Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity

被引：367

作者：

Kraus, Daniel ^{[1
,2
]}

Yang, Qin ^{[1
,2
]}

Kong, Dong ^{[1
,2
]}

Banks, Alexander S. ^{[3
]}

Zhang, Lin ^{[1
,2
]}

Rodgers, Joseph T. ^{[3
]}

Pirinen, Eija ^{[4
]}

Pulinilkunnil, Thomas C. ^{[1
,2
]}

Gong, Fengying ^{[1
,2
]}

Wang, Ya-chin ^{[1
,2
]}

Cen, Yana ^{[5
]}

Sauve, Anthony A. ^{[5
]}

Asara, John M. ^{[2
,6
]}

Peroni, Odile D. ^{[1
,2
]}

Monia, Brett P. ^{[7
]}

Bhanot, Sanjay ^{[7
]}

Alhonen, Leena ^{[4
]}

Puigserver, Pere ^{[3
]}

Kahn, Barbara B. ^{[1
,2
]}

机构：

[1] Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Boston, MA 02215 USA

[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Univ Eastern Finland, Bioctr Kuopio, AI Virtanen Inst Mol Sci, FI-70211 Kuopio, Finland

[5] Cornell Univ, Weill Med Coll, Dept Pharmacol, New York, NY 10065 USA

[6] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA

[7] ISIS Pharmaceut, Carlsbad, CA 92008 USA

来源：

NATURE | 2014年 / 508卷 / 7495期

基金：

芬兰科学院;

关键词：

ADIPOSE-TISSUE; CDNA CLONING; EXPRESSION; MOUSE; LIVER; SIRT1; MICE; METABOLISM; RESISTANCE; CANCER;

D O I：

10.1038/nature13198

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes(1). Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity(2). 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 Glut4k-nockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor(3,4). Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism(5). SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation(6). 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(7,8). 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.

引用

页码：258 / +

页数：7

共 43 条

[1] Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver [J].