Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity

Nicotinamide N -methyltransferase (NNMT) expression is increased in white adipose tissue and liver of obese and diabetic mice, Nnmt knockdown protects against diet-induced obesity by altering the availability of adipose S -adenosylmethionine and NAD + , rendering Nnmt a novel target for treating obesity and type 2 diabetes. NNMT a possible drug target in diabetes Nicotinamide N -methyltransferase (NNMT), an enzyme that methylates nicotinamide (vitamin B3) using S -adenosylmethionine (SAM) as a methyl donor, is present at high levels in adipose tissue and is increased in some cancers, neurodegenerative diseases, obesity and diabetes. Barbara Kahn and colleagues report that NNMT is elevated in adipose tissue and liver in obese and diabetic mice. Knockdown of NNMT in adipose tissue protects against diet-induced obesity and its metabolic consequences such as glucose intolerance and fatty liver. NNMT inhibition in adipocytes leads to consumption of metabolic substrates coupled with increased energy expenditure, resulting in increased leanness. These findings identify NNMT as a potential target for treating obesity and type 2 diabetes. In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes 1 . Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity 2 . Here we show, using DNA array analyses, that nicotinamide N -methyltransferase ( Nnmt ) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4 -knockout or adipose-specific Glut4 -overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S -adenosylmethionine (SAM) as a methyl donor 3 , 4 . Nicotinamide is a precursor of NAD + , an important cofactor linking cellular redox states with energy metabolism 5 . SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation 6 . Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine–spermine N 1 -acetyltransferase (SSAT; encoded by Sat1 ) and by polyamine oxidase (PAO), and has a major role in energy metabolism 7 , 8 . We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibitio