METHODS: We first assessed bone marrow hematopoietic stem and progenitor cell phenotype using postnatal day 21 (P21) and 8-week-old C57BL/6J mice born to control and diet-induced obese dams. We also sorted HSPC (Lineage-, Sca1+, cKit + cells) from P21 mice for competitive primary and secondary transplant, as well as transcriptomic analysis. Body weight, adiposity, insulin tolerance test and glucose tolerance tests were performed in primary and secondary transplant recipient animals.
RESULTS: We discovered sex-differences in offspring HSPC function in response to maternal obesity exposure, where male offspring of obese dams (MatOb) showed decreased HSPC numbers and engraftment, while female MatOb offspring remained largely unaffected. RNA-seq revealed immune stimulatory pathways in female MatOb offspring. Finally, only recipients of male MatOb offspring HSPC exhibited glucose intolerance.
CONCLUSIONS: This study demonstrated the lasting effect of maternal obesity exposure on offspring HSPC function and implicates HSPC in metabolic regulation.
方法:我们首先使用出生后第21天(P21)和8周龄的C57BL/6J小鼠评估骨髓造血干细胞和祖细胞表型。我们还对HSPC(线-,Sca1+,cKit+细胞)来自P21小鼠,用于竞争性初次和二次移植,以及转录组学分析。体重,肥胖,在初次和二次移植受体动物中进行胰岛素耐量试验和葡萄糖耐量试验.
结果:我们发现了后代HSPC功能对母亲肥胖暴露的反应的性别差异,肥胖水坝(MatOb)的雄性后代显示出减少的HSPC数量和植入,而雌性MatOb后代基本上未受影响。RNA-seq揭示了雌性MatOb后代的免疫刺激途径。最后,只有男性MatOb后代HSPC的接受者表现出葡萄糖耐受不良。
结论:这项研究证明了母亲肥胖暴露对后代HSPC功能的持久影响,并暗示HSPC参与了代谢调节。