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Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice.

机译:烟酰胺单核苷酸,一种关键的NAD(+)中间体,可治疗饮食和年龄诱发的小鼠糖尿病的病理生理。

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摘要

Type 2 diabetes (T2D) has become epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD(+) biosynthesis, and the NAD(+)-dependent protein deacetylase SIRT1. Here, we show that NAMPT-mediated NAD(+) biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD(+) intermediate, ameliorates glucose intolerance by restoring NAD(+) levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD(+) and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a potential nutriceutical intervention against diet- and age-induced T2D.
机译:2型糖尿病(T2D)在我们的现代生活方式中已成为流行病,可能是由于富含卡路里的饮食压倒了我们的适应性代谢途径。一种这样的途径是由烟酰胺磷酸核糖基转移酶(NAMPT),哺乳动物NAD(+)生物合成中的限速酶和NAD(+)依赖性蛋白脱乙酰基酶SIRT1介导的。在这里,我们表明,NAMPT介导的NAD(+)生物合成被高脂饮食(HFD)严重损害了代谢器官。令人惊讶的是,NAMPT反应和关键NAD(+)中间产物的烟酰胺单核苷酸(NMN)通过恢复HFD诱导的T2D小鼠中NAD(+)的水平来改善葡萄糖耐量。 NMN还可以部分通过SIRT1激活来增强肝胰岛素敏感性,并恢复与氧化应激,炎症反应和昼夜节律有关的基因表达。此外,在衰老过程中,NAD(+)和NAMPT水平在多个器官中均显着降低,而NMN改善了年龄诱发的T2D小鼠的葡萄糖耐量和脂质分布。这些发现为针对饮食和年龄引起的T2D的潜在营养干预提供了重要的见识。

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