Novel Transcriptome Profiling Analyses Demonstrate that Selective PPARg Modulators Display Attenuated and Selective Gene Regulatory Activity in Comparison with PPARg Full Agonists

We conducted extensive transcriptome profiling studies to characterize 70 SPPARgMs and seven PPARg full agonists in 3T3-L1 adipocytes, and a subset of these ligands in adipose tissue of diabetic db/db mice. In both cases, the SPPARgMs generated attenuated gene regulatory responses, and their gene expression signatures were more enriched in metabolic pathways that are likely to mediate anti-diabetic efficacy than those of PPARg full agonists. More importantly, our profiling results demonstrated that in both 3T3-L1 adipocytes and db/db mice, SPPARgMs regulate the expression of anti-diabetic efficacy-associated genes to a greater extent than that of adverse effect-associated genes, while PPARg full agonists regulate both gene sets proportionally. We conducted 10 independent batches of profiling experiments. Within each batch, drug treatment and pool of vehicle controls were hybridized to the Agilent two channel microarray. Generally 2-3 biological replicates for each condition.

本研究开展了大规模转录组谱分析实验，以表征3T3-L1脂肪细胞中的70种选择性PPARγ调节剂（SPPARgMs）与7种PPARγ全激动剂（PPARg full agonists），并针对其中部分配体在糖尿病db/db小鼠的脂肪组织中开展了同类表征实验。两种实验模型中，SPPARgMs所介导的基因调控反应均呈现衰减特征；且相较于PPARγ全激动剂，SPPARgMs的基因表达特征更显著富集于可能介导抗糖尿病药效的代谢通路之中。更为关键的是，本研究的谱分析结果证实，在3T3-L1脂肪细胞与db/db糖尿病小鼠两种模型中，SPPARgMs对抗糖尿病药效相关基因的表达调控幅度显著高于其对不良反应相关基因的调控幅度；而PPARγ全激动剂则会对两类基因集产生比例相当的调控作用。本研究共开展了10批独立的转录组谱分析实验，每一批次中，药物处理组与溶剂对照混合样本均采用安捷伦（Agilent）双通道微阵列进行杂交，通常每个实验条件设置2-3次生物学重复。