Nicotinamide N-methyltransferase (NNMT) in obesity and insulin resistance

烟酰胺 N-甲基转移酶 (NNMT) 在肥胖和胰岛素抵抗中的作用

• 批准号: 8397656
• 负责人: Qin Yang
• 金额: $ 15.05万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397656
• 关键词: 3T3-L1 Cells; Acetyl Coenzyme A; Adipocytes; Adipose tissue; Advisory Committees; Animal Model; Antisense Oligonucleotides; Bioinformatics; Biological; Body Weight; Cardiovascular Diseases; DL-alpha-Difluoromethylornithine; Data; Development; Development Plans; Diabetes Mellitus; Diet; Endocrinology; Enzymes; Faculty; Fatty acid glycerol esters; General Hospitals; Glucose; Goals; Health; Hepatic; Hepatocyte; Homologous Gene; Institutes; Institution; Insulin; Insulin Resistance; Israel; Knockout Mice; Laboratories; Liver; Malonyl Coenzyme A; Massachusetts; Mating Types; Measures; Mediating; Medical center; Medicine; Mentors; Metabolic Diseases; Metabolic Pathway; Methionine; Methylation; Modeling; Mus; NADP; NF-kappa B; Niacinamide; Nicotinamide N-Methyltransferase; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Ornithine Decarboxylase; Pathway interactions; Phosphoenolpyruvate Carboxylase; Physicians; Play; Poly(ADP-ribose) Polymerases; Polyamines; Positioning Attribute; Postdoctoral Fellow; Public Health; Regulation; Research; Research Personnel; Research Project Grants; Resources; Role; Scientist; Spermidine/Spermine N1-Acetyltransferase; Techniques; Testing; Thinness; Tissues; Training; Transgenic Mice; Transgenic Organisms; Weight; career; career development; clinical application; enzyme activity; feeding; glucose production; hepatic gluconeogenesis; improved; inhibitor/antagonist; insulin sensitivity; knock-down; member; metabolomics; mouse model; new therapeutic target; novel; overexpression; prevent; professor; small hairpin RNA; training project

DESCRIPTION (provided by applicant): This proposal describes a 5 year project for training the applicant to achieve his goal to become an independent investigator in diabetes research. The training and career development plan include a compelling research project with potential clinical applications, training in laboratory techniques, and didactic scientific and career development seminars and courses. Dr. Barbara Kahn, a well-recognized leader in the field of insulin resistance and obesity, will mentor the applicant's scientific development. She has trained numerous postdoctoral fellows who now have faculty positions in academic institutions. The applicant chooses Dr. Robert Gerszten as a co-mentor. Dr. Gerszten is an Associate Professor of Medicine at Massachusetts General Hospital. Both Drs. Gerszten and Kahn are Associate members of the Broad Institute. Dr. Gerszten has been a pioneer in metabolomic analysis of cardiovascular and metabolic diseases. In addition, an advisory committee of highly-recognized experts will provide scientific and career advice. The overall goal of the project is to determine the role of Nicotinamide N-methyltransferase (NNMT) in regulating body weight and insulin sensitivity. NNMT is an enzyme that converts nicotinamide to N-methylnicotinamide. NNMT is expressed at high levels in adipocytes and liver. However its role in obesity and diabetes is not clear. The applicant's preliminary data show that NNMT expression is increased in adipose tissue and liver of obese mouse models. Knockdown of NNMT with antisense oligonucleotides (ASO) in adipose tissue and liver of mice fed a high fat diet induces expression of spermine/spermidine acetyltransferase (SSAT), a key enzyme regulating polyamine flux in adipose tissue, and causes leanness. Overexpression of NNMT in hepatocytes results in increased glucose production. Aim #1 is to determine whether altered polyamine flux mediates the leanness caused by knockdown of NNMT. Aim #2 is to determine whether overexpression of NNMT in adipose tissue causes obesity and whether this results from inhibition of polyamine flux. This will be achieved by establishing new adipose NNMT transgenic mice. Aim #3 is to identify novel NNMT-regulated metabolites in adipoctyes that may contribute to obesity and insulin resistance using metabolomics analysis. Aim #4 is to determine whether NNMT enhances hepatic gluconeogenesis by activating Sirt1, PGC-1a and FOXO1. This project will elucidate the role of a novel molecule and novel pathways in obesity and type 2 diabetes. The Department of Medicine and Division of Endocrinology at Beth Israel Deaconess Medical Center provide an ideal setting for training physician-scientists. The applicant will also have access to the resources of the Broad Institute including the metabolomics platform and bioinformatics. These outstanding resources will maximize the potential for the applicant to successfully transition to an independent investigator.

描述（由申请人提供）：该提案描述了一个为期5年的项目，用于培训申请人，以实现其成为糖尿病研究独立研究者的目标。培训和职业发展计划包括一个引人入胜的研究项目，具有潜在的临床应用，实验室技术的培训以及教学科学和职业发展研讨会和课程。芭芭拉·卡恩（Barbara Kahn）博士是胰岛素抵抗和肥胖领域公认的领导者，将指导申请人的科学发展。她培训了许多博士后研究员，他们现在在学术机构中担任教职员工。申请人选择Robert Gerszten博士作为同事。 Gerszten博士是马萨诸塞州综合医院的医学副教授。两个博士。 Gerszten和Kahn是Broad Institute的副成员。 Gerszten博士一直是心血管和代谢疾病代谢组分析的先驱。此外，由高度认可的专家组成的咨询委员会将提供科学和职业建议。该项目的总体目标是确定烟酰胺N-甲基转移酶（NNMT）在调节体重和胰岛素敏感性中的作用。 NNMT是一种将烟酰胺转化为N-甲基二酰胺的酶。 NNMT在脂肪细胞和肝脏中以高水平表达。但是，其在肥胖和糖尿病中的作用尚不清楚。申请人的初步数据表明，肥胖小鼠模型的脂肪组织和肝脏中NNMT表达增加。用反义寡核苷酸（ASO）敲低脂肪组织中的NNMT（ASO）和喂养高脂饮食的小鼠的肝脏会诱导精子/精子乙酰基转移酶（SSAT）的表达，这是一种调节脂肪组织中多胺通量的关键酶，并导致脂肪组织中的多胺通量。 NNMT在肝细胞中的过表达导致葡萄糖产生增加。目标＃1是确定改变的多胺通量是否介导了NNMT敲低引起的瘦弱。目标＃2是确定脂肪组织中NNMT的过表达是否会导致肥胖，这是否是由于抑制多胺通量而导致的。这将通过建立新的脂肪NNMT转基因小鼠来实现。目的＃3是在脂肪症中鉴定NNMT调节的新代谢产物，这些代谢物可能使用代谢组学分析有助于肥胖和胰岛素抵抗。 AIM＃4是通过激活SIRT1，PGC-1A和FOXO1来确定NNMT是否增强了肝糖生成。该项目将阐明一种新的分子和新途径在肥胖和2型糖尿病中的作用。贝丝以色列执事医学中心医学和内分泌科部门为培训医师科学家提供了理想的环境。申请人还将访问广泛研究所的资源，包括代谢组学平台和生物信息学。这些杰出的资源将最大程度地提高申请人成功过渡到独立研究者的潜力。