MECHANISMS OF METABOLIC REGULATION BY DIETARY METHIONINE RESTRICTION

饮食蛋氨酸限制的代谢调节机制

基本信息

批准号：
8686834
负责人：
Thomas W Gettys
金额：
$ 32.19万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686834
关键词：
Address Adipose tissue Affect Age Animal Model Behavioral Biochemical Biological Biological Markers Cell Line Cells Chronic Clinic Comorbidity Complement Coupled Data Development Diabetes Mellitus Diet Diet Modification Disease Essential Amino Acids Event Failure Fatty acid glycerol esters Glutathione Glutathione Metabolism Pathway Goals Health Heart Diseases Hepatic Human In Vitro Individual Insulin Insulin Resistance Letters Leucine Link Lipids Liver Mediating Metabolic Metabolic Diseases Metabolic syndrome Methionine Modeling Mouse Strains Mus Obesity Peripheral Phase Phenotype Physiological Plasma Procedures Protein Kinase Protein Tyrosine Phosphatase Proteins Publishing Rattus Regulation Research Rodent Role Series Severities Signal Transduction Specificity Stroke System Testing Tissues Transfer RNA Aminoacylation Translating Translations Work base detection of nutrient effective therapy efficacy testing energy balance glucose production improved in vivo insight insulin sensitivity insulin signaling lipid metabolism loss of function oxidation preclinical study programs response

项目摘要

DESCRIPTION: Dietary methionine restriction (MR) produces a highly integrated series of biochemical and physiological responses that reduce adiposity, improve biomarkers of metabolic health and enhance insulin sensitivity. Our data make a compelling case that dietary MR acts through both centrally-mediated effects on energy balance, and direct effects on peripheral tissues that remodel lipid metabolism and enhance insulin sensitivity. We hypothesize that sensing of dietary MR is coupled to these responses through a combination of essential amino acid- dependent signaling and methionine-specific effects on cell glutathione which serve to enhance insulin signaling. We will use a combination of in vivo metabolic phenotyping and ex vivo biochemical analysis with loss of function animal models to examine the role of essential amino acid sensing in the respective responses to dietary MR. These studies will be complemented by a two-pronged in vivo and in vitro approach to establish the specificity of restricting dietary methionine versus other essential amino acids. The goal of this work is to identify the nutrient sensing and signaling systems which detect the restriction of methionine and translate this dietary modification into a highly integrated and beneficial set of physiological responses. The significant unanswered question addressed by this proposal is whether and how restriction of methionine provides significant additional benefits compared to restriction other essential amino acids.

描述：饮食中的蛋氨酸限制（MR）产生一系列高度综合的生化和生理反应，可降低肥胖，改善代谢健康的生物标志物并增强胰岛素敏感性。我们的数据表达了一个令人信服的案例，即饮食MR通过中央介导的能量平衡的影响以及对重塑脂质代谢并增强胰岛素敏感性的外周组织的直接影响。我们假设通过必需氨基酸依赖性信号传导和蛋氨酸特异性对细胞谷胱甘肽的影响的结合，将饮食中的MR感测与这些反应，从而增强胰岛素信号传导。我们将使用体内代谢表型和外体生物化学分析与功能动物模型丧失的结合，以检查必需氨基酸传感在各自对饮食MR的反应中的作用。这些研究将以两种供体内的体内和体外方法进行补充，以建立限制饮食中蛋氨酸与其他必需氨基酸的特异性。这项工作的目的是确定养分感应和信号系统，这些传感和信号系统检测蛋氨酸的限制，并将这种饮食修饰转化为高度综合且有益的生理反应集。该提案解决的重要问题是，与限制其他必需氨基酸相比，甲硫氨酸的限制是否以及如何提供额外的好处。