Molecular, Structural and Computational Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
St Vincents Clinical School, Faculty of Medicine, University of New South Wales, Kensington, New South Wales, Australia.
Int J Obes (Lond). 2018 Apr;42(4):911-914. doi: 10.1038/ijo.2017.247. Epub 2017 Oct 6.
Maternal obesity can program offspring metabolism across multiple generations. It is not known whether multigenerational effects reflect true inheritance of the induced phenotype, or are due to serial propagation of the phenotype through repeated exposure to a compromised gestational milieu. Here we sought to distinguish these possibilities, using the A mouse model of maternal obesity. In this model, F1 sons of obese dams display a predisposition to hepatic insulin resistance, which remains latent unless the offspring are challenged with a Western diet. We find that F2 grandsons and F3 great grandsons of obese dams also carry the latent predisposition to metabolic dysfunction, but remain metabolically normal on a healthy diet. Given that the breeding animals giving rise to F2 and F3 were maintained on a healthy diet, the latency of the phenotype permits exclusion of serial programming; we also confirmed that F1 females remained metabolically healthy during pregnancy. Molecular analyses of male descendants identified upregulation of hepatic Apoa4 as a consistent signature of the latent phenotype across all generations. Our results exclude serial programming as a factor in transmission of the metabolic phenotype induced by ancestral maternal obesity, and indicate inheritance through the germline, probably via some form of epigenetic inheritance.
母体肥胖会在多代中影响后代的新陈代谢。目前尚不清楚这种多代效应是反映所诱导表型的真正遗传，还是由于在反复接触受损的妊娠环境下通过表型的连续传播所致。在这里，我们使用 A 鼠肥胖母鼠模型来试图区分这些可能性。在该模型中，肥胖母鼠的 F1 雄性后代表现出肝脏胰岛素抵抗的倾向，如果不给它们喂食西式饮食，这种倾向就会一直处于潜伏状态。我们发现，肥胖母鼠的 F2 孙代和 F3 曾孙代也携带代谢功能障碍的潜伏倾向，但在健康饮食下仍保持代谢正常。鉴于产生 F2 和 F3 的繁殖动物一直维持在健康饮食，该表型的潜伏性排除了连续编程的可能性；我们还证实，F1 雌性在怀孕期间仍保持代谢健康。对雄性后代的分子分析表明，Apoa4 肝上调是所有代中潜伏表型的一致特征。我们的结果排除了连续编程作为祖先母体肥胖所诱导代谢表型传递的一个因素，并表明通过生殖系遗传，可能通过某种形式的表观遗传遗传。
