Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging

以NAD代谢为靶点改善肥胖和衰老中的葡萄糖平衡我们正在探索这样一种假设，即烟酰胺腺嘌呤二核苷酸(NAD)代谢可以靶向改善老年人和肥胖者的生理状况。NAD是一种普遍存在的分子，是细胞内数百种酶所必需的氧化还原辅因子或底物。它来自饮食中的色氨酸、烟酸、烟酰胺或合成中间体。所有这些前体的长期缺乏会导致青光眼(以皮炎、腹泻和痴呆症为特征)，并最终死亡。近年来，人们认识到许多组织中的NAD浓度随着年龄的增长或肥胖期间的下降而下降，许多疾病的发病机制包括靶组织内NAD耗竭的成分。包括我们在内的多个小组已经证实，高剂量的前体在许多啮齿动物的疾病模型中具有治疗效果。然而，尽管含有前体的营养制剂正在向普通公众销售，但仍有许多关于NAD新陈代谢的知识需要了解。在这里，我们建议建立在我们使用稳定同位素方法来了解补充NAD前体如何在体内代谢的基础上(目标1)。我们已经证明，对于最常用的前体-烟酰胺核苷(NR)和烟酰胺单核苷酸(NMN)-口服给药只会导致化合物进入肝脏，而静脉给药会到达许多组织。我们建议扩大这些方法，以包括实验中常用的其他前体、组织和递送方法，并解决悬而未决的问题，如前体是否跨越血脑屏障以及它们如何影响线粒体NAD水平。除了稳态浓度外，我们还应用新的方法来检查NAD的周转率。在目标2中，我们利用在前一个获奖期间开发的两个NAD限制的模型系统(肝脏再生和肌肉特异性NAMPT基因敲除)来探索受NAD供应不足影响的下游机制。最后，在目标3中，我们探讨了NAD耗竭在一种具有巨大临床意义的情况下的后果：心力衰竭。现在已经证实，NAD耗竭发生在人类心力衰竭中，几个小鼠模型表明NAD前体具有保护作用。在这里，我们建议建立一种新的小鼠模型来测试NAD缺乏本身是否足以导致与心力衰竭相关的代谢或功能变化。根据我们的数据显示，与口服给药相比，静脉注射前体药物对心脏的好处更多，我们还将与宾夕法尼亚大学的Dan Kelly团队合作，在两种与人类相关的模型中测试静脉注射NR的有效性：心脏继发于缺血损伤或化疗药物治疗。总之，这些研究将揭示NAD代谢如何影响生理的基本细节，并将有助于指导开发治疗或预防与肥胖和衰老相关的疾病的新治疗方法的努力。

Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging We are exploring the hypothesis that nicotinamide adenine dinucleotide (NAD) metabolism can be targeted to improve physiology in aged and obese individuals. NAD is a ubiquitous molecule that is required as a redox cofactor or substrate for hundreds of enzymes within the cell. It is derived from dietary tryptophan, niacin, nicotinamide, or synthetic intermediates. Prolonged deficiency in all of these precursors leads to pellagra (characterized by dermatitis, diarrhea, and dementia) and eventually death. It recent years, it has become appreciated that NAD concentration falls in many tissues with age or during obesity, and that the pathogenesis of many diseases includes a component of NAD depletion within the target tissue. Multiple groups, including ours, have established that high doses of precursors have therapeutic effects in many rodent models of disease. However, much remains to be learned about NAD metabolism, even as nutraceutical formulations containing precursors are being marketed to the general public. Here, we propose building on our use of stable-isotope methods to understand how supplemental NAD precursors are metabolized in vivo (Aim 1). We have already shown that for the most commonly administered precursors, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), oral dosing results in the delivery of compounds to the liver only, whereas intravenous delivery reaches many tissues. We propose expanding these methods to include other precursors, tissues, and delivery methods that are commonly used in experiments, and to address outstanding questions such as whether precursors cross the blood-brain barrier and how they influence mitochondrial NAD levels. We also apply new methodology to examine NAD turnover rates in addition to steady state concentrations. In Aim 2, we take advantage of two model systems for NAD limitation that were developed during the previous award period (liver regeneration and muscle-specific Nampt knockout) to explore the downstream mechanisms that are affected by insufficient NAD availability. Finally, in Aim 3, we explore the consequences of NAD depletion in a condition with enormous clinical significance: heart failure. It is now established that NAD depletion occurs in human heart failure and several mouse models have suggested a protective effect of NAD precursors. Here, we propose the generation of a novel mouse model to test whether NAD deficiency per se is sufficient to cause the metabolic or functional changes associated with heart failure. Based on our data suggesting that the heart benefits more from intravenous precursors that from oral dosing, we will also collaborate with Dan Kelly's group here at Penn to test the utility of intravenous NR in two human-relevant models: heart secondary to ischemic injury or treatment with a chemotherapeutic drug. Together, these studies will reveal fundamental details of how NAD metabolism influences physiology, and will help guide efforts to develop novel therapeutic approaches for the treatment or prevention of diseases associated with obesity and aging.