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型糖尿病会影响超过2900万美国人（20岁以上成年人的12.3％）。流行率 退伍军人中的糖尿病大约是普通人群的两倍，并且继续增加。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，但卡路里降低了 从长远来看，饮食已被证明是不可持续的。饮食计划没有量减少热量消耗 因此，这改变了特定大量营养素的水平 研究人员和公众。有趣的是，最近对小鼠和人类的研究发现饮食中的蛋白质较低 摄入量与健康和胰岛素敏感性呈正相关；但是，生理和分子 低蛋白质饮食促进代谢健康的机制尚不完全了解。 我们最近确定，三种分支链氨基酸的饮食摄入量降低（BCAAS； 亮氨酸，异亮氨酸和缬氨酸）概括了低蛋白质饮食的许多代谢益处，促进瘦肉 即使在患有饮食诱导的肥胖症和2型糖尿病的小鼠中，血糖控制也是如此。我们的初步 数据表明，低BCAA饮食会通过降低肝糖异生，从而促进葡萄糖耐受性 并提高肝胰岛素敏感性，这种作用可能由AA敏感激酶GCN2介导。 此处检查的中心假设是一个或多个饮食BCAA的降低水平改变了信号传导 通过氨基酸的激酶GCN2或其他介体，导致了有利的生理变化 这促进了近交和遗传异质小鼠以及人类的代谢健康。我们的 长期目标是获得机械洞察力，了解减少饮食BCAA如何促进代谢健康， 确定可能针对药品干预或饮食的新干预点 策略并实现更好的治疗选择，以预防和治疗退伍军人中的肥胖和2型糖尿病。 在此提案中，我们将确定三个BCAA中的每个BCAA对代谢健康的具体贡献 西方饮食的背景，进行代谢表型和定量确定的影响 使用高胰岛素血糖夹在体内的肝脏在体内改变BCAA，而原发性的exbcaA 肝细胞。我们将测试我们的发现是否适用于近交C57BL/6J小鼠以外的适用 减少BCAA可促进遗传异质小鼠的代谢健康。最后，我们将承担 两种普通的方法，以获取对分子机制减少BCAA的机制的洞察力 促进代谢健康。首先，我们将使用缺乏肝的遗传小鼠模型测试GCN2的作用 GCN2。其次，我们将通过蛋白质组学和代谢组学分析鉴定候选分子介质 小鼠的肝脏喂养降低BCAA饮食，并测试这些候选者在调节中的作用 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大大提高我们对如何的理解 特定的饮食BCAA调节小鼠的代谢健康，填补了当前知识的重要空白。尽管 本研究将在小鼠中进行，所有问题与我们的当前和 正在进行的努力将我们的初步发现转化为人类，目的是改善预防措施和 肥胖或患有2型糖尿病的退伍军人的治疗选择。