The role of nicotinamide N-methyltransferase in glucose and lipid homeostasis

描述(申请人提供)：代谢综合征的特征是一组因素，如腰围增加，血脂异常(低高密度脂蛋白，高低密度脂蛋白)，血压升高和胰岛素抵抗或葡萄糖耐量增加。据估计，美国有5000万人患有代谢综合征。患有代谢综合征的人患心血管疾病和2型糖尿病(T2D)的风险更高。我们发现烟酰胺N-甲基转移酶(NNMT)是一种新的糖脂平衡调节剂。NNMT使烟酰胺甲基化。烟酰胺和N1-甲基烟酰胺都具有生物活性。烟酰胺是一种强有力的sirtuins抑制剂，sirtuins是最近发现的肝脏和其他组织中重要的代谢调节剂。N1-甲基烟酰胺增加前列腺素的产生，前列腺素对脂肪组织的功能有深远的影响。我们假设NNMT活性通过sirtuin依赖和独立的途径调节肝脏和脂肪的糖脂代谢。其目的是：1)评价NNMT在体内糖脂平衡中的作用。我们将在肥胖和糖尿病小鼠模型中研究NNMT过表达或基因敲除对糖、脂和胆固醇代谢的影响。2)探讨NNMT体外调节脂类和胆固醇代谢途径的机制。我们将使用具有靶向NNMT过表达或敲除的原代肝细胞来直接评估脂质和胆固醇代谢途径的活性。我们将评估主要转录调控因子LXRa和PPARa的活性，为观察到的变化提供机制解释。3)探讨NNMT在3T3-L1细胞成脂过程中的作用。我们将研究NNMT和烟酰胺在脂肪形成过程中的调控途径，为维生素B3在脂肪组织发育过程中发挥重要作用提供证据。这项提议与NIDDK任务直接相关，并将使NNMT成为治疗代谢综合征的潜在新候选基因。

DESCRIPTION (provided by applicant): Metabolic syndrome is characterized by a group of factors, such as increased waist circumference, dyslipidemia (low HDL, high LDL), increased blood pressure and increased insulin resistance or glucose intolerance. It is estimated that 50 million people in the US suffer from metabolic syndrome. People with metabolic syndrome are at higher risk for developing cardiovascular disease and type-2 diabetes (T2D). We have identified the enzyme Nicotinamide N-methyltransferase (NNMT) as a novel regulator of glucose and lipid homeostasis. NNMT methylates nicotinamide. Both compounds nicotinamide and N1-methylnicotinamide have biological activity. Nicotinamide is a potent inhibitor of sirtuins, recently recognized important metabolic regulators in the liver and other tissues. N1-methylnicotinamide increases the production of prostaglandins, which among other actions have profound effects on the function of adipose tissue. We hypothesize that NNMT activity regulates hepatic and fat glucose and lipid metabolism through sirtuin-dependent and independent pathways. The aims are: 1) To assess the in vivo role of NNMT in glucose and lipid homeostasis. We will investigate the effects of NNMT overexpression or knockdown on glucose, lipid and cholesterol metabolism in mouse models of obesity and diabetes. 2) To investigate the mechanisms by which NNMT regulates pathways of lipid and cholesterol metabolism in vitro. We will use primary hepatocytes with targeted NNMT overexpression or knockdown to directly assess the activity of pathways in lipid and cholesterol metabolism. We will assess the activity of the master transcriptional regulators LXRa and PPARa to provide a mechanistic explanation for the observed changes. 3) To evaluate the role of NNMT in adipogenesis of 3T3-L1 cells. We will investigate the pathways regulated by NNMT and nicotinamide during adipogenesis to provide evidence that vitamin B3 plays an essential role during the development of adipose tissue. This proposal has direct relevance to the NIDDK mission and will establish NNMT as a potential new candidate gene for the treatment of the metabolic syndrome.