In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes1. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity2. 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 donor3,4. Nicotinamide is a precursor of NAD+, an important cofactor linking cellular redox states with energy metabolism5. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation6. 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 metabolism7,8. 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.
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Gene Expression Omnibus
The microarray data from adipose tissue of adipose-specific knockout and adipose-specific overexpression have been published by our laboratory and are available in NCBI Gene Expression Omnibus under accession number GSE35378.
We thank R. Weinshilboum for NNMT antibody; P. Woster for DFMO; M. Yuan for tandem mass spectrometry; A. Karppinen, A. Korhonen, T. Reponen, A. Uimari, S. Pirnes-Karhu and T. Koponen for measurements of ODC and SSAT activity; C. Semenkovich and S. Fried for protocols for FAS activity measurements; and P. Aryal for assistance with real-time qPCR. D.Kr. is supported by the Deutsche Forschungsgemeinschaft (KR 3475/1-1) and American Heart Association (AHA) (09POST2250499); Q.Y. is a Klarman Scholar at the Beth Israel Deaconess Medical Center. This work is supported by grants from the NIH (R37 DK43051, P30 DK57521) and a grant from the JPB foundation to B.B.K.; grants from the NIH (KO8 DK090149, R01 DK100385, BNORC P30 DK046200 and NORCH P30 DK040561) to Q.Y.; grant RO1 DK69966 to P.P.; P01CA120964 and P30CA006516-46 to J.M.A.; AHA 13SDG14620005 and P&F P30 DK0460200 to D.K.; the Ellison Medical Foundation New Scholar in Aging Award to A.A.S.; and academy of Finland grant 118590 to L.A.
This file contains Supplementary Figures 1-21.
About this article
Frontiers in Nutrition (2019)