目的:母亲肥胖越来越普遍,并对后代健康产生负面影响。肥胖母亲的孩子患造血系统异常和代谢相关疾病的风险更高,如2型糖尿病。有趣的是,疾病风险通常取决于后代的性别,提示母亲肥胖对后代造血干细胞和祖细胞(HSPC)功能的性别特异性重编程作用。然而,母亲肥胖暴露对后代HSPC功能的影响,HSPC调节后代代谢健康的能力在很大程度上被研究不足。本研究旨在验证肥胖小鼠的后代在HSPC功能上表现出性别差异,从而影响后代的代谢健康这一假设。
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。
OBJECTIVE: Maternal obesity is increasingly common and negatively impacts offspring health. Children of mothers with obesity are at higher risk of developing diseases linked to hematopoietic system abnormalitiesand metabolism such as type 2 diabetes. Interestingly, disease risks are often dependent on the offspring\'s sex, suggesting sex-specific reprogramming effect of maternal obesity on offspring hematopoietic stem and progenitor cell (HSPC) function. However, the impact of maternal obesity exposure on offspring HSPC function, and the capability of HSPC to regulate offspring metabolic health is largely understudied. This study aims to test the hypothesis that offspring of obese mice exhibit sex-differences in HSPC function that affect offspring\'s metabolic health.
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.