Data from: Cd36-deficient congenic strains show improved glucose tolerance and distinct shifts in metabolic and transcriptomic profiles

Deficiency of fatty acid translocase Cd36 has been shown to have a major role in the pathogenesis of metabolic syndrome in the spontaneously hypertensive rat (SHR). We have tested the hypothesis that the effects of Cd36 mutation on the features of metabolic syndrome are contextually dependent on genomic background. We have derived two new congenic strains by introgression of limited chromosome 4 regions of SHR origin, both including the defective Cd36 gene, into the genetic background of a highly inbred model of insulin resistance and dyslipidemia, polydactylous (PD) rat strain. We subjected standard diet-fed adult males of PD and the congenic PD.SHR4 strains to metabolic, morphometric and transcriptomic profiling. We observed significantly improved glucose tolerance and lower fasting insulin levels in PD.SHR4 congenics than in PD. One of the PD.SHR4 strains showed lower triglyceride concentrations across major lipoprotein fractions combined with higher levels of low-density lipoprotein cholesterol compared with the PD progenitor. The hepatic transcriptome assessment revealed a network of genes differentially expressed between PD and PD.SHR4 with significant enrichment by members of the circadian rhythmicity pathway (Arntl (Bmal1), Clock, Nfil3, Per2 and Per3). In summary, the introduction of the chromosome 4 region of SHR origin including defective Cd36 into the PD genetic background resulted in disconnected shifts of metabolic profile along with distinct changes in hepatic transcriptome. The synthesis of the current results with those obtained in other Cd36-deficient strains indicates that the eventual metabolic effect of a deleterious mutation such as that of SHR-derived Cd36 is not absolute, but rather a function of complex interactions between environmental and genomic background, upon which it operates.

已有研究表明，脂肪酸转位酶Cd36（fatty acid translocase Cd36）的缺乏在自发性高血压大鼠（spontaneously hypertensive rat, SHR）的代谢综合征（metabolic syndrome）发病机制中发挥关键作用。本研究验证了如下假说：Cd36突变对代谢综合征表型的影响，取决于其所处的基因组背景环境。我们通过将SHR来源的、均携带缺陷型Cd36基因的有限4号染色体区域，回交导入至一种高近交化的胰岛素抵抗（insulin resistance）伴血脂异常（dyslipidemia）多指（polydactylous, PD）大鼠品系的遗传背景中，成功构建了两种全新的同类系品系（congenic strain）。我们对标准饲料喂养的PD品系及同类系PD.SHR4品系的成年雄性个体，开展了代谢表型、形态计量学及转录组学（transcriptomic profiling）分析。结果显示，相较于亲代PD品系，PD.SHR4同类系大鼠的葡萄糖耐量显著改善，空腹胰岛素水平显著降低。其中一种PD.SHR4品系相较于PD亲本品系，其主要脂蛋白组分中的甘油三酯浓度更低，而低密度脂蛋白胆固醇（low-density lipoprotein cholesterol）水平更高。肝脏转录组分析显示，PD与PD.SHR4品系间存在差异表达基因网络，且该网络显著富集于昼夜节律通路（circadian rhythmicity pathway）相关基因（包括Arntl（Bmal1）、Clock、Nfil3、Per2及Per3）。综上，将携带缺陷型Cd36的SHR来源4号染色体区域导入PD遗传背景后，可导致代谢谱呈现非一致性改变，同时伴随肝脏转录组的显著变化。结合本研究结果与其他Cd36缺陷品系的相关研究结果可知，诸如SHR来源的Cd36缺陷这类有害突变，其最终的代谢效应并非绝对的，而是取决于其发挥作用的环境与基因组背景之间的复杂相互作用。