Brown adipose NADH oxidase for thermogenesis

棕色脂肪 NADH 氧化酶用于产热

基本信息

批准号：
10629810
负责人：
Hei Sook Sul
金额：
$ 38.66万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-09 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10629810
关键词：
Ablation Adipocytes Adipose tissue Adult Agonist Biochemical Biological Biological Assay Biology Biosensor Body Temperature Brown Fat Cell Fractionation Cells Chronic Disease Cytoplasm Cytosol Data Diabetes Mellitus Disease Management Electron Transport Electrons Energy Metabolism Enzymes Epidemic Exhibits Fasting Flavoproteins Glucose Glycolysis Hand Health Homeostasis Impairment Insulin Insulin Resistance Knockout Mice Lentivirus Lipids LoxP-flanked allele Measures Mediating Metabolic Metabolic syndrome Mitochondria Mus NADH NADH oxidase Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Oxygen Consumption Physiological Proteins Regulation Research Respiration Role Testing Thermogenesis Tissues Transgenic Mice adipocyte differentiation apoptosis inducing factor design diabetes control extracellular gain of function glucose metabolism improved in vivo insulin sensitivity interest mouse model mutant new therapeutic target novel overexpression oxidation small hairpin RNA subcutaneous

项目摘要

Obesity has become a global epidemic and is associated with type 2 diabetes and other chronic diseases. While WAT is the primary energy storage organ, brown adipose tissue (BAT) dissipates energy through non-shivering thermogenesis to maintain body temperature. Recently, a new brown fat specific cold inducible protein that has a NADH oxidase domain has been identified in the lab. While this NADH oxidase is lipid droplet associated, it localizes at the mitochondria during thermogenesis. The hypothesis of this research is that, through NADH oxidation, this enzyme uniquely functions in brown fat to regenerate NAD from NADH for optimal glycolysis in cytosol, while transferring electrons to mitochondrial electron transport chain, during thermogenesis. Initial examinations of NADH oxidase knockout mice that recently have generated show impaired thermogenesis with increased adiposity. In addition, transgenic mice overexpressing this NADH oxidase protein in brown adipocytes have been generated that showed enhanced thermogenesis. With these loss- and gain-of function mouse models in hand, the role and the underlying mechanism for this NADH oxidase in cold induced thermogenesis will be investigated.

肥胖已成为全球流行病，并与 2 型糖尿病和其他慢性病有关。虽然 WAT 是主要的能量储存器官，但棕色脂肪组织 (BAT) 通过非颤抖产热来消耗能量以维持体温。最近，实验室鉴定出一种新的棕色脂肪特异性冷诱导蛋白，其具有 NADH 氧化酶结构域。虽然这种 NADH 氧化酶与脂滴相关，但它在产热过程中定位于线粒体。这项研究的假设是，通过 NADH 氧化，这种酶在棕色脂肪中发挥独特的作用，从 NADH 再生 NAD，以实现细胞质中的最佳糖酵解，同时在产热过程中将电子转移到线粒体电子传递链。对最近产生的 NADH 氧化酶敲除小鼠的初步检查显示，产热作用受损，肥胖增加。此外，在棕色脂肪细胞中过度表达这种 NADH 氧化酶蛋白的转基因小鼠已产生，其产热作用增强。有了这些功能丧失和获得功能的小鼠模型，我们将研究这种 NADH 氧化酶在冷诱导生热作用中的作用和潜在机制。