Nicotinamide N-methyltransferase is a novel regulator of energy expenditure

烟酰胺 N-甲基转移酶是一种新型的能量消耗调节剂

基本信息

批准号：
9212132
负责人：
Qin Yang
金额：
$ 33.6万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212132
关键词：
Acetyl Coenzyme A Adipocytes Adipose tissue Anabolism Antisense Oligonucleotides Biological 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 Transcription Glucose Transporter Goals Histones Human Insulin Insulin Resistance Knock-out Knockout Mice Link Liver Lysine Mediating Metabolism 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 Pharmacology Play Polyamines Propylamines Putrescine Reaction Role S-Adenosylhomocysteine S-Adenosylmethionine SIRT1 gene Signal Transduction Specificity Spermidine Spermidine/Spermine N1-Acetyltransferase Spermine Tissues Transcriptional Regulation Transgenic Mice Urine Vasodilation cell growth cofactor genetic approach histone methylation improved inhibitor/antagonist innovation insight insulin sensitivity knock-down methyl group novel overexpression polycation prevent public health relevance urinary wasting

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：当前提案的总体目标是研究烟酰胺N-甲基转移酶（NNMT）在调节能量消耗和肥胖方面的新作用。 NNMT 催化烟酰胺（维生素 B3）（烟酰胺腺嘌呤二核苷酸 (NAD+) 的前体）的 S-腺苷甲硫氨酸 (SAM) 依赖性甲基化。 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 为多胺代谢提供底物丙胺，并为组蛋白甲基化提供甲基。多胺代谢和组蛋白甲基化都参与能量消耗的调节。 NAD+ 是 Sirt1 的辅助因子，Sirt1 是一种脱乙酰酶，可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。使用反义寡核苷酸 (ASO) 从生物学角度敲除脂肪组织和肝脏中的 NNMT，可增加能量消耗、预防饮食引起的肥胖并提高胰岛素敏感性。 NNMT 敲低增加了 SAM 和 NAD+ 水平，增强了多胺通量，并增强了脂肪组织中 H3 (H3K4) 组蛋白甲基化上赖氨酸 4 的单甲基化、二甲基化和三甲基化。总体假设是：NNMT 是能量消耗和肥胖的新型调节剂，它通过引起代谢物分流导致细胞 SAM 和 NAD+ 水平变化来发挥作用，从而调节能量消耗。在目标 1 中，我们将利用药理学和遗传学方法进一步阐明 NNMT 在调节能量消耗中的作用。对于药理学方法，我们将使用 NNMT 反馈抑制剂 N-甲基烟酰胺 (MNA) 来抑制 NNMT 活性。对于遗传方法，我们计划生成脂肪特异性 NNMT 敲除小鼠。我们将研究这些小鼠的能量消耗和肥胖情况。在目标 2 中，我们将确定 SAM 的改变介导 NNMT 对能量消耗的影响的机制。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 调节的能量消耗。该方案在新发现、新机制、综合方法等方面具有很强的创新性。它还具有重大的翻译意义。 NNMT ASO 和 MNA 都可以直接用于临床试验。事实上，MNA 已用于人体研究其血管舒张作用。