Life-long caloric restriction-associated remodeling of rat white adipose tissue

This study explored the role of the growth hormone (GH) / insulin-like growth factor 1 (IGF-1) axis on the life-long caloric restriction (CR)-associated remodeling of white adipose tissue (WAT). Adipocyte size and gene expression profiles, using high-density oligonucleotide microarrays, were analyzed in WAT of six- to seven-month old wild Wistar rats fed ad libitum (AL) or subjected to a 30% caloric restriction (CR), and heterozygous transgenic dwarf rats bearing an anti-sense GH transgene fed ad libitum (Tg). While not significant in Tg rats, adipocyte size was significantly reduced in CR rats compared with AL rats. The microarray data based on the principal component analysis demonstrated that the gene expression profile of CR rats markedly differed from the AL rats, while Tg hardly differed, suggesting that CR-associated WAT remodeling was predominantly regulated in a GH/IGF-1-independent manner. The gene cluster with the largest change induced by CR included several genes involved in lipid biosynthesis and inflammation. Moreover, many of the genes transcriptionally regulated by sterol regulatory element binding proteins (SREBPs) were found in the cluster related to lipid biosynthesis. Real-time reverse transcription polymerase chain reaction analysis confirmed that the expression of SREBP-1 and its down-stream targets was particularly up-regulated in CR rats compared with SREBP-2 and its down-stream targets. Our findings suggest that SREBP-1 is a major transcription factor in CR-associated remodeling of WAT, and might be one of the key regulators of the anti-aging and pro-longevity effects of CR.本研究探究了生长激素（GH）/胰岛素样生长因子1（IGF-1）轴在终身热量限制（CR）相关白色脂肪组织（WAT）重塑中的调控作用。本研究以6~7月龄野生型Wistar大鼠为实验对象，设置自由进食（AL）组与30%热量限制（CR）组，同时纳入携带反义GH转基因的杂合转基因矮小大鼠自由进食组（Tg组），采用高密度寡核苷酸微阵列（high-density oligonucleotide microarrays）技术分析各组大鼠白色脂肪组织的脂肪细胞大小与基因表达谱。结果显示，与AL组相比，CR组大鼠的脂肪细胞体积显著减小，而Tg组未观察到明显变化。基于主成分分析的微阵列数据表明，CR组大鼠的基因表达谱与AL组存在显著差异，而Tg组与AL组的差异极小，提示CR相关的WAT重塑主要以不依赖GH/IGF-1的方式进行调控。CR诱导变化最为显著的基因簇包含多个参与脂质生物合成与炎症反应的基因。此外，固醇调节元件结合蛋白（SREBPs）转录调控的诸多基因均富集于脂质生物合成相关基因簇中。实时逆转录聚合酶链反应（real-time reverse transcription polymerase chain reaction）分析证实，相较于SREBP-2及其下游靶基因，CR组大鼠中SREBP-1及其下游靶基因的表达水平显著上调。本研究结果表明，SREBP-1是CR相关WAT重塑的核心转录因子，或可成为CR发挥抗衰老与延长寿命效应的关键调控因子之一。