Project 3 - Regulation of Metabolism by Nitric Oxide

项目 3 - 一氧化氮代谢调节

• 批准号: 8711512
• 负责人: Bradford Guy Hill
• 金额: $ 24.4万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8711512
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; Bile Acid Biosynthesis Pathway; Bile Acids; Biogenesis; Body fat; Branched-Chain Amino Acids; Burn injury; Cardiovascular system; Cell Differentiation process; Centers for Disease Control and Prevention (U.S.); Cyclic GMP; Development; Diabetes Mellitus; Diet; Endothelium; Epidemic; Europe; Fatty acid glycerol esters; Human; In Vitro; Individual; Insulin; Insulin Resistance; Lead; Link; Lipids; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mus; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Overweight; Phenotype; Population; Predisposition; Production; Regulation; Reporting; Research; Resistance; Risk; Risk Factors; Role; Secondary to; Signal Transduction; Stem cells; Testing; Tissues; Transplantation; Weight Gain; absorption; adipocyte differentiation; cofactor; diabetic; endothelial dysfunction; enzyme activity; feeding; human NOS3 protein; in vivo; metabolomics; novel; novel therapeutic intervention; overexpression; prevent; stem

Obesity and type 2 diabetes (T2D) are epidemics in the U.S. and abroad. A better understanding ofthe mechanisms that promote obesity and induce T2D is urgently needed to stem the tide of these epidemics and to control their cardiovascular complications. We suggest that endothelial dysfunction induced by nutrient excess is the primary cause that leads to metabolic changes resulting in an increase in adiposity and whole-body insulin resistance. Our studies show that overexpression of eNOS in mice prevents diet-induced obesity. These changes are accompanied by systemic and adipose tissue-specific changes in metabolism. Our metabolomic analyses indicate that eNOS over expression increases the abundance of circulating bile acids, which have been shown to be potent effectors of metabolism and regulators of adipose tissue phenotype. Nevertheless, we do not know how NO regulates bile acid production or which metabolic pathways triggered by bile acids are responsible for the lean phenotype of eNOS-TG mice. Therefore, we will test the hypothesis that NO exerts an anti-obesogenic effect by regulating bile acid metabolism, which promotes the development of adipocytes into a novel "lean" phenotype characterized by high mitochondrial content and fat burning capacity. To test this hypothesis, we will: (1) Examine the effects of NO on diet induced obesity; (2) Determine how NO regulates metabolism; and (3) Elucidate the mechanisms regulating adipocyte phenotype. The experimental approaches in these aims will test whether NO directly regulates obesity and whether the anti-obesity effects of NO are mediated through the ability of eNOS to increase bile acid production and to regulate adipose tissue phenotype. The results of these studies will develop a strong platform for constructing a competitive ROI application and will lead to a new understanding of the role of NO in regulating the metabolic changes that contribute to diabetes and obesity. These studies could lay the groundwork for the development of novel therapeutic interventions to prevent, manage or reverse obesity and insulin resistance.

肥胖和 2 型糖尿病 (T2D) 在美国和国外都很流行。迫切需要更好地了解促进肥胖和诱发 T2D 的机制，以阻止这些流行病的蔓延并控制其心血管并发症。我们认为，营养过剩引起的内皮功能障碍是导致代谢变化导致肥胖和全身胰岛素抵抗增加的主要原因。我们的研究表明，小鼠体内 eNOS 的过度表达可以预防饮食引起的肥胖。这些变化伴随着全身和脂肪组织特异性的代谢变化。我们的代谢组学分析表明，eNOS 过度表达会增加循环胆汁酸的丰度，而胆汁酸已被证明是代谢的有效效应器和脂肪组织表型的调节器。然而，我们不知道NO如何调节胆汁酸的产生，也不知道胆汁酸触发的哪些代谢途径导致了eNOS-TG小鼠的瘦表型。因此，我们将检验NO通过调节胆汁酸代谢发挥抗肥胖作用的假设，促进脂肪细胞发育成一种以高线粒体含量和脂肪燃烧能力为特征的新型“瘦”表型。为了检验这一假设，我们将：（1）检验一氧化氮对饮食引起的肥胖的影响； (2)确定NO如何调节代谢； (3)阐明脂肪细胞表型的调节机制。这些目的的实验方法将测试NO是否直接调节肥胖以及NO的抗肥胖作用是否是通过eNOS增加胆汁酸产生和调节脂肪组织表型的能力介导的。这些研究的结果将开发一个强大的平台来构建有竞争力的 ROI 应用，并将导致人们对 NO 在调节导致糖尿病和肥胖的代谢变化中的作用有新的认识。这些研究可以为开发预防、控制或逆转肥胖和胰岛素抵抗的新型治疗干预措施奠定基础。