Role of Nicotinamide N-Methyltransferase in Obesity and Diabetes

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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.