NNAT in metabolic regulation

NNAT 在代谢调节中的作用

• 批准号: 10521829
• 负责人: JOHN C YOON
• 金额: $ 40.04万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521829
• 关键词: ATP Hydrolysis; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Receptor; Affect; Alanine; Anti-Obesity Agents; Area; Back; Binding; Biological Assay; Body Composition; Body Weight; Brown Fat; Ca(2+)-Transporting ATPase; Chemicals; Consumption; Creatine; Data; Desire for food; Ectopic Expression; Endoplasmic Reticulum; Energy Metabolism; Exhibits; Extravasation; Fatty acid glycerol esters; Fluorescence Resonance Energy Transfer; Future; Genes; Genetic Polymorphism; Health; Health Care Costs; High Fat Diet; Human; Indirect Calorimetry; Knock-out; Knockout Mice; Lead; Link; Lipids; Lipolysis; Measures; Mediating; Membrane Proteins; Metabolic; Modeling; Monitor; Mus; Mutagenesis; Obesity; Parents; Pharmacology; Physiological; Play; Positron-Emission Tomography; Process; Proteins; Pump; Reagent; Regulation; Reporting; Resistance; Respiration; Role; Signal Transduction; Site; Stimulus; Temperature; Testing; Therapeutic; Thermogenesis; Tissues; United States; Work; base; blood glucose regulation; combat; endoplasmic reticulum stress; energy balance; fluorodeoxyglucose; gain of function; improved; in vivo; inhibitor; insight; medical complication; mouse model; novel; novel strategies; novel therapeutic intervention; obesity in children; obesity treatment; overexpression; phospholamban; response; sarcolipin; small molecule; trafficking; uncoupling protein 1; uptake; warm temperature; wasting

PROJECT SUMMARY/ABSTRACT Obesity is associated with serious medical complications and responsible for a rising percentage of health care costs in the United States. While most anti-obesity drugs in the market work by suppressing appetite, increasing energy expenditure by stimulating thermogenesis is an alternative strategy. Humans and mice both possess constitutively active and inducible thermogenic fat, commonly called brown and beige fat. While Uncoupling Protein 1 (UCP1) has long been considered essential for non-shivering thermogenesis in adipose tissues, recent studies have demonstrated UCP1-independent thermogenic mechanisms, and they may be especially important in beige fat. We recently identified the endoplasmic reticulum (ER) membrane protein Nnat as a novel inhibitor of adipocyte thermogenesis and have shown that its effects on thermogenesis are UCP1-independent. We hypothesize that Nnat in adipose tissue plays a key role in controlling thermogenesis and glucose homeostasis. In Aim 1, we will characterize the regulation of systemic energy metabolism by adipose tissue Nnat. In Aim 2, we will investigate the mechanistic basis of Nnat action and will examine its interactions with the ER calcium pump SERCA and other possible ways that Nnat can impact thermogenesis. These studies will produce new insights into the control of adipose tissue thermogenesis and potentially lead to new strategies for anti-obesity therapy.

项目摘要/摘要 肥胖与严重的医疗并发症有关，并导致医疗保健比例上升 在美国的成本。虽然市场上的大多数减肥药物都是通过抑制食欲来发挥作用的， 通过刺激生热作用来增加能量消耗是一种替代策略。人和老鼠都是 具有结构性活性和诱导性的生热脂肪，通常称为棕色和米色脂肪。而当 解偶联蛋白1(UCP1)长期以来被认为是脂肪中非颤抖产热所必需的 组织，最近的研究证明了UCP1不依赖的生热机制，它们可能是 在米色脂肪中尤为重要。我们最近发现了内质网(ER)膜蛋白 NNAT作为一种新的脂肪细胞产热抑制物，已表明其对产热的影响是 UCP1-独立。我们推测，脂肪组织中的NNAT在控制产热方面起着关键作用 和葡萄糖动态平衡。在目标1中，我们将描述全身能量代谢的调节 脂肪组织NNAT。在目标2中，我们将研究NNAT作用的机制基础，并将研究其 与内质网钙泵SERCA的相互作用以及NNAT影响产热的其他可能方式。 这些研究将对脂肪组织产热的控制产生新的见解，并可能导致 抗肥胖治疗的新策略。