Genetic Nicotinamide N-Methyltransferase (Nnmt) 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 N-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 Nnmt 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 NNMT (aNNMT) 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 NNMT expression in human fat biopsy samples increased during WR, corresponding plasma MNAM levels significantly declined, suggesting that other mechanisms besides aNNMT 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.

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

“…Husemoen et al [ [94], Tang et al [95], Goodier et al [96], Petyuk et al [97], Roux et al [98], Castrogiovanni et al [99], Suleiman et al [100] [111], Ma et al [112], Chabbert et al [113], Abramsson et al [114], Aeby et al [115] and Roll et al [116] found that the expression of DCC (DCC netrin 1 receptor), PLP1, SNX19, SH3RF1, TNFRSF1A, NCSTN (nicastrin), DGCR2, NPAS2, CDNF (cerebral dopamine neurotrophic factor), SMCR8, HSPA2, STUB1, CHID1, ATP13A2, SQSTM1, LIG3, SP4, ACSL6, ERN1, ATF6B, LRFN2, NRG3, LRRTM3, GABRA2, ADAM30, GABRR2, TSHZ3, LOXL1, SCN1B and SRPX2 are associated with the prognosis of patients with cognitive impairment, but these genes might be novel target for T1DM. Recent studies found that KCP (kielin cysteine rich BMP regulator) [117], NOG (noggin) [118], COL6A3 [119], BTG2 [120], RPS6 [121], KLF15 [122], KLF3 [123], ZFP36 [124], ETV5 [125], TLE3 [126], NNMT (nicotinamide Nmethyltransferase) [127], WDTC1 [128], ZFHX3 [129], SIAH2 [130], MBOAT7 [131], RUNX1T1 [132], MAPK4 [133], KLF9 [134], SELENBP1 [135], HELZ2 [136], ELK1 [137], SERTAD2 [138], CRTC3 [139], ABCB11 [140], TACR1 [141], SLC22A11 [142], PER3 [143], P2RX5 [144], MF...…”

“…GABRR2, TSHZ3, LOXL1, SCN1B and SRPX2 are associated with the prognosis of patients with cognitive impairment, but these genes might be novel target for T1DM. Recent studies found that KCP (kielin cysteine rich BMP regulator) [117], NOG (noggin) [118], COL6A3 [119], BTG2 [120], RPS6 [121], KLF15 [122], KLF3 [123], ZFP36 [124], ETV5 [125], TLE3 [126], NNMT (nicotinamide N-methyltransferase) [127], WDTC1 [128], ZFHX3 [129], SIAH2 [130], MBOAT7 [131], RUNX1T1 [132], MAPK4 [133], KLF9 [134], SELENBP1 [135], HELZ2 [136], ELK1 [137], SERTAD2 [138], CRTC3 [139], ABCB11 [140], TACR1 [141], SLC22A11 [142], PER3 [143], P2RX5 [144], MFAP5 [145], FGL1 [146], OLFM4 [147], NTN1 [148], ESR1 [149], ABCB1 [150], VAV3 [151] and LAMB3 [152] plays an important role in the occurrence and development of obesity, but these genes might be novel target for T1DM. STAR (steroidogenic acute regulatory protein) [153], IL1RN [154], AQP5 [155], EGR1 [156], SFTPD (surfactant protein D) [157], KLF10 [158], PODXL (podocalyxin like) [159], FOXN3 [160], IL6R [161], PBX1 [162], APOD (apolipoprotein D) [163], ACVR2B [164], CD34 [165], INSR (insulin receptor) [166], APOA5 [167], STAR (steroidogenic acute regulatory protein) [168], PDK4 [169], GLS (glutaminase) [170], FKBP5 [171], SLC6A15 [172], MT2A [173], SLC38A4 [174], AQP7 [175], ABHD15 [176], ABCA1 [177], ZNRF1 [178], PPP1R3B [179], MAOA (monoamine oxidase A) [180], UBE2E2 [181], RNASEK (ribonuclease K) [182], PREX1 [183], DGKG (diacylglycerol kinase gamma) [184], POS...…”

Impaired nicotinamide adenine dinucleotide (NAD+) metabolism in diabetes and diabetic tissues: Implications for nicotinamide‐related compound treatment

“…NNMT inhibitor has been developed and tested in mice 137,138 . Inhibition of the enzyme might divert nicotinamide from catabolism toward more NAD + synthesis.…”

Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders

“…It is expressed in most tissues including the liver, adipose tissue, and skeletal muscle [3], and also in several human cancers [4]. NNMT is the major Nam-metabolizing enzyme, and systemic knockout in mice fully prevents MNam formation [5,6]. MNam can either be excreted via urine or further metabolized to 1-methyl-2-pyridone-5-carboxamide (Me2PY) or 1-methyl-4-pyridone-5-carboxamide (Me4PY) in a reaction catalyzed by aldehyde oxidase [7].…”

“…Reduction in hepatic and adipose tissue NNMT with an antisense oligonucleotide led to lower weight gain, a decrease in relative fat mass, lower plasma insulin levels and improved glucose tolerance in mice on a high-fat diet (HFD) [6,8]. Likewise, treatment with the selective NNMT inhibitors 5-amino-1-methylquinoline [17] or 6-methoxynicotinamide [5] resulted in reduced body weight, higher insulin sensitivity, and improved glucose tolerance in mice with diet-induced obesity (Figure 1).…”