A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-γ nuclear translocation
A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-γ nuclear translocation
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DOI：
10.1073/pnas.1000788107
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发表时间：
2010-06-08
影响因子：
11.1
通讯作者：
Rosen, Clifford J.
中科院分区：
文献类型：
--
作者：
Kawai, Masanobu;Green, Carla B.;Rosen, Clifford J.
Nocturnin（NOC）是一种昼夜节律调节蛋白，与参与细胞对营养状态反应的酵母转录因子家族相关。在哺乳动物中，NOC作为去腺苷酶发挥功能，但缺乏转录激活结构域。它在骨髓基质细胞（BMSC）、肝细胞和脂肪细胞中高度表达。在暴露于PPAR-gamma（过氧化物酶体增殖物激活受体-gamma）激动剂罗格列酮的BMSCs中，Noc表达增强了30倍。以前，我们报道了Noc（-/-）小鼠体温低，不受饮食诱导的肥胖的影响，最重要的是在高脂饮食中表现出Pparg昼夜节律性的缺失。与其影响BMSC分配的作用一致，Noc（-/-）小鼠具有减少的骨髓肥胖和高骨量。在同一静脉中，NOC过表达增强3 T3-L1细胞中的脂肪生成，但负调控MC 3 T3-E1细胞中的骨生成。NOC和缺乏去腺苷酸酶活性的突变形式结合到PPAR-gamma并显著增强PPAR-gamma转录活性。野生型和突变型NOC都促进了PPAR-gamma的核转位。重要的是，NOC介导的PPAR-gamma核转位被NOC的短肽片段阻断，该短肽片段抑制其与PPAR-gamma的物理相互作用。这种NOC-肽的抑制作用被罗格列酮部分逆转，表明NOC对PPAR-gamma核转位的作用可能不依赖于配体介导的PPAR-gamma激活。总之，Noc通过核转位调节PPAR-gamma活性，在间充质干细胞谱系分配的调节中起着独特的作用。这些数据说明了一种独特的机制，即营养反应基因影响BMSCs分化，脂肪形成，并最终身体组成。
Nocturnin (NOC) is a circadian-regulated protein related to the yeast family of transcription factors involved in the cellular response to nutrient status. In mammals, NOC functions as a deadenylase but lacks a transcriptional activation domain. It is highly expressed in bone-marrow stromal cells (BMSCs), hepatocytes, and adipocytes. In BMSCs exposed to the PPAR-gamma (peroxisome proliferator-activated receptor-gamma) agonist rosiglitazone, Noc expression was enhanced 30-fold. Previously, we reported that Noc(-/-) mice had low body temperature, were protected from diet-induced obesity, and most importantly exhibited absence of Pparg circadian rhythmicity on a high-fat diet. Consistent with its role in influencing BMSCs allocation, Noc(-/-) mice have reduced bone marrow adiposity and high bone mass. In that same vein, NOC overexpression enhances adipogenesis in 3T3-L1 cells but negatively regulates osteogenesis in MC3T3-E1 cells. NOC and a mutated form, which lacks deadenylase activity, bind to PPAR-gamma and markedly enhance PPAR-gamma transcriptional activity. Both WT and mutant NOC facilitate nuclear translocation of PPAR-gamma. Importantly, NOC-mediated nuclear translocation of PPAR-gamma is blocked by a short peptide fragment of NOC that inhibits its physical interaction with PPAR-gamma. The inhibitory effect of this NOC-peptide was partially reversed by rosiglitazone, suggesting that effect of NOC on PPAR-gamma nuclear translocation may be independent of ligand-mediated PPAR-gamma activation. In sum, Noc plays a unique role in the regulation of mesenchymal stem-cell lineage allocation by modulating PPAR-gamma activity through nuclear translocation. These data illustrate a unique mechanism whereby a nutrient-responsive gene influences BMSCs differentiation, adipogenesis, and ultimately body composition.