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（通过应用程序提供）：尽管进行了数十年的研究，但在流行比例的情况下，2型糖尿病的患病率正在增加。我们的长期目标是确定导致代谢功能障碍和胰岛素抵抗的分子机制。在本应用程序中，我们将基于实验室的激动人心的数据来解决这些挑战，该数据揭示了控制脂肪细胞生物学的一种新型分子机制。我们发现了一种新的机制，该机制有助于胰岛素抵抗 - 由线粒体Sirtuin的SIRT4丢失触发。 SIRT4 脱乙酰酸盐并抑制malonyl COA脱羧酶（MCD）以控制脂质合成和脂肪氧化的平衡。因此，SIRT4KO小鼠的表现超过脂肪氧化，并降低了脂质合成。令人惊讶的是，尽管瘦弱，但SIRT4的损失导致胰岛素抵抗增加。这项工作阐明了SIRT4是脂质稳态的重要，新的调节剂，将MCD识别为新型SIRT4靶标，并加深了我们对Malonyl COA调节轴的理解。我们的总体假设是，SIRT4通过脂肪细胞中MCD的修饰来调节线粒体氧化代谢和脂质稳态的平衡，从而导致过量的线粒体通量，改善脂联素分泌和胰岛素抵抗。 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 replicas MCD to regulate lipid homeostasis, 2) To examine SIRT4 and MCD control of oxidative mitochondrial metabolism in adipocyte biology, and elucidate the该节点在脂联素的产生中的作用，以及3）通过采用新工具和方法（包括脂肪特异性的SIRT4基因敲除小鼠）来研究SIRT4介导的代谢和胰岛素抵抗的调节。该提案的创新在于新型工具和独特的假设，即线粒体Sirtuins Sirt4可以调节多个底物以控制脂肪细胞中的线粒体通量和脂肪因子分泌，从而有助于肥胖和胰岛素抵抗。这项研究的意义在于，我们将定义脂肪细胞中的分子途径，该脂肪细胞独立于肥胖而调节胰岛素抵抗。我们还将探测线粒体SIRTUIN SIRT4促进线粒体代谢，正常脂肪因子分泌和胰岛素敏感性的酶活性和能力。在这些实验中的成功将为新一代诊断方法和药物疗法打开大门，以治疗适用于许多代谢综合症的胰岛素抵抗。