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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：
10442498
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/10442498
关键词：
Ablation Adipocytes Adipose tissue Automobile Driving Biochemical Biochemistry Blood Circulation Cardiovascular Diseases Cell membrane Cells Complement Cysteine Data Development Diabetes Mellitus Energy Metabolism Fatty acid glycerol esters Generations Genetic 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 Pharmacology Physiological Physiology Process Proteins Reactive Oxygen Species Regulation Respiration Risk Factors Role Signal Transduction Site Succinates System Testing Therapeutic Thermogenesis base diet-induced obesity extracellular in vivo loss of function metabolic phenotype molecular phenotype mouse model novel obesity treatment obesogenic oxidation 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.

确定琥珀酸盐调节脂肪组织产热的机制