Brown adipose NADH oxidase for thermogenesis

棕色脂肪 NADH 氧化酶用于产热

• 批准号: 10579854
• 负责人: Hei Sook Sul
• 金额: $ 46.01万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-09 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579854
• 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; Visualization; adipocyte differentiation; apoptosis inducing factor; design; extracellular; gain of function; glucose metabolism; improved; in vivo; insulin sensitivity; interest; loss of function; mouse model; mutant; new therapeutic target; novel; overexpression; oxidation; small hairpin RNA; subcutaneous

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.

肥胖已经成为一种全球流行病，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)通过非颤抖的生热作用来分散能量，以维持体温。最近，在实验室中发现了一种新的具有NADH氧化酶结构域的棕色脂肪特异的冷诱导蛋白。虽然这种NADH氧化酶是与脂滴相关的，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，该酶在棕色脂肪中发挥独特的功能，在产热过程中从NADH再生NAD，以在胞浆中进行最佳糖酵解，同时将电子转移到线粒体电子传输链。对最近产生的NADH氧化酶基因敲除小鼠的初步检查显示，随着肥胖的增加，产热功能受损。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经被产生，显示出增强的产热能力。随着这些功能丧失和获得的小鼠模型的建立，这种NADH氧化酶在冷诱导产热中的作用和潜在机制将被研究。