Paternal High-Fat Diet Altered Sperm 5'tsRNA-Gly-GCC Is Associated With Enhanced Gluconeogenesis in the Offspring.
Paternal High-Fat Diet Altered Sperm 5'tsRNA-Gly-GCC Is Associated With Enhanced Gluconeogenesis in the Offspring.
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DOI：
10.3389/fmolb.2022.857875
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发表时间：
2022
影响因子：
5
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中科院分区：
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背景：父亲的生活方式、压力和环境暴露对后代的健康起着至关重要的作用，并与后天性状的非遗传性相关，但其潜在机制尚不清楚。本研究旨在探究参与父本高脂饮食的精子tsRNA如何诱导F1代后代糖异生异常，并探讨其调控的潜在分子机制。 方法：我们建立了父亲高脂肪饮食（42% kcal 脂肪）模型，以研究父亲饮食影响后代代谢的机制。 4 周大的 C57BL/6J 雄性小鼠被随机分为两组，接受对照饮食（CD；10% kcal 脂肪）或高脂肪（HFD；42% kcal 脂肪）饮食，为期 10 周，然后将每组小鼠与 8 周龄的对照饮食雌性小鼠以 1:2 的比例交配，产生 F1。分离 F0 精子并通过高通量测序对小 RNA 进行测序。使用 F0 和 F1 检查代谢表型。 结果：与同龄 CD 小鼠相比，8 周龄时 HFD-F0 小鼠的体重显着增加。 F0 小鼠在 14 周时表现出葡萄糖耐量受损 (GTT)、胰岛素耐量抵抗 (ITT) 和丙酮酸耐量增加 (PTT)。 HFD-F1雄性小鼠的体重没有显着差异。 13 周龄时发现 PTT 有所增加，而 GTT 和 ITT 没有显着变化。 HFD-F1雄性小鼠肝脏中与糖异生相关的PEPCK和G6Pase显着增加。精子测序结果显示，源自 tRNA-Gly-GCC-2 的 5'tsRNA-Gly-GCC 在 HFD F0 小鼠精子中特异性显着上调。 Q-PCR 进一步表明，与 CD-F1 小鼠相比，HFD-F1 小鼠的肝脏中这种 tsRNA 也有所增加。此外，我们发现5'tsRNA-Gly-GCC可以调节Sirt6-FoxO1通路并参与肝脏的糖异生通路。 结论：HFD小鼠成熟精子中增加的5′tsRNA-Gly-GCC可以通过调节Sirt6-FoxO1通路促进肝脏糖异生，这可能是介导饮食诱导代谢改变代际遗传的潜在父系表观遗传因素。
Background: Paternal lifestyle, stress and environmental exposures play a crucial role in the health of offspring and are associated with non-genetic inheritance of acquired traits, however the underlying mechanisms are unclear. In this study, we aimed to find out how the sperm tsRNA involved in paternal high-fat diet induced abnormal gluconeogenesis of F1 offspring, and explore the underlying molecular mechanism of its regulation. Method: We generated a paternal high fat diet (42% kcal fat) model to investigate the mechanism by which paternal diet affects offspring metabolism. Four-week-old C57BL/6J male mice were randomly assigned into two groups to receive either a control diet (CD; 10% kcal fat) or a high-fat (HFD; 42% kcal fat) diet for 10 weeks, and mice from each group were then mated with 8-week-old females with control diet in a 1:2 ratio to generate F1. F0 sperms were isolated and small RNAs was sequenced by high-throughput sequencing. Metabolic phenotypes were examined with both F0 and F1. Results: A significant increase in body weight was observed with HFD-F0 mice at 8 weeks of age as compared to CD mice at the same age. F0 mice showed impaired glucose tolerance (GTT), resistance to insulin tolerance (ITT) and increased pyruvate tolerance (PTT) at 14 weeks. HFD-F1 male mice showed no significant difference in body weight. An increase in PTT was found at 13 weeks of age and no significant changes in GTT and ITT. PEPCK and G6Pase that related to gluconeogenesis increased significantly in the liver of HFD-F1 male mice. Sperm sequencing results showed that 5′tsRNA-Gly-GCC derived from tRNA-Gly-GCC-2 specifically was remarkably upregulated in sperm of HFD F0 mice. Q-PCR further showed that this tsRNA was also increased in the liver of HFD-F1 comparison with CD-F1 mice. In addition, we found that 5′tsRNA-Gly-GCC can regulate Sirt6-FoxO1 pathway and be involved in the gluconeogenesis pathway in liver. Conclusion: 5′tsRNA-Gly-GCC that increased in HFD mice mature sperms can promote gluconeogenesis in liver by regulating Sirt6-FoxO1 pathway, which might represent a potential paternal epigenetic factor mediating the intergenerational inheritance of diet-induced metabolic alteration.