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Ampk Regulates Energy Expenditure By Modulating Nad~+ Metabolism And Sirt1 Activity

机译：Ampk通过调节Nad〜+代谢和Sirt1活性来调节能量消耗。

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摘要

AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD~+-dependent type Ⅲ deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD~+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-γ coactivator la and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.
机译：AMP激活蛋白激酶（AMPK）是一种在真核生物中沿进化尺度守恒的代谢燃料量表，可检测细胞内AMP / ATP比值的变化。最近的证据表明，AMPK在二甲双胍，噻唑烷二酮和运动的治疗益处中起着重要作用，这构成了2型糖尿病和相关代谢性疾病临床管理的基石。通常，激活AMPK可以维持细胞的能量储存，主要通过增强氧化代谢和线粒体的生物合成来打开产生ATP的分解代谢途径，同时关闭消耗ATP的合成代谢途径。通过快速翻译后事件的调控，也可以通过对细胞进行转录重编程以满足能量需求，来实现这种调控。在这里，我们证明了AMPK通过与另一种代谢传感器NAD〜+依赖型Ⅲ型脱乙酰基酶SIRT1协同作用来控制参与小鼠骨骼肌能量代谢的基因的表达。 AMPK通过增加细胞中NAD〜+的水平来增强SIRT1的活性，从而导致下游SIRT1靶标的脱乙酰化和调节活性，这些靶标包括过氧化物酶体增殖物激活的受体-γ共激活剂la和叉头盒O1（FOXO1）和O3（FOXO3a）转录因子。 AMPK诱导的SIRT1介导的这些目标脱乙酰基解释了AMPK和SIRT1对能量代谢的许多融合生物学效应。

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