Brown adipose NADH oxidase for thermogenesis

棕色脂肪 NADH 氧化酶用于产热

• 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
• 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

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.

肥胖已成为一种全球流行病，并与2型糖尿病和其他慢性疾病有关。虽然WAT是主要的能量储存器官，但棕色脂肪组织（BAT）通过非颤抖性产热来消耗能量以维持体温。最近，一种新的棕色脂肪特异性冷诱导蛋白，具有NADH氧化酶结构域已在实验室中确定。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的独特功能是从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，产热受损伴肥胖增加。此外，已经产生了在棕色脂肪细胞中过表达这种NADH氧化酶蛋白的转基因小鼠，其显示出增强的产热作用。随着这些功能丧失和获得的小鼠模型在手，这种NADH氧化酶在冷诱导产热的作用和潜在机制将进行研究。