Role of Nicotinamide N-Methyltransferase in Obesity and Diabetes

烟酰胺 N-甲基转移酶在肥胖和糖尿病中的作用

• 批准号: 212336727
• 负责人: Privatdozent Dr. Daniel Kraus
• 金额: --
• 依托单位: Schwerpunkt für Nephrologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/212336727?language=en
• 关键词: Role; Nicotinamide; Methyltransferase; Obesity; Diabetes

Nicotinamide N-methyltransferase was recently discovered by the applicant as a novel regulator of energy homeostasis in adipose tissue. NNMT is overexpressed in fat of obese and diabetic mice. Knockdown of NNMT in liver and fat protects mice from diet-induced obesity and diabetes. Besides adipose tissue and liver, NNMT activity is found in several organs, and NNMT overexpression has been described in various cancers and in neurodegenerative disease. Thus, it is important to understand the tissue-specific roles of this enzyme. The current project aims to elucidate the specific role of NNMT in adipose tissue and to understand why NNMT expression is increased in obesity and diabetes. To this end, a conditional knockout mouse model will be generated to study the specific effect of NNMT in adipose tissue on systemic energy homeostasis. In addition, this project will test the hypothesis that the chronic, low-grade inflammation that occurs in adipose tissue of obese and diabetic subjects is the cause of increased NNMT expression, and whether suppression of inflammatory signaling prevents the increase in NNMT expression and the development of obesity. These studies will address NNMT as be a potential druggable target for the treatment of obesity.

烟酰胺N-甲基转移酶是申请人最近发现的一种新的脂肪组织能量稳态调节剂。NNMT在肥胖和糖尿病小鼠的脂肪中过表达。在肝脏和脂肪中敲除NNMT可以保护小鼠免受饮食诱导的肥胖和糖尿病的影响。除了脂肪组织和肝脏，NNMT在几个器官中都有活性，并且NNMT在各种癌症和神经退行性疾病中都有过表达的报道。因此，了解这种酶的组织特异性作用是很重要的。目前的项目旨在阐明NNMT在脂肪组织中的具体作用，并了解NNMT在肥胖和糖尿病中表达增加的原因。为此，将建立条件性基因敲除小鼠模型，研究脂肪组织中NNMT对全身能量稳态的特异性影响。此外，该项目将测试肥胖和糖尿病受试者脂肪组织中发生的慢性低度炎症是NNMT表达增加的原因这一假设，以及抑制炎症信号是否阻止NNMT表达增加和肥胖的发展。这些研究将把NNMT作为治疗肥胖症的潜在可用药靶点。