Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide using SAM as a methyl donor and generates S-adenosylhomocysteine (SAH). SAM has two major functions: on hand, providing propylamine groups for polyamine biosynthesis; on another hand, donating methyl groups to substrates including histones. 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-over expressing mice with their respective controls.
Recently, there is a 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 enhancing cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD1 levels and up regulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3K4 methylation. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine. NNMT inhibition increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner.
To summary, NNMT is a novel regulator of histone methylation, polyamine flux and NAD1-dependent SIRT1 signaling, and is a unique and attractive target for treating obesity and type 2 diabetes.