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：
9896807
负责人：
Thomas W Gettys
金额：
$ 37万
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896807
关键词：
Address Adipocytes Adipose tissue Affect Animal Model Back Binding Biochemical Biological Markers Brain Brown Fat Cell Culture Techniques Cell Line Chronic Collaborations Consumption Coupled Cyclic AMP-Responsive DNA-Binding Protein Cysteine Data Deposition Development Diabetes Mellitus Diet Diet Modification Disease Endoplasmic Reticulum Energy Metabolism Essential Amino Acids Event FGF21 gene Fatty acid glycerol esters Gene Expression Genetic Transcription Glutathione Goals Health Heart Diseases Hepatic Hepatocyte In Vitro Individual Insulin Resistance Letters Link Liver Mediating Metabolic Metabolic Diseases Metabolic hormone Metabolic syndrome Methionine Mouse Strains Mus Obesity Peripheral Phenotype Phosphotransferases Physiological Play Proteins Publishing Regulation Research Role Series Signal Transduction Stroke System Testing Thermogenesis Tissues Transactivation Translating Triglycerides Work base comorbidity detection of nutrient dietary restriction effective intervention effective therapy energy balance experimental study improved in vivo insulin sensitivity knock-down lipid disorder lipid metabolism liquid chromatography mass spectrometry loss of function metabolic phenotype preclinical study programs promoter recruit response transcription factor

项目摘要

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 white adipose tissue, activate thermogenesis in brown adipose tissue, and enhance insulin sensitivity. We hypothesize that sensing of dietary MR is coupled to these responses through hepatic sensing of reduced methionine through a glutathione-dependent mechanism that activates CREBH and the eIF2 kinase, PERK. The activation of CREBH and PERK results in activation eIF2α- and NRF2-dependent transcriptional programs that increase hepatic expression and release of FGF21. We hypothesize that the increase in FGF21 acts through direct and centrally-mediated mechanisms to activate thermogenesis, increase energy expenditure, reduce fat deposition, and enhance overall insulin sensitivity. 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. 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.

饮食中的蛋氨酸限制（MR）产生一系列高度综合的生化和降低肥胖，改善代谢健康的生物标志物的身体反应和增强胰岛素敏感性。我们的数据使饮食MR通过两者都作用的令人信服的案例集中介导的对能量平衡的影响，并直接对周围组织的影响重塑白色脂肪组织，激活棕色脂肪组织的热发生，并增强胰岛素灵敏度。我们假设饮食MR的敏感性与这些反应耦合通过通过谷胱甘肽依赖性机制对甲硫氨酸还原的肝感测激活CREBH和EIF2激酶，Perk。 CREBH和PERK结果的激活在激活中，EIF2α-和NRF2依赖性转录程序增加了肝 FGF21的表达和释放。我们假设FGF21的增加通过直接和集中介导的机制激活热生成，增加能量支出，减少脂肪沉积并增强整体胰岛素敏感性。我们将使用一个体内代谢表型和离体生化分析的结合与丧失功能动物模型以检查必需氨基酸敏感性在相对中的作用对饮食MR的反应。这项工作的目的是确定营养感和信号传导检测蛋氨酸限制并将这种饮食修饰转化为限制的系统高度整合和有益的物理反应集。