饮食计划 因此，两者都认为， 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， 低蛋白饮食促进代谢健康的机制尚未完全了解。 我们最近确定，减少三种支链氨基酸（BCAAs; 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， 和血糖控制，甚至在预先存在饮食诱导的肥胖和2型糖尿病的小鼠中。我们的初步 数据表明，低支链氨基酸饮食促进葡萄糖耐量的部分原因是减少肝细胞再生 以及增加肝脏胰岛素敏感性，这一作用可能由AA敏感激酶GCN 2介导。 这里研究的中心假设是，降低一种或多种饮食BCAA的水平会改变信号传导 通过氨基酸敏感激酶GCN 2或其他介质，导致有利的生理变化 促进近交系和遗传异质性小鼠以及人类的代谢健康。我们 长期目标是获得关于减少饮食中BCAA如何促进代谢健康的机理性见解， 确定新的干预点，可以通过药物干预或饮食干预来实现 战略和使更好的治疗选择，以预防和治疗肥胖和2型糖尿病的退伍军人。 在本提案中，我们将确定三种BCAA中的每一种对代谢健康的具体贡献， 西方饮食的背景下，进行代谢表型和定量确定的影响， 使用高胰岛素-正常血糖钳夹在体内改变肝脏上的BCAA， 肝细胞我们将通过确定我们的发现是否适用于近交系C57 BL/6 J小鼠， 减少支链氨基酸促进遗传异质性小鼠的代谢健康。最后，我们将进行一项 双管齐下的方法，以获得对减少支链氨基酸的分子机制的机械见解， 促进新陈代谢健康。首先，我们将使用缺乏肝脏的遗传小鼠模型来测试GCN 2的作用。 GCN 2.其次，我们将通过蛋白质组学和代谢组学分析来鉴定候选分子介质， 小鼠肝脏喂食减少BCAA饮食，并测试这些候选介质在调节 细胞培养系统中肝细胞葡萄糖代谢。 本提案中描述的创新性临床前研究将大大促进我们对如何实现这些目标的理解。 特定的饮食支链氨基酸调节小鼠的代谢健康，填补了目前知识的重要空白。而 目前的研究将在小鼠中进行，所有的问题都与我们目前的研究直接相关， 目前正在努力将我们的初步研究结果转化为人类，目的是提高预防和 肥胖或患有2型糖尿病的退伍军人的治疗选择。