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: 8731882
• 负责人: Joseph A. Baur
• 金额: $ 36.5万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731882
• 关键词: Activities of Daily Living; Adipose tissue; Affect; Aging; Animals; Antidiabetic Drugs; Beta Cell; Biochemical; Biological Assay; Blindness; Blood Circulation; Caloric Restriction; Cardiovascular Diseases; Cells; Cessation of life; Collaborations; Data; Deacetylase; Dependence; Diabetes Mellitus; Diabetes prevention; Diabetic mouse; Diet; Disease; Enzymes; Functional disorder; Generations; Genetic; Glucose; Health; High Pressure Liquid Chromatography; Human; Individual; Injection of therapeutic agent; Insulin Resistance; Intervention; Kidney Failure; Lead; Link; Liver; LoxP-flanked allele; Measures; Mediating; Metabolic; Metabolism; Modeling; Monkeys; Mouse Strains; Mus; Muscle; Niacinamide; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Organ; Oxidation-Reduction; Pancreas; Pathway interactions; Pellagra; Phenotype; Physiology; Play; Production; Reagent; Regulation; Reporting; Risk Factors; Role; Sirtuins; Skeletal Muscle; Specificity; Structure of beta Cell of islet; Supplementation; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; Transgenic Mice; Tryptophan; Universities; age related; aged; blood glucose regulation; cofactor; combat; diabetic; extracellular; falls; improved; in vivo; insulin secretion; insulin sensitivity; islet; liquid chromatography mass spectrometry; loss of function; mortality; muscle aging; nicotinamide phosphoribosyltransferase; nicotinamide-beta-riboside; novel; novel therapeutic intervention; overexpression; protective effect; public health relevance; research study; restoration

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.

描述（由申请人提供）：靶向 NAD 代谢以改善肥胖和衰老中的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的生理机能的假设。 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。 它源自多种膳食化合物，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，然后导致死亡。 最近的研究表明，衰老或肥胖小鼠的组织中 NAD 水平大幅下降。 我们假设这限制了 NAD 依赖性酶的活性，例如脱乙酰酶 SIRT1，它对糖尿病和其他与年龄相关的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) 会增加 SIRT1 活性并改善老年或肥胖动物的胰岛素抵抗。 我们培育了一种小鼠品系，可以在组织中特异性过度表达烟酰胺磷酸核糖转移酶 (Nampt)，这种酶可产生 NMN。 Leo 实验室（布鲁塞尔自由大学）创造了一种互补的小鼠品系，可以对 Nampt 进行组织特异性删除，并慷慨地向我们提供了用于产生肌肉特异性功能丧失的动物。 我们的初步数据表明，Nampt 靶向骨骼肌可显着提高 NAD 水平，并且不会在年轻健康小鼠中引起明显的表型。 具体目标 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 消耗是否足以诱发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依赖性方式促进胰岛素分泌，但细节有些争议。 有人提出，Nampt 的细胞外形式通过在循环中产生 NMN 来介导这种作用，然后 NMN 被胰腺 β 细胞吸收以提高 NAD 水平。 然而，细胞外Nampt参与NAD产生的说法，甚至细胞外NMN的存在，都受到了挑战。 具体目标 2 是确定 NAD 代谢如何调节胰岛素分泌。 总之，这些研究将揭示 NAD 代谢如何影响生理学的基本细节，并可能为治疗或预防糖尿病和其他与年龄相关的疾病的新治疗方法指明道路。