Genetic Nicotinamide N-Methyltransferase Deficiency Improves Insulin Sensitivity in DIO Mice

Nicotinamide N-methyltransferase (NNMT) is expressed in most tissues including muscle, adipose tissue, liver and digestive organs. Recent research suggests the involvement of NNMT in the pathogenesis of obesity, insulin resistance and related metabolic disease. Antisense oligonucleotide (ASO) knockdown in high-fat diet (HFD)-fed mice led to reduced weight gain, relative fat mass, plasma insulin levels and improved glucose tolerance. We tested the hypothesis, that genetic NNMT deletion protects mice on HFD and Western diet (WD) against obesity and explored the metabolic effects of NNMT. Using NNMT ASO treatment and a NNMT knockout mouse (NNMT^-/-), we investigate the effects of NNMT deletion on energy metabolism, glucose homeostasis and the development of obesity. We also examined data from a human study concerning NNMT expression and 1-methylnicotinamide (MNA) levels regarding weight reduction. In WD-fed mice, NNMT ASO treatment improved acute glucose tolerance, reduced weight gain and fat mass increase and, consequently, lowered plasma insulin levels. NNMT^-/- mice exhibited virtually no MNA but threefold higher nicotinamide levels. Whereas NNMT^-/- male and female mice on normal chow revealed no metabolic phenotype, NNMT^-/- males on HFD showed improved glucose infusion rates, nearly complete insulin-mediated suppression of endogenous glucose production and an enhanced glucose uptake during a hyperinsulinemic-euglycemic clamp. Furthermore, NNMT^-/- females on WD showed reduced weight gain, less fat mass and lower plasma insulin levels compared to controls. While NNMT gene expression in human fat biopsies increased over weight loss, corresponding plasma MNA levels significantly declined after weight reduction, suggesting that other mechanisms rather than adipose NNMT expression modulate circulating MNA levels during weight reduction.

In conclusion, we observed an improvement of basal metabolic parameters and insulin sensitivity in NNMT-deficient mouse models.