Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity.
Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity.
复制标题
作者：
在肥胖和2型糖尿病中，脂肪细胞中Glut 4葡萄糖转运蛋白表达选择性降低。脂肪特异性Glut 4基因敲除或过表达改变全身胰岛素敏感性在这里，我们表明，使用DNA阵列分析，烟酰胺N-甲基转移酶（Nnmt）是最强烈的调节基因时，比较基因表达的白色脂肪组织（WAT）从脂肪特异性谷氨酸4基因敲除或脂肪特异性谷氨酸4基因过表达小鼠与各自的控制。NNMT使用S-腺苷甲硫氨酸（SAM）作为甲基供体甲基化烟酰胺（维生素B3）。烟酰胺是NAD+的前体，NAD+是连接细胞氧化还原状态与能量代谢的重要辅因子。SAM为多胺生物合成提供丙胺，并为组蛋白甲基化提供甲基。多胺通量包括合成、催化和排泄，由限速酶鸟氨酸脱羧酶（ODC）和精脒-精胺N1-乙酰转移酶（SSAT;由Sat 1编码）以及多胺氧化酶（PAO）控制，并且在能量代谢中具有主要作用。我们报道了NNMT在肥胖和糖尿病小鼠的WAT和肝脏中的表达增加。WAT和肝脏中的Nnmt敲低通过增加细胞能量消耗来防止饮食诱导的肥胖。由于NNMT对脂肪组织中组蛋白H3赖氨酸4甲基化的影响，NNMT抑制增加脂肪SAM和NAD+水平，上调ODC和SSAT活性以及表达。NNMT抑制导致多胺通量增加的直接证据包括尿排泄和脂肪细胞分泌的二乙酰精胺（多胺代谢产物）增加。脂肪细胞中的NNMT抑制以ODC、SSAT和PAO依赖性方式增加耗氧量。因此，NNMT是组蛋白甲基化、多胺通量和NAD+依赖性SIRT 1信号传导的新型调节剂，并且是治疗肥胖和2型糖尿病的独特且有吸引力的靶点。
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.
登录
查看更多内容
DOI：
10.1126/science.1226603
发表时间：
2013-01-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Shyh-Chang N;Locasale JW;Lyssiotis CA;Zheng Y;Teo RY;Ratanasirintrawoot S;Zhang J;Onder T;Unternaehrer JJ;Zhu H;Asara JM;Daley GQ;Cantley LC
通讯作者：
Cantley LC
DOI：
10.1007/978-1-61779-034-8_1
发表时间：
2011
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Pegg, Anthony E;Casero, Robert A Jr
通讯作者：
Casero, Robert A Jr
影响因子：
29
作者：
Eguchi, Jun;Yan, Qing-Wu;Rosen, Evan D.
通讯作者：
Rosen, Evan D.
DOI：
10.1152/ajpheart.00717.2011
发表时间：
2012-02-01
影响因子：
4.8
作者：
Bubolz, Aaron H.;Mendoza, Suelhem A.;Zhang, David X.
通讯作者：
Zhang, David X.
影响因子：
64.8
作者：
Rodgers, JT;Lerin, C;Puigserver, P
通讯作者：
Puigserver, P