Role of Nicotinamide N-Methyltransferase in Obesity and Diabetes

烟酰胺N-甲基转移酶最近被申请人发现为脂肪组织中能量稳态的新型调节剂。NNMT在肥胖和糖尿病小鼠的脂肪中过表达。敲低肝脏和脂肪中的NNMT可保护小鼠免于饮食诱导的肥胖和糖尿病。除了脂肪组织和肝脏，NNMT活性在几个器官中被发现，并且NNMT过表达已在各种癌症和神经退行性疾病中被描述。因此，重要的是要了解这种酶的组织特异性作用。目前的项目旨在阐明NNMT在脂肪组织中的具体作用，并了解为什么NNMT表达在肥胖和糖尿病中增加。为此，将产生条件性基因敲除小鼠模型以研究脂肪组织中NNMT对全身能量稳态的特异性作用。此外，该项目还将验证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表达增加的原因的假设，以及抑制炎症信号是否会阻止NNMT表达增加和肥胖的发展。这些研究将说明NNMT是治疗肥胖症的潜在药物靶点。

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.