Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity

Daniel Kraus, Qin Yang, Dong Kong, Alexander S. Banks, Lin Zhang, Joseph T. Rodgers, Eija Pirinen, Thomas C. Pulinilkunnil, Fengying Gong, Ya Chin Wang, Yana Cen, Anthony A. Sauve, John M. Asara, Odile D. Peroni, Brett P. Monia, Sanjay Bhanot, Leena Alhonen, Pere Puigserver, Barbara B. Kahn

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Abstract

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 N1-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.

Original languageEnglish (US)
Pages (from-to)258-262
Number of pages5
JournalNature
Volume508
Issue number7495
DOIs
Publication statusPublished - Apr 9 2014
Externally publishedYes

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Kraus, D., Yang, Q., Kong, D., Banks, A. S., Zhang, L., Rodgers, J. T., ... Kahn, B. B. (2014). Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature, 508(7495), 258-262. https://doi.org/10.1038/nature13198