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
基本信息
- 批准号:8731882
- 负责人:
- 金额:$ 36.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Activities of Daily LivingAdipose tissueAffectAgingAnimalsAntidiabetic DrugsBeta CellBiochemicalBiological AssayBlindnessBlood CirculationCaloric RestrictionCardiovascular DiseasesCellsCessation of lifeCollaborationsDataDeacetylaseDependenceDiabetes MellitusDiabetes preventionDiabetic mouseDietDiseaseEnzymesFunctional disorderGenerationsGeneticGlucoseHealthHigh Pressure Liquid ChromatographyHumanIndividualInjection of therapeutic agentInsulin ResistanceInterventionKidney FailureLeadLinkLiverLoxP-flanked alleleMeasuresMediatingMetabolicMetabolismModelingMonkeysMouse StrainsMusMuscleNiacinamideNicotinamide MononucleotideNicotinamide adenine dinucleotideNon-Insulin-Dependent Diabetes MellitusObese MiceObesityOrganOxidation-ReductionPancreasPathway interactionsPellagraPhenotypePhysiologyPlayProductionReagentRegulationReportingRisk FactorsRoleSirtuinsSkeletal MuscleSpecificityStructure of beta Cell of isletSupplementationTestingTherapeuticTherapeutic EffectTherapeutic InterventionTissuesTransgenic MiceTryptophanUniversitiesage relatedagedblood glucose regulationcofactorcombatdiabeticextracellularfallsimprovedin vivoinsulin secretioninsulin sensitivityisletliquid chromatography mass spectrometryloss of functionmortalitymuscle agingnicotinamide phosphoribosyltransferasenicotinamide-beta-ribosidenovelnovel therapeutic interventionoverexpressionprotective effectpublic health relevanceresearch studyrestoration
项目摘要
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或肥胖个体的生理。 NAD是一种普遍存在的分子,作为细胞内数百种酶的氧化还原辅因子或底物。 它来自许多饮食化合物,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,然后死亡。 最近显示,NAD水平在老年或肥胖小鼠的组织中大幅下降。 我们假设这限制了NAD依赖性酶的活性,如脱乙酰酶SIRT1,它对糖尿病和其他与年龄相关的疾病有很强的保护作用。 与此一致,NA前体烟酰胺单核苷酸(NMN)或烟酰胺核苷(NR)的给药增加了SIRT1活性,并改善了老年或肥胖动物的胰岛素抵抗。 我们已经建立了一种小鼠品系,允许组织特异性过表达烟酰胺磷酸核糖基转移酶(Nampt),这种酶产生NMN。 Leo实验室(University Libre de Bruxelles)已经创建了一种允许组织特异性缺失Nampt的互补小鼠品系,并慷慨地提供给我们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靶向骨骼肌显着提高NAD水平,并导致年轻,健康的小鼠没有明显的表型。 具体目标1是测试老年或肥胖小鼠的肝脏和肌肉中NAD水平的恢复是否可以挽救器官功能障碍,以及NAD消耗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依赖的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来介导这种效应,NMN然后被胰腺β细胞吸收以提高NAD水平。 然而,细胞外Nampt参与NAD产生的断言,甚至细胞外NMN的存在,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年龄相关疾病的新治疗方法指明方向。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joseph A. Baur其他文献
Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome
人类遗传学确定了心血管-肾脏-代谢综合征中线粒体 LACTB 介导的脂质代谢中的趋同信号。
- DOI:
10.1016/j.cmet.2024.10.007 - 发表时间:
2025-01-07 - 期刊:
- 影响因子:30.900
- 作者:
Shen Li;Hongbo Liu;Hailong Hu;Eunji Ha;Praveena Prasad;Brenita C. Jenkins;Ujjalkumar Subhash Das;Sarmistha Mukherjee;Kyosuke Shishikura;Renming Hu;Daniel J. Rader;Liming Pei;Joseph A. Baur;Megan L. Matthews;Garret A. FitzGerald;Melanie R. McReynolds;Katalin Susztak - 通讯作者:
