Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging

靶向 NAD 代谢以改善肥胖和衰老过程中的血糖稳态

• 批准号: 10327314
• 负责人: Joseph A. Baur
• 金额: $ 56.07万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327314
• 关键词: ADP ribosylation; Acetylation; Address; Affect; Age; Aging; Anabolism; Animal Model; Area; Attention; Award; Biochemical Reaction; Biological Models; Biology; Blood - brain barrier anatomy; Caloric Restriction; Cardiac; Cells; Cessation of life; Data; Dementia; Dermatitis; Diarrhea; Disease; Disease model; Dose; Drug Exposure; Enzymes; Exercise; Fatty acid glycerol esters; Formulation; General Population; Generations; Genetic; Genetic Models; Glycolysis; Grant; Health; Health Care Costs; Heart; Heart Diseases; Heart failure; Human; Intervention; Intravenous; Isotope Labeling; Knock-out; Knockout Mice; Label; Liver; Liver Regeneration; Longevity; Mass Spectrum Analysis; Measures; Metabolic; Metabolism; Methodology; Methods; Mitochondria; Modeling; Mus; Muscle; Mutation; Myocardial Infarction; Myopathy; Neurodegenerative Disorders; Niacinamide; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Nicotinic Acids; Nuclear; Nucleotides; Nutraceutical; Obesity; Oral; Outcome; Oxidation-Reduction; Pathogenesis; Pellagra; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Physiological; Physiology; Process; Quality of life; Respiration; Rodent Model; Role; Route; Secondary to; Signal Transduction; Skeletal Muscle; Stable Isotope Labeling; Surgical Models; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissues; Tryptophan; Uncertainty; Vitamins; Work; age related; aged; base; blood glucose regulation; clinical translation; clinically significant; cofactor; diet-induced obesity; dietary; disorder prevention; experimental study; falls; heart function; improved; in vivo; innovation; intraperitoneal; ischemic injury; metabolomics; mouse model; nicotinamide-beta-riboside; novel; novel therapeutic intervention; obese person; oxidation; potential biomarker; pressure; protective effect; regeneration model; restoration; side effect; stable isotope

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.

以 NAD 代谢为目标，改善肥胖和衰老过程中的血糖稳态 我们正在探索这样的假设：烟酰胺腺嘌呤二核苷酸 (NAD) 代谢可以有针对性地改善老年人和肥胖个体的生理机能。 NAD 是一种普遍存在的分子，是细胞内数百种酶所需的氧化还原辅因子或底物。它源自膳食色氨酸、烟酸、烟酰胺或合成中间体。所有这些前体物质的长期缺乏会导致糙皮病（以皮炎、腹泻和痴呆为特征）并最终导致死亡。近年来，人们逐渐认识到许多组织中的 NAD 浓度会随着年龄的增长或肥胖而下降，并且许多疾病的发病机制都包括靶组织内 NAD 消耗的一个组成部分。包括我们在内的多个研究小组已经证实，高剂量的前体对许多啮齿动物疾病模型具有治疗作用。然而，尽管含有前体的营养保健品正在向公众销售，但关于 NAD 代谢仍有很多知识有待了解。在这里，我们建议利用稳定同位素方法来了解补充 NAD 前体如何在体内代谢（目标 1）。我们已经表明，对于最常用的前体烟酰胺核苷（NR）和烟酰胺单核苷酸（NMN）来说，口服给药只会将化合物输送到肝脏，而静脉内输送会到达许多组织。我们建议扩展这些方法，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。除了稳态浓度之外，我们还应用新方法来检查 NAD 周转率。在目标 2 中，我们利用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，在目标 3 中，我们探讨了 NAD 消耗在具有巨大临床意义的病症（心力衰竭）中的后果。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型小鼠模型来测试 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。根据我们的数据表明，与口服给药相比，心脏从静脉注射前体中获益更多，我们还将与宾夕法尼亚大学的 Dan Kelly 团队合作，测试静脉注射 NR 在两个人类相关模型中的效用：继发于缺血性损伤或治疗的心脏与化疗药物。这些研究将共同​​揭示 NAD 代谢如何影响生理学的基本细节，并将有助于指导开发新的治疗方法来治疗或预防与肥胖和衰老相关的疾病。

项目成果

Optical Redox Imaging of Fixed Unstained Muscle Slides Reveals Useful Biological Information.

固定未染色肌肉切片的光学氧化还原成像揭示了有用的生物学信息。

• 发表时间: 2019-06
• 影响因子: 3.1
• 作者: Xu, He N;Zhao, Huaqing;Chellappa, Karthikeyani;Davis, James G;Nioka, Shoko;Baur, Joseph A;Li, Lin Z
• 通讯作者: Li, Lin Z

Role of NAD+ in regulating cellular and metabolic signaling pathways.

NAD 在调节细胞和代谢信号通路中的作用。

• 发表时间: 2021
• 影响因子: 8.1
• 作者: Amjad, Sara;Nisar, Sabah;Bhat, Ajaz A;Shah, Ab Rauf;Frenneaux, Michael P;Fakhro, Khalid;Haris, Mohammad;Reddy, Ravinder;Patay, Zoltan;Baur, Joseph;Bagga, Puneet
• 通讯作者: Bagga, Puneet

Longevity pathways in stress resistance: targeting NAD and sirtuins to treat the pathophysiology of hemorrhagic shock.

抗应激的长寿途径：靶向 NAD 和 Sirtuins 治疗失血性休克的病理生理学。

• 发表时间: 2021
• 影响因子: 5.6
• 作者: Sims, Carrie A;Labiner, Hanna E;Shah, Sohini S;Baur, Joseph A
• 通讯作者: Baur, Joseph A

Thermogenic T cells: a cell therapy for obesity?

产热 T 细胞：肥胖症的细胞疗法？

• 发表时间: 2022-06-01
• 作者: Beier, Ulf H;Baker, Daniel J;Baur, Joseph A
• 通讯作者: Baur, Joseph A

Extended wakefulness: compromised metabolics in and degeneration of locus ceruleus neurons.

长时间的清醒：蓝斑神经元的代谢受损和退化。

• 发表时间: 2014-03-19
• 作者: Zhang, Jing;Zhu, Yan;Zhan, Guanxia;Fenik, Polina;Panossian, Lori;Wang, Maxime M;Reid, Shayla;Lai, David;Davis, James G;Baur, Joseph A;Veasey, Sigrid
• 通讯作者: Veasey, Sigrid