Dataset Information

Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme.

ABSTRACT: Nicotinamide (NAM) N-methyltransferase (NNMT) was originally identified as the enzyme responsible for the methylation of NAM, one of the forms of vitamin B3. Methylated NAM is eventually excreted from the body. Recent evidence has expanded the role of NNMT beyond clearance of excess vitamin B3. NNMT has been implicated in the regulation of multiple metabolic pathways in tissues such as adipose and liver as well as cancer cells through the consumption of methyl donors and generation of active metabolites. This review examines recent findings regarding the function of NNMT in physiology and disease and highlights potential new avenues for therapeutic intervention. Finally, key gaps in our knowledge about this enzymatic system and future areas of investigation are discussed.

SUBMITTER: Pissios P

PROVIDER: S-EPMC5446048 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme.

Pissios Pavlos P

Trends in endocrinology and metabolism: TEM 20170311 5

Nicotinamide (NAM) N-methyltransferase (NNMT) was originally identified as the enzyme responsible for the methylation of NAM, one of the forms of vitamin B3. Methylated NAM is eventually excreted from the body. Recent evidence has expanded the role of NNMT beyond clearance of excess vitamin B3. NNMT has been implicated in the regulation of multiple metabolic pathways in tissues such as adipose and liver as well as cancer cells through the consumption of methyl donors and generation of active met ...[more]

PMID: 28291578

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Project description:In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity. 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. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. 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. 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 inhibition increases adipose SAM and NAD(+) levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD(+)-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.

Dataset Information

Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme.

Publications

Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzyme.

Similar Datasets

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