Nicotinamide N-methyltransferase is a novel regulator of energy expenditure

烟酰胺 N-甲基转移酶是一种新型能量消耗调节剂

基本信息

批准号：
8610487
负责人：
Qin Yang
金额：
$ 37.85万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610487
关键词：
Acetyl Coenzyme A Adipocytes Adipose tissue Anabolism Antisense Oligonucleotides Catabolism Cell Survival Clinical Trials DNA Data Deacetylase Development Diabetes Mellitus Diet Energy Metabolism Enzymes Epidemic Excretory function Fatty acid glycerol esters Feedback Futile Cycling Genes Genetic Glucose Transporter Goals Histones Human Insulin Insulin Resistance Knock-out Knockout Mice Link Liver Lysine Mediating Metabolism Methionine Methylation Mono-S Mus Niacinamide Nicotinamide N-Methyltransferase Nicotinamide adenine dinucleotide Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Ornithine Decarboxylase Oxidation-Reduction Oxygen Consumption Pathway interactions Play Polyamines Propylamines Putrescine Reaction Role S-Adenosylmethionine Signal Transduction Specificity Spermidine Spermidine/Spermine N1-Acetyltransferase Spermine Tissues Transcriptional Regulation Transgenic Mice Urine Vasodilation Work cell growth cofactor improved inhibitor/antagonist innovation insight insulin sensitivity knock-down methyl group novel overexpression polycation prevent public health relevance urinary wasting

项目摘要

PROJECT SUMMARY The overall goal of the current proposal is to investigate the novel roles of nicotinamide N- methyltransferase (NNMT) in regulating energy expenditure and adiposity. NNMT catalyzes the S- adenosylmethionine (SAM)-dependent methylation of nicotinamide (vitamin B3), a precursor of nicotinamide adenine dinucleotide (NAD+). NNMT is a unique enzyme in that it regulates both SAM and NAD+, two fundamental metabolites for cellular energy metabolism. SAM provides substrate propylamine for polyamine metabolism and donates a methyl group for histone methylation. Both polyamine metabolism and histone methylation are involved in regulating energy expenditure. NAD+ is a cofactor of Sirt1, a deacetylase that regulates multiple important targets related to energy metabolism. The applicant found that NNMT was elevated in adipose tissue and liver in obesity. Biologically knocking down NNMT in adipose tissue and liver using antisense oligonucleotides (ASO) increased energy expenditure, prevented diet-induced obesity and improved insulin sensitivity. NNMT knockdown increased SAM and NAD+ levels, enhanced polyamine flux and augmented mono-, di- and tri-methylation of lysine 4 on H3 (H3K4) histone methylation in adipose tissue. The overall hypothesis is: NNMT is a novel regulator of energy expenditure and adiposity, and it exerts its effects by causing metabolite shunting leading to changes in cellular SAM and NAD+ levels, which in turn regulate energy expenditure. In Aim 1, we will use pharmacological and genetic approaches to further elucidate the roles of NNMT in regulating energy expenditure. For pharmacological approach, we will use N-methylnicotinamide (MNA), an NNMT feedback inhibitor, to inhibit NNMT activity. For genetic approach, we plan to generate adipose-specific NNMT knockout mice. We will investigate energy expenditure and adiposity in these mice. In Aim 2, we will determine the mechanisms by which alterations in SAM mediate the effects of NNMT on energy expenditure. We will focus on SAM-regulated polyamine metabolism and histone methylation. In Aim 3, we will investigate whether NAD+ and NAD+-dependent Sirt1 are involved in NNMT-regulated energy expenditure. The proposal is highly innovative in the aspects of new discovery, novel mechanisms and comprehensive approaches. It also has significant translational implications. Both NNMT ASOs and MNA can potentially be used directly in clinical trials. In fact, MNA has been used in humans for studying its vasorelaxation effects.

项目概要当前提案的总体目标是研究烟酰胺 N-的新作用甲基转移酶（NNMT）调节能量消耗和肥胖。 NNMT 催化 S- 烟酰胺（维生素 B3）的腺苷甲硫氨酸 (SAM) 依赖性甲基化，烟酰胺的前体烟酰胺腺嘌呤二核苷酸 (NAD+)。 NNMT 是一种独特的酶，它可以调节 SAM 和 NAD+，细胞能量代谢的两种基本代谢物。 SAM 提供底物丙胺用于多胺代谢，并提供一个甲基用于组蛋白甲基化。均多胺新陈代谢和组蛋白甲基化参与调节能量消耗。 NAD+ 是一个辅助因子 Sirt1，一种脱乙酰酶，调节与能量代谢相关的多个重要靶标。申请人发现肥胖者的脂肪组织和肝脏中的NNMT升高。生物敲击使用反义寡核苷酸 (ASO) 降低脂肪组织和肝脏中的 NNMT 增加能量支出，预防饮食引起的肥胖并提高胰岛素敏感性。 NNMT 击倒增加 SAM 和 NAD+ 水平，增强多胺通量并增强单甲基化、二甲基化和三甲基化赖氨酸 4 对脂肪组织中 H3 (H3K4) 组蛋白甲基化的影响。总体假设是：NNMT 是能量消耗和肥胖的新型调节剂，它通过引起代谢物发挥其作用分流导致细胞 SAM 和 NAD+ 水平发生变化，进而调节能量消耗。在目标 1 中，我们将使用药理学和遗传学方法进一步阐明 NNMT 在调节能量消耗。对于药理学方法，我们将使用 N-甲基烟酰胺 (MNA)， NNMT 反馈抑制剂，抑制 NNMT 活性。对于遗传方法，我们计划生成脂肪特异性 NNMT 基因敲除小鼠。我们将调查这些人群的能量消耗和肥胖情况老鼠。在目标 2 中，我们将确定 SAM 的改变介导以下影响的机制： NNMT 关于能量消耗。我们将重点关注 SAM 调节的多胺代谢和组蛋白甲基化。在目标 3 中，我们将研究 NAD+ 和 NAD+ 依赖性 Sirt1 是否参与 NNMT 调节的能量支出。该方案在新发现、新机制、综合性等方面具有很强的创新性。接近。它还具有重大的翻译意义。 NNMT ASO 和 MNA 都有可能直接用于临床试验。事实上，MNA 已用于人体研究其血管舒张作用。