Katalin Susztak
Mitochondrial NAD+ transporter SLC25A51 linked to human aortic disease
线粒体 NAD+转运蛋白 SLC25A51 与人类主动脉疾病相关
- DOI:
10.1038/s44161-024-00599-6 - 发表时间:
2025-01-22 - 期刊:
- 影响因子:10.800
- 作者:
Gabriel K. Adzika;Ricardo A. Velázquez Aponte;Joseph A. Baur - 通讯作者:
Joseph A. Baur
Swine Models for NAD + Supplementation in Heart Failure
补充 NAD 治疗心力衰竭的猪模型
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Joseph A. Baur - 通讯作者:
Joseph A. Baur
Resveratrol for primary prevention of atherosclerosis: Clinical trial evidence for improved gene expression in vascular endothelium
- DOI:
10.1016/j.ijcard.2012.09.027 - 发表时间:
2013-06-05 - 期刊:
- 影响因子:
- 作者:
Beamon Agarwal;Matthew J. Campen;Meghan M. Channell;Sarah J. Wherry;Behzad Varamini;James G. Davis;Joseph A. Baur;James M. Smoliga - 通讯作者:
James M. Smoliga
Regulation of and challenges in targeting NAD+ metabolism
靶向 NAD+代谢的调控与挑战
- DOI:
10.1038/s41580-024-00752-w - 发表时间:
2024-07-18 - 期刊:
- 影响因子:90.200
- 作者:
Marie E. Migaud;Mathias Ziegler;Joseph A. Baur - 通讯作者:
Joseph A. Baur
Joseph A. Baur的其他文献
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{{ truncateString('Joseph A. Baur', 18)}}的其他基金
Mechanisms and therapeutic potential of blocking the mitochondrial Mg2+ channel Mrs2 in obesity and NAFLD
阻断线粒体 Mg2 通道 Mrs2 在肥胖和 NAFLD 中的机制和治疗潜力
- 批准号:
10679847 - 财政年份:2023
- 资助金额:
$ 36.5万 - 项目类别:
HTS to identify compounds that increase NAD+ levels in neurons and muscle cells
HTS 鉴定可增加神经元和肌肉细胞中 NAD 水平的化合物
- 批准号:
10665088 - 财政年份:2022
- 资助金额:
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Understanding the roles of cardiac NAD pools and therapeutic effects of precursor supplements in heart failure
了解心脏 NAD 池的作用以及前体补充剂对心力衰竭的治疗作用
- 批准号:
10539858 - 财政年份:2022
- 资助金额:
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Understanding the roles of cardiac NAD pools and therapeutic effects of precursor supplements in heart failure
了解心脏 NAD 池的作用以及前体补充剂对心力衰竭的治疗作用
- 批准号:
10680576 - 财政年份:2022
- 资助金额:
$ 36.5万 - 项目类别:
HTS to identify compounds that increase NAD+ levels in neurons and muscle cells
HTS 鉴定可增加神经元和肌肉细胞中 NAD 水平的化合物
- 批准号:
10618481 - 财政年份:2022
- 资助金额:
$ 36.5万 - 项目类别:
Mechanisms underlying the genetic association between PPP1R3B and Alzheimer's Disease
PPP1R3B 与阿尔茨海默病之间遗传关联的潜在机制
- 批准号:
10288770 - 财政年份:2018
- 资助金额:
$ 36.5万 - 项目类别:
Molecular mechanisms underlying the genetic association between PPP1R3B and hepatic steatosis
PPP1R3B与肝脂肪变性遗传关联的分子机制
- 批准号:
10224175 - 财政年份:2018
- 资助金额:
$ 36.5万 - 项目类别:
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:
10288703 - 财政年份:2013
- 资助金额:
$ 36.5万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 36.5万 - 项目类别:
Molecular Mechanisms of Rapamycin's effects on Health and longevity.
雷帕霉素对健康和长寿影响的分子机制。
- 批准号:
8852520 - 财政年份:2013
- 资助金额:
$ 36.5万 - 项目类别:
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