Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging

描述（由申请人提供）：靶向NAD代谢改善肥胖和衰老中葡萄糖稳态我们将测试烟酰胺腺嘌呤二核苷酸（NAD）代谢可以靶向改善老年或肥胖个体生理的假设。NAD是一种普遍存在的分子，是细胞内数百种酶的氧化还原辅助因子或底物。它来源于许多膳食化合物，包括色氨酸和维生素B3，长期缺乏所有这些前体会导致糙皮病，然后死亡。最近的研究表明，老年或肥胖小鼠组织中的NAD水平大幅下降。我们假设这限制了nad依赖性酶的活性，如去乙酰化酶SIRT1，它对糖尿病和其他年龄相关疾病具有很强的保护作用。与此一致的是，给予NA前体烟酰胺单核苷酸（NMN）或烟酰胺核苷（NR）可增加SIRT1活性并改善老年或肥胖动物的胰岛素抵抗。我们已经创造了一种小鼠品系，它允许组织特异性过表达烟酰胺磷酸核糖基转移酶（Nampt），这种酶产生NMN。Leo实验室（布鲁塞尔自由大学）已经创建了一种允许组织特异性缺失Nampt的补充小鼠菌株，并慷慨地为我们提供了具有肌肉特异性功能丧失的动物的一代。我们的初步数据显示，靶向骨骼肌的Nampt显著提高了NAD水平，并且在年轻健康小鼠中没有引起明显的表型。具体目的1是测试恢复老年或肥胖小鼠肝脏和肌肉中的NAD水平是否可以挽救器官功能障碍，以及NAD消耗是否足以诱导年轻健康动物的功能障碍。此外，有强有力的证据表明NAD以sirt1依赖的方式促进胰岛素分泌，但细节上存在一些争议。有人提出，细胞外形式的Nampt通过在循环中产生NMN介导这种作用，然后被胰腺细胞吸收以提高NAD水平。然而，细胞外Nampt参与NAD生成的断言，甚至细胞外NMN的存在，都受到了挑战。特异性目的2是确定胰岛素分泌如何受NAD代谢调节。总之，这些研究将揭示NAD代谢如何影响生理的基本细节，并可能为治疗或预防糖尿病和其他与年龄有关的疾病指明新的治疗方法。

DESCRIPTION (provided by applicant): Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging We will test the hypothesis that nicotinamide adenine dinucleotide (NAD) metabolism can be targeted to improve physiology in aged or obese individuals. NAD is a ubiquitous molecule that is required as a redox cofactor or substrate fo hundreds of enzymes within the cell. It is derived from a number of dietary compounds, including tryptophan and vitamin B3, and prolonged deficiency in all of these precursors leads to Pellagra, and then death. It was recently shown that NAD levels fall substantially in the tissues of aged or obese mice. We hypothesize that this limits the activity of NAD-dependent enzymes, such as the deacetylase SIRT1, which has strong protective effects against diabetes and other age-related diseases. Consistent with this, administration of the NA precursors nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) increases SIRT1 activity and ameliorates insulin resistance in aged or obese animals. We have created a strain of mice that allows tissue-specific overexpression of Nicotinamide phosphoribosyltransferase (Nampt), the enzyme that produces NMN. A complementary strain of mice that allows tissue-specific deletion of Nampt has been created by the Leo lab (University Libre de Bruxelles), and generously provided to us for the generation of animals with muscle-specific loss of function. Our preliminary data show that Nampt targeted to skeletal muscle significantly enhances NAD levels, and causes no overt phenotype in young, healthy mice. Specific Aim 1 is to test whether restoration of NAD levels in liver and muscles of aged or obese mice can rescue organ dysfunction, and whether NAD depletion is sufficient to induce dysfunction in young, healthy animals. In addition, there is strong evidence that NAD promotes insulin secretion in a SIRT1-dependent manner, but the details are somewhat controversial. It has been proposed that an extracellular form of Nampt mediates this effect by producing NMN in the circulation, which is then taken up by pancreatic beta cells to enhance NAD levels. However, the assertion that extracellular Nampt participates in NAD production, and even the existence of extracellular NMN, have been challenged. Specific Aim 2 is to determine how insulin secretion is regulated by NAD metabolism. Together, these studies will reveal fundamental details of how NAD metabolism influences physiology, and are likely to point the way to novel therapeutic approaches for the treatment or prevention of diabetes and other age-related diseases.