Pharmacological stimulation of NADH oxidation ameliorates obesity and related phenotypes in mice.
Pharmacological stimulation of NADH oxidation ameliorates obesity and related phenotypes in mice.
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作者：
Hwang JH;Kim DW;Jo EJ;Kim YK;Jo YS;Park JH;Yoo SK;Park MK;Kwak TH;Kho YL;Han J;Choi HS;Lee SH;Kim JM;Lee I;Kyung T;Jang C;Chung J;Kweon GR;Shong M
烟酰胺腺嘌呤二核苷酸（NAD+和NADH）在细胞能量代谢中起关键作用，并且失调的NAD+与NADH比率与代谢综合征有关。然而，调节细胞内NAD+与NADH的比率是否有益于治疗代谢综合征仍然是未知的。我们试图确定药理学刺激NADH氧化是否在代谢综合征的啮齿动物模型中提供治疗效果。我们使用β-拉帕酮（βL），一种天然底物的NADH：醌氧化还原酶1（NQO 1），以刺激NADH氧化。在NQO 1缺陷小鼠来源的细胞中评价β L诱导的对细胞能量代谢的药理作用。在饮食诱导的肥胖（DIO）和ob/ob小鼠中检查βL对代谢综合征的体内治疗作用。NQO 1依赖的NADH氧化βL强烈引起线粒体脂肪酸氧化在体外和体内。这些作用伴随着AMP激活的蛋白激酶和肉毒碱棕榈酰转移酶的激活和乙酰辅酶A（CoA）羧化酶活性的抑制。一致的是，代谢综合征啮齿动物模型中的全身βL给药显著改善了其关键症状，如肥胖增加、葡萄糖耐受不良、血脂异常和脂肪肝。经处理的小鼠还显示出与线粒体能量代谢相关的基因（PPARγ共激活因子-1 α、核呼吸因子-1）和热量限制（Sirt 1）的较高表达，这与线粒体生物合成和能量消耗增加一致。NQO 1对NADH氧化的药理学激活解决了小鼠的肥胖和相关表型，这可能为治疗代谢综合征的新疗法提供基础。
Nicotinamide adenine dinucleotides (NAD+ and NADH) play a crucial role in cellular energy metabolism, and a dysregulated NAD+-to-NADH ratio is implicated in metabolic syndrome. However, it is still unknown whether a modulating intracellular NAD+-to-NADH ratio is beneficial in treating metabolic syndrome. We tried to determine whether pharmacological stimulation of NADH oxidation provides therapeutic effects in rodent models of metabolic syndrome. We used β-lapachone (βL), a natural substrate of NADH:quinone oxidoreductase 1 (NQO1), to stimulate NADH oxidation. The βL-induced pharmacological effect on cellular energy metabolism was evaluated in cells derived from NQO1-deficient mice. In vivo therapeutic effects of βL on metabolic syndrome were examined in diet-induced obesity (DIO) and ob/ob mice. NQO1-dependent NADH oxidation by βL strongly provoked mitochondrial fatty acid oxidation in vitro and in vivo. These effects were accompanied by activation of AMP-activated protein kinase and carnitine palmitoyltransferase and suppression of acetyl-coenzyme A (CoA) carboxylase activity. Consistently, systemic βL administration in rodent models of metabolic syndrome dramatically ameliorated their key symptoms such as increased adiposity, glucose intolerance, dyslipidemia, and fatty liver. The treated mice also showed higher expressions of the genes related to mitochondrial energy metabolism (PPARγ coactivator-1α, nuclear respiratory factor-1) and caloric restriction (Sirt1) consistent with the increased mitochondrial biogenesis and energy expenditure. Pharmacological activation of NADH oxidation by NQO1 resolves obesity and related phenotypes in mice, opening the possibility that it may provide the basis for a new therapy for the treatment of metabolic syndrome.
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影响因子：
158.5
作者：
Knowler, WC;Barrett-Connor, E;Nathan, DM
通讯作者：
Nathan, DM
影响因子：
64.8
作者：
Guarente, Leonard
通讯作者：
Guarente, Leonard
影响因子：
3.5
作者：
CARLING, D;ZAMMIT, VA;HARDIE, DG
通讯作者：
HARDIE, DG
影响因子：
10.5
作者：
Kim, JB;Spiegelman, BM
通讯作者：
Spiegelman, BM
影响因子：
10.5
作者：
Lin, SJ;Ford, E;Guarente, L
通讯作者：
Guarente, L