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: 8596305
• 负责人: Joseph A. Baur
• 金额: $ 39.36万
• 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/8596305
• 关键词: Activities of Daily Living; Adipose tissue; Affect; Aging; Alleles; 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; 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，我们将检验以下假设：烟酰胺腺苷二核苷酸（NAD）代谢可以针对改善老年人或肥胖个体的生理学。 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因子或底物所需的。 它源自许多饮食化合物，包括色氨酸和维生素B3，并且所有这些前体的长期缺乏导致毛lag骨，然后导致死亡。 最近显示，NAD水平在老年或肥胖小鼠的组织中大大落下。 我们假设这限制了NAD依赖性酶的活性，例如脱乙酰基酶SIRT1，该酶对糖尿病和其他与年龄相关的疾病具有强大的保护作用。 与此相一致，NA前体的烟酰胺单核苷酸（NMN）或烟酰胺核糖苷（NR）会增加SIRT1活性，并改善老年或肥胖动物的胰岛素抵抗。 我们创建了一组小鼠菌株，该菌株允许组织特异性的烟酰胺磷酸贝糖基转移酶（NAMPT）（NAMPT），该酶是产生NMN的酶。 Leo Lab（大学Libre de Bruxelles）创建了一种允许组织特异性缺失的小鼠的互补菌株，并慷慨地为我们提供了用于产生具有功能特异性肌肉特异性丧失的动物。 我们的初步数据表明，针对骨骼肌的NAMPT显着提高了NAD水平，并且在年轻健康的小鼠中不会引起明显的表型。 具体目的1是测试老年或肥胖小鼠肝脏和肌肉中NAD水平的恢复是否可以挽救器官功能障碍，以及NAD耗竭是否足以诱导年轻，健康动物的功能障碍。 此外，有强有力的证据表明NAD以SIRT1依赖性方式促进胰岛素分泌，但细节有些争议。 已经提出，NAMPT的细胞外形式通过在循环中产生NMN来介导这种作用，然后由胰腺β细胞吸收，以提高NAD水平。 但是，挑战了细胞外NAMPT参与NAD的生产，甚至存在细胞外NMN的主张。 具体目的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相关的疾病的新型治疗方法指向新的方法。