Project 3 - Regulation of Metabolism by Nitric Oxide

肥胖和2型糖尿病（T2D）是美国和国外的流行病。迫切需要更好地了解促进肥胖和诱导T2D的机制，以遏制这些流行病的趋势并控制其心血管并发症。我们认为，由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，小鼠中过度表达eNOS可以预防饮食性肥胖。这些变化伴随着代谢的全身和脂肪组织特异性变化。我们的代谢组学分析表明，eNOS的过表达增加了循环胆汁酸的丰度，而循环胆汁酸已被证明是代谢和脂肪组织表型调节剂的有效效应器。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代谢途径是导致eNOS-TG小鼠瘦表型的原因。因此，我们将验证NO通过调节胆汁酸代谢发挥抗肥胖作用的假设，从而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。为了验证这一假设，我们将：(1)研究NO对饮食性肥胖的影响；(2)确定NO调节代谢的机制；(3)阐明脂肪细胞表型的调控机制。这些目的的实验方法将测试NO是否直接调节肥胖，以及NO的抗肥胖作用是否通过eNOS增加胆汁酸产生和调节脂肪组织表型的能力来介导。这些研究的结果将为构建具有竞争力的ROI应用程序提供一个强大的平台，并将导致对NO在调节导致糖尿病和肥胖的代谢变化中的作用的新理解。这些研究可以为开发新的治疗干预措施奠定基础，以预防、管理或逆转肥胖和胰岛素抵抗。

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.