Chujo Yoshikazu, Fujii Namiki, Okita Naoyuki, Konishi Tomokazu, Narita Takumi, Yamada Atsushi, Haruyama Yushi, Tashiro Kosuke, Chiba Takuya, Shimokawa Isao, Higami Yoshikazu
Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
Age (Dordr). 2013 Aug;35(4):1143-56. doi: 10.1007/s11357-012-9439-1. Epub 2012 May 28.
The role of the growth hormone (GH)-insulin-like growth factor (IGF)-1 axis in the lifelong caloric restriction (CR)-associated remodeling of white adipose tissue (WAT), adipocyte size, and gene expression profiles was explored in this study. We analyzed the WAT morphology of 6-7-month-old wild-type Wistar rats fed ad libitum (WdAL) or subjected to CR (WdCR), and of heterozygous transgenic dwarf rats bearing an anti-sense GH transgene fed ad libitum (TgAL) or subjected to CR (TgCR). Although less effective in TgAL, the adipocyte size was significantly reduced in WdCR compared with WdAL. This CR effect was blunted in Tg rats. We also used high-density oligonucleotide microarrays to examine the gene expression profile of WAT of WdAL, WdCR, and TgAL rats. The gene expression profile of WdCR, but not TgAL, differed greatly from that of WdAL. The gene clusters with the largest changes induced by CR but not by Tg were genes involved in lipid biosynthesis and inflammation, particularly sterol regulatory element binding proteins (SREBPs)-regulated and macrophage-related genes, respectively. Real-time reverse-transcription polymerase chain reaction analysis confirmed that the expression of SREBP-1 and its downstream targets was upregulated, whereas the macrophage-related genes were downregulated in WdCR, but not in TgAL. In addition, CR affected the gene expression profile of Tg rats similarly to wild-type rats. Our findings suggest that CR-associated remodeling of WAT, which involves SREBP-1-mediated transcriptional activation and suppression of macrophage infiltration, is regulated in a GH-IGF-1-independent manner.
本研究探讨了生长激素（GH）-胰岛素样生长因子（IGF）-1轴在终身热量限制（CR）相关的白色脂肪组织（WAT）重塑、脂肪细胞大小和基因表达谱中的作用。我们分析了自由采食（WdAL）或接受CR（WdCR）的6-7月龄野生型Wistar大鼠，以及自由采食（TgAL）或接受CR（TgCR）的携带反义GH转基因的杂合转基因侏儒大鼠的WAT形态。尽管在TgAL中效果较差，但与WdAL相比，WdCR中的脂肪细胞大小显著减小。这种CR效应在Tg大鼠中减弱。我们还使用高密度寡核苷酸微阵列来检测WdAL、WdCR和TgAL大鼠WAT的基因表达谱。WdCR而非TgAL的基因表达谱与WdAL有很大差异。由CR而非Tg诱导的变化最大的基因簇分别是参与脂质生物合成和炎症的基因，特别是甾醇调节元件结合蛋白（SREBPs）调节基因和巨噬细胞相关基因。实时逆转录聚合酶链反应分析证实，SREBP-1及其下游靶点的表达在WdCR中上调，而巨噬细胞相关基因在WdCR中下调，但在TgAL中未下调。此外，CR对Tg大鼠基因表达谱的影响与野生型大鼠相似。我们的研究结果表明，CR相关的WAT重塑，涉及SREBP-1介导的转录激活和巨噬细胞浸润的抑制，是以一种不依赖GH-IGF-1的方式调节的。
