Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging

针对NAD代谢改善肥胖和衰老过程中葡萄糖稳态我们正在探索尼古丁酰胺腺嘌呤二核苷酸（NAD）代谢可以改善老年和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。它来源于膳食色氨酸、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糙皮病（以皮炎、腹泻和痴呆为特征），最终导致死亡。近年来，人们认识到，随着年龄增长或肥胖，许多组织中的NAD浓度下降，许多疾病的发病机制包括靶组织中NAD消耗的一个组成部分。包括我们在内的多个小组已经确定，高剂量的前体对许多啮齿动物疾病模型具有治疗效果。然而，即使含有前体的营养制剂正在向公众销售，关于NAD的代谢仍有许多有待了解的地方。在这里，我们建议使用稳定同位素方法来了解补充的NAD前体如何在体内代谢（目的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），口服给药只会将化合物递送到肝脏，而静脉给药则会到达许多组织。我们建议将这些方法扩展到包括实验中常用的其他前体、组织和递送方法，并解决诸如前体是否穿过血脑屏障以及它们如何影响线粒体NAD水平等悬而未决的问题。除了稳态浓度外，我们还应用新的方法来检查NAD周转率。在Aim 2中，我们利用在上一个奖励期间开发的两个NAD限制模型系统（肝脏再生和肌肉特异性Nampt敲除）来探索受NAD可用性不足影响的下游机制。最后，在Aim 3中，我们探讨了NAD消耗在具有巨大临床意义的情况下的后果：心力衰竭。现在已经确定NAD耗竭发生在人类心力衰竭中，并且一些小鼠模型表明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缺乏本身是否足以引起与心力衰竭相关的代谢或功能变化。基于我们的数据表明心脏从静脉注射前体比口服剂量获益更多，我们还将与宾夕法尼亚大学的Dan Kelly小组合作，在两种与人类相关的模型中测试静脉注射NR的效用：继发于缺血性损伤的心脏或用化疗药物治疗。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新的治疗方法，以治疗或预防与肥胖和衰老相关的疾病。

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.