Control of metabolic homeostasis in diabetes by sirtuins

通过 Sirtuins 控制糖尿病的代谢稳态

基本信息

批准号：
9012089
负责人：
MARCIA HAIGIS
金额：
$ 38.14万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9012089
关键词：
ADP ribosylation Acetyl Coenzyme A Acetylation Address Adipocytes Adipose tissue Animals Automobile Driving Biochemical Biological Assay Biological Markers Biology Body Weight Carbon Cell Respiration Cultured Cells Data Development Diabetes Mellitus Diagnostic Procedure Diet Disease Progression Endocrine Glands Enzymes Epidemic Equilibrium Fatty acid glycerol esters Functional disorder Generations Genetic Glucose Goals Health High Fat Diet Homeostasis Individual Insulin Insulin Resistance Knock-out Knockout Mice Lead Link Lipids Malonyl Coenzyme A Measures Mediating Metabolic Metabolic Control Metabolic syndrome Metabolism Methods Mitochondria Mitochondrial Proteins Modeling Modification Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Prevalence Production Reaction Regulation Reporting Research Role Sirtuins Site Techniques Testing Work adipocyte biology adipokines adiponectin cell type cytokine deacylation disorder prevention energy balance fitness improved innovation insight insulin sensitivity lipid biosynthesis lipid metabolism malonyl-CoA decarboxylase mitochondrial metabolism mouse model novel overexpression oxidation prevent research study success tool

项目摘要

DESCRIPTION (provided by applicant): Despite decades of research, the prevalence of Type 2 diabetes is increasing at epidemic proportions. Our long-term goal is to identify the molecular mechanisms that lead to metabolic dysfunction and insulin resistance. In this application, we will address these challenges, building upon exciting data from our lab that reveals a novel molecular mechanism in controlling adipocyte biology. We have discovered a novel mechanism that contributes to insulin resistance - triggered by loss of SIRT4, a mitochondrial sirtuin. SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD) to control the balance of lipid synthesis and fat oxidation. Consequently, SIRT4KO mice display excessive fat oxidation, and lowered lipid synthesis. Strikingly, though lean, loss of SIRT4 leads to increased insulin resistance. This work elucidates SIRT4 as an important, new, regulator of lipid homeostasis, identifies MCD as a novel SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis. Our overall hypothesis is that SIRT4 regulates the balance in mitochondrial oxidative metabolism and lipid homeostasis through the modification of MCD in adipocytes, leading to the contribution of excessive mitochondrial flux, decreased adiponectin secretion and insulin resistance. This proposal will test these ideas by our strategy of utilizing biochemical techniques and novel mouse models in the following Aims: 1) To define the enzymatic activity of SIRT4 and identify the molecular mechanism(s) by which SIRT4 represses MCD to regulate lipid homeostasis, 2) To examine SIRT4 and MCD control of oxidative mitochondrial metabolism in adipocyte biology, and elucidate the role of this node in adiponectin production, and 3) To investigate SIRT4- mediated regulation of metabolism and insulin resistance during metabolic challenge by employing novel tools and methods, including fat-specific SIRT4 knockout mice. The innovation of this proposal lies in both the novel tools and the unique hypothesis that SIRT4, a mitochondrial sirtuin, can regulate multiple substrates to control mitochondrial flux and adipokine secretion in adipocytes to contribute to obesity and insulin resistance. The significance of this study is that we will define a molecular pathway in adipocytes that regulates insulin resistance independently of obesity. We will also probe the enzymatic activity and ability of SIRT4, a mitochondrial sirtuin, to promote mitochondrial metabolism, normal adipokine secretion and insulin sensitivity. Success in these experiments would open the door for a new generation of diagnostic methods and pharmacological therapies for treating insulin resistance that would be applicable to many metabolic syndromes.

描述（由申请人提供）：尽管进行了数十年的研究，2 型糖尿病的患病率仍在以流行的程度增加。在本申请中，我们将确定导致代谢功能障碍和胰岛素抵抗的分子机制。我们实验室的数据揭示了一种控制脂肪细胞生物学的新分子机制，我们发现了一种由 SIRT4（一种线粒体 SIRT4）缺失引发的胰岛素抵抗新机制，以应对这些挑战。去乙酰化并抑制丙二酰辅酶 A 脱羧酶 (MCD)，以控制脂质合成测试和脂肪氧化的平衡。SIRT4KO 小鼠表现出过度的脂肪氧化，并降低了脂质合成，尽管很瘦，但 SIRT4 的缺失会导致胰岛素抵抗增加。阐明 SIRT4 作为一种重要的、新型的脂质稳态调节剂，将 MCD 确定为新的 SIRT4 靶点，并深入研究我们对丙二酸单酰 CoA 调节轴的理解是，SIRT4 通过修饰脂肪细胞中的 MCD 来调节线粒体氧化代谢和脂质稳态的平衡，从而导致线粒体通量过多、脂联素分泌减少和胰岛素抵抗。该提案将通过我们利用生化技术和新型小鼠模型的策略来测试这些想法，目的如下：1) 定义 SIRT4 的酶活性并鉴定分子SIRT4 抑制 MCD 调节脂质稳态的机制，2) 检查脂肪细胞生物学中 SIRT4 和 MCD 对氧化线粒体代谢的控制，并阐明该节点在脂联素产生中的作用，以及 3) 研究 SIRT4 介导的调节通过采用新的工具和方法，包括脂肪特异性 SIRT4 敲除小鼠，研究代谢挑战期间的代谢和胰岛素抵抗。新颖的工具和独特的假设，即 SIRT4（一种线粒体去乙酰化酶）可以调节多种底物来控制脂肪细胞中的线粒体通量和脂肪因子分泌，从而导致肥胖和胰岛素抵抗。这项研究的意义在于，我们将定义脂肪细胞中的分子途径。我们还将探讨 SIRT4（一种线粒体去乙酰化酶）的酶活性和能力，以促进线粒体代谢、正常脂肪因子分泌和胰岛素敏感性。这些实验将为治疗胰岛素抵抗的新一代诊断方法和药物疗法打开大门，这些方法和药物疗法将适用于许多代谢综合征。