Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age-associated insulin resistance.
Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age-associated insulin resistance.
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DOI：
10.1111/acel.12798
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发表时间：
2018-08
期刊：
影响因子：
7.8
通讯作者：
Nakagawa T
中科院分区：
文献类型：
--
作者：
Gulshan M;Yaku K;Okabe K;Mahmood A;Sasaki T;Yamamoto M;Hikosaka K;Usui I;Kitamura T;Tobe K;Nakagawa T
烟酰胺腺嘌呤二核苷酸（NAD）是一种重要的辅因子，调节各种生物过程，包括代谢和基因表达。作为辅酶，NAD通过三羧酸（TCA）循环、β-氧化和氧化磷酸化的酶来控制线粒体呼吸，并且还作为翻译后蛋白质修饰的底物，例如分别通过沉默调节蛋白和聚（ADP-核糖）聚合酶（PARP）进行的脱乙酰化和ADP-核糖基化。许多研究表明，NAD水平随着衰老而下降，这些下降会导致各种与衰老相关的疾病。相比之下，NAD代谢的激活可以防止衰老过程中NAD水平的下降。特别是，饮食补充NAD前体与防止年龄相关的胰岛素抵抗有关。然而，仍不清楚哪种NAD合成途径在体内增加NAD水平方面是重要的和/或有效的。在这项研究中，小鼠中的Nmnat 3过表达有效地增加了各种组织中的NAD水平，并阻止了NAD水平的衰老相关下降。我们还证明了Nmnat 3过表达（Nmnat 3 Tg）小鼠可免受饮食诱导和衰老相关的胰岛素抵抗。此外，在Nmnat 3 Tg小鼠的骨骼肌中，TCA循环活性显著增强，氧化磷酸化的能量来源向脂肪酸氧化转移。此外，活性氧（ROS）的产生显着抑制老年Nmnat 3 Tg小鼠。有趣的是，我们还发现NAD类似物烟酰胺鸟嘌呤二核苷酸（NGD）的浓度在Nmnat 3 Tg小鼠中显著增加。这些结果表明，Nmnat 3过表达可以改善代谢健康，并且Nmnat 3是衰老引起的代谢障碍的一个有吸引力的治疗靶点。
Nicotinamide adenine dinucleotide (NAD) is an important cofactor that regulates various biological processes, including metabolism and gene expression. As a coenzyme, NAD controls mitochondrial respiration through enzymes of the tricarboxylic acid (TCA) cycle, β‐oxidation, and oxidative phosphorylation and also serves as a substrate for posttranslational protein modifications, such as deacetylation and ADP‐ribosylation by sirtuins and poly(ADP‐ribose) polymerase (PARP), respectively. Many studies have demonstrated that NAD levels decrease with aging and that these declines cause various aging‐associated diseases. In contrast, activation of NAD metabolism prevents declines in NAD levels during aging. In particular, dietary supplementation with NAD precursors has been associated with protection against age‐associated insulin resistance. However, it remains unclear which NAD synthesis pathway is important and/or efficient at increasing NAD levels in vivo. In this study, Nmnat3 overexpression in mice efficiently increased NAD levels in various tissues and prevented aging‐related declines in NAD levels. We also demonstrated that Nmnat3‐overexpressing (Nmnat3 Tg) mice were protected against diet‐induced and aging‐associated insulin resistance. Moreover, in skeletal muscles of Nmnat3 Tg mice, TCA cycle activity was significantly enhanced, and the energy source for oxidative phosphorylation was shifted toward fatty acid oxidation. Furthermore, reactive oxygen species (ROS) generation was significantly suppressed in aged Nmnat3 Tg mice. Interestingly, we also found that concentrations of the NAD analog nicotinamide guanine dinucleotide (NGD) were dramatically increased in Nmnat3 Tg mice. These results suggest that Nmnat3 overexpression improves metabolic health and that Nmnat3 is an attractive therapeutic target for metabolic disorders that are caused by aging.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
15.8
作者：
Civitarese AE;Carling S;Heilbronn LK;Hulver MH;Ukropcova B;Deutsch WA;Smith SR;Ravussin E;CALERIE Pennington Team
通讯作者：
CALERIE Pennington Team
影响因子：
29
作者：
Frederick DW;Loro E;Liu L;Davila A Jr;Chellappa K;Silverman IM;Quinn WJ 3rd;Gosai SJ;Tichy ED;Davis JG;Mourkioti F;Gregory BD;Dellinger RW;Redpath P;Migaud ME;Nakamaru-Ogiso E;Rabinowitz JD;Khurana TS;Baur JA
通讯作者：
Baur JA
影响因子：
29
作者：
Chalkiadaki A;Guarente L
通讯作者：
Guarente L
影响因子：
4.7
作者：
Liu, YB;Fiskum, G;Schubert, D
通讯作者：
Schubert, D