Defining mechanisms of succinate regulation over adipose tissue thermogenesis

琥珀酸对脂肪组织产热调节的定义机制

基本信息

批准号：
10649729
负责人：
Edward Thomas Chouchani
金额：
$ 41.87万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10649729
关键词：
Ablation Adipocytes Adipose tissue Automobile Driving Biochemical Biochemistry Cardiovascular Diseases Cell membrane Cells Circulation Cysteine Data Development Diabetes Mellitus Energy Metabolism Fatty acid glycerol esters Generations Genetic Genetic Complementation Test Genetic Models Health Lead Malignant Neoplasms Maps Mass Spectrum Analysis Membrane Transport Proteins Metabolic Metabolic Diseases Methods Mitochondria Mitochondrial Proteins Modification Molecular Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Pathway interactions Peripheral Physiological Physiology Process Proteins Reactive Oxygen Species Regulation Respiration Risk Factors Role Signal Transduction Site Succinates System Testing Therapeutic Thermogenesis diet-induced obesity extracellular in vivo loss of function metabolic phenotype molecular phenotype mouse model novel obesity treatment obesogenic oxidation pharmacologic programs protonation uptake

项目摘要

Defining mechanisms of succinate regulation over adipose tissue thermogenesis PROJECT SUMMARY: Obesity is a major risk factor for type-2 diabetes, cardiovascular disease, and many cancers. Thermogenic brown and beige adipose tissues can catabolize stored fat and are potently anti-obesogenic. The anti-obesity activity of thermogenic adipocytes requires activation by peripheral signals, and the identification of these activating mechanisms is key to leveraging the therapeutic activity of these cells. We recently discovered that the mitochondrial metabolite succinate is a potent molecular activator of thermogenic respiration in brown and beige adipocytes. Remarkably, these cells can utilize succinate to drive thermogenesis by sequestering it from the circulation, which is a newfound unique activity of thermogenic adipocytes. Our current objective is to investigate the molecular mechanisms that control this newfound pathway of succinate-dependent thermogenesis, and to also determine its physiological consequences. To build on our identification of the succinate thermogenesis pathway we propose specific hypotheses to test that will determine the mechanisms through which brown and beige adipocytes acquire and utilize succinate to control their anti-obesity activity. Based on extensive preliminary data, we hypothesize an essential role for the plasma membrane transporter monocarboxylate transporter 1 (MCT1) in controlling succinate uptake specifically in brown adipocytes. Our findings have led us to hypothesize that MCT1 is subject to unique regulation in thermogenic adipocytes that re-purposes its activity to facilitate succinate uptake. In Aim 1 using a combination of genetic, biochemical, and mass spectrometry approaches, we will establish the quantitative contribution and mechanisms through which MCT1 is repurposed to drive succinate uptake in brown and beige adipocytes, and the molecular consequences of inhibiting this pathway. In Aim 2, using a new mouse model of MCT1 ablation in thermogenic fat (MCT1 TF-KO already in the lab) we will establish the in vivo physiological consequences of selective inhibition of succinate uptake by thermogenic adipocytes. In Aim 3 we will establish the mechanisms through which succinate controls thermogenic respiration in brown and beige adipocytes. We will build on our discovery that the thermogenic activity of succinate requires its oxidation, consequent generation of reactive oxygen species, and modification of cysteine residues on proteins. We will apply new mass spectrometry approaches developed by our lab to map succinate-induced ROS modifications of thermogenic proteins. In addition, we will use newly developed loss of function genetic models of the major thermogenic effectors to establish their relative importance for succinate-induced energy expenditure. Together, we will determine the mechanisms of adipose tissue succinate uptake and thermogenesis, and its causal role in manipulating metabolic disease. We predict that these findings will characterize a novel activation pathway that is required for the anti-obesity effects of adipose tissue thermogenesis, which could lead to new pharmacological approaches to treat obesity and diabetes.

定义琥珀酸调节的机制，对脂肪组织热发生项目摘要：肥胖是2型糖尿病，心血管疾病和许多癌症的主要危险因素。热棕色米色脂肪组织可以分解储存的脂肪，并具有有效的抗肥料。抗肥胖活动热脂肪细胞需要通过外围信号激活，并鉴定这些激活机制是利用这些细胞的治疗活性的关键。我们最近发现，线粒体代谢物琥珀酸酯是一种有效的分子活化剂棕色和米色脂肪细胞中的热呼吸。值得注意的是，这些细胞可以利用琥珀酸酯驱动从循环中隔离的热生成，这是一种新发现的热作用的独特活动脂肪细胞。我们目前的目标是研究控制这种新发现途径的分子机制依赖琥珀酸酯的生热作用，还可以确定其生理后果。为了建立我们对琥珀酸酯生热途径的识别，我们提出了特定的假设以测试这将决定棕色和米色脂肪细胞获得并利用琥珀酸盐的机制控制他们的抗肥胖活动。基于广泛的初步数据，我们假设质膜转运蛋白单羧酸盐转运蛋白1（MCT1）在控制琥珀酸酯摄取方面在棕色脂肪细胞中。我们的发现使我们假设MCT1受到独特的监管热脂肪细胞重新促成其活性以促进琥珀剂的吸收。在AIM 1中，结合了遗传，生化和质谱法的组合，我们将建立定量贡献和MCT1通过重新利用以驱动棕色效果的机制和米色脂肪细胞，以及抑制该途径的分子后果。在AIM 2中，使用新鼠标热脂肪脂肪中的MCT1消融模型（MCT1 TF-KO已经在实验室中），我们将建立体内选择性抑制热脂肪细胞对琥珀酸盐摄取的生理后果。在目标3中我们将建立琥珀酸酯控制棕色和米色的热呼吸的机制脂肪细胞。我们将基于发现，琥珀酸酯的热活动需要其氧化，因此产生活性氧，并在蛋白质上修饰半胱氨酸残基。我们将应用我们实验室开发的新质谱法来绘制浅酸ROS修饰热蛋白。此外，我们将使用新的主要功能遗传模型的新开发热效应子确定其对琥珀酸酯诱导的能量消耗的相对重要性。我们将共同确定脂肪组织的琥珀酸盐摄取和热生成的机制，以及它因果关系在操纵代谢疾病中的作用。我们预测这些发现将表征新颖的激活脂肪组织热发生的抗肥胖作用所必需的途径，这可能导致新治疗肥胖和糖尿病的药理方法。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Correction: Suppressive effects of the obese tumor microenvironment on CD8 T cell infiltration and effector function.

DOI：
10.1084/jem.2021004202072022c
发表时间：
2022-03-07
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Dyck L;Prendeville H;Raverdeau M;Wilk MM;Loftus RM;Douglas A;McCormack J;Moran B;Wilkinson M;Mills EL;Doughty M;Fabre A;Heneghan H;LeRoux C;Hogan A;Chouchani ET;O'Shea D;Brennan D;Lynch L
通讯作者：
Lynch L

Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer's disease.

DOI：
10.1038/s42003-021-02259-y
发表时间：
2021-06-10
期刊：
Communications biology
影响因子：
5.9
作者：
Guillot-Sestier MV;Araiz AR;Mela V;Gaban AS;O'Neill E;Joshi L;Chouchani ET;Mills EL;Lynch MA
通讯作者：
Lynch MA

Logic and mechanisms of metabolite signalling.