Genetic Nicotinamide <i>N</i>-Methyltransferase (<i>Nnmt</i>) Deficiency in Male Mice Improves Insulin Sensitivity in Diet-Induced Obesity but Does Not Affect Glucose Tolerance

Abstract

Antisense oligonucleotide knockdown (ASO-KD) of nicotinamide <i>N</i>-methyltransferase (NNMT) in high-fat diet (HFD)-fed mice has been reported to reduce weight gain and plasma insulin levels and to improve glucose tolerance. Using NNMT-ASO-KD or NNMT knockout mice (NNMT^-/-), we tested the hypothesis that <i>Nnmt</i> deletion protects against diet-induced obesity and its metabolic consequences in males and females on obesity-inducing diets. We also examined samples from a human weight reduction (WR) study for adipose <i>NNMT</i> (a<i>NNMT</i>) expression and plasma 1-methylnicotinamide (MNAM) levels. In Western diet (WD)-fed female mice, NNMT-ASO-KD reduced body weight, fat mass, and insulin level and improved glucose tolerance. Although NNMT^-/- mice fed a standard diet had no obvious phenotype, NNMT^-/- males fed an HFD showed strongly improved insulin sensitivity (IS). Furthermore, NNMT^-/- females fed a WD showed reduced weight gain, less fat, and lower insulin levels. However, no improved glucose tolerance was observed in NNMT^-/- mice. Although <i>NNMT</i> expression in human fat biopsy samples increased during WR, corresponding plasma MNAM levels significantly declined, suggesting that other mechanisms besides a<i>NNMT</i> expression modulate circulating MNAM levels during WR. In summary, upon NNMT deletion or knockdown in males and females fed different obesity-inducing diets, we observed sex- and diet-specific differences in body composition, weight, and glucose tolerance and estimates of IS.