Parental obesity leads to metabolic changes in the F2 generation in Drosophila.
Parental obesity leads to metabolic changes in the F2 generation in Drosophila.
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DOI：
10.1016/j.molmet.2017.03.012
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发表时间：
2017-07
影响因子：
8.1
通讯作者：
Thummel CS
中科院分区：
文献类型：
--
作者：
Palu RAS;Praggastis SA;Thummel CS
复杂代谢紊乱的遗传风险的很大一部分不能归因于经典的孟德尔遗传因素。这种缺失的遗传性中至少有一部分被认为是由于父母和祖父母的代谢状态对后代健康的表观遗传影响。以前的工作表明，这种跨代现象在果蝇中是进化保守的。然而，这些研究都依赖于饮食模式来改变父母的代谢状态，这可能对后代的代谢产生不一致的遗传效应。在这里，我们使用AKHR无效等位基因诱导父母一代肥胖，然后在AKHR杂合子F1后代和遗传野生型F2后代中对代谢参数和全基因组转录反应进行评分。出乎意料的是，我们观察到升高的糖原水平和AKHR杂合子的基因表达的变化，由于在这个位点的单倍不足。我们还表明，使用AKHR突变的亲本代谢的遗传操作导致显着的生理变化，在F2野生型后代的祖父/母亲的血统。我们的研究结果表明，果蝇亲本代谢的遗传操作可以对F2子代的健康产生影响，提供了一个非饮食范式，以更好地了解代谢状态的跨代遗传背后的机制。AKHR的单倍不足影响代谢物水平和基因表达。父母代谢的遗传改变导致对后代的遗传影响父母肥胖选择性地影响祖父母/母亲谱系。
A significant portion of the heritable risk for complex metabolic disorders cannot be attributed to classic Mendelian genetic factors. At least some of this missing heritability is thought to be due to the epigenetic influence of parental and grandparental metabolic state on offspring health. Previous work suggests that this transgenerational phenomenon is evolutionarily conserved in Drosophila. These studies, however, have all depended on dietary paradigms to alter parental metabolic state, which can have inconsistent heritable effects on the metabolism of offspring. Here we use AKHR null alleles to induce obesity in the parental generation and then score both metabolic parameters and genome-wide transcriptional responses in AKHR heterozygote F1 progeny and genetically wild-type F2 progeny. Unexpectedly, we observe elevated glycogen levels and changes in gene expression in AKHR heterozygotes due to haploinsufficiency at this locus. We also show that genetic manipulation of parental metabolism using AKHR mutations results in significant physiological changes in F2 wild-type offspring of the grandpaternal/maternal lineage. Our results demonstrate that genetic manipulation of parental metabolism in Drosophila can have an effect on the health of F2 progeny, providing a non-dietary paradigm to better understand the mechanisms behind the transgenerational inheritance of metabolic state. Haploinsufficiency for AKHR affects metabolite levels and gene expression. Genetic alteration of parental metabolism leads to heritable effects on offspring Parental obesity selectively affects the grandpaternal/maternal lineage.