Maternal obesity heritably perturbs offspring metabolism for three generations without serial programming
Maternal obesity heritably perturbs offspring metabolism for three generations without serial programming
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DOI：
10.1038/ijo.2017.247
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发表时间：
2018-04-01
影响因子：
4.9
通讯作者：
Suter, C. M.
中科院分区：
文献类型：
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作者：
Eaton, S. A.;Aiken, A. J.;Suter, C. M.
母亲肥胖可以在多代人中规划后代代谢。目前尚不清楚多代效应是否反映了诱导表型的真正遗传，或者是由于通过反复暴露于受损的妊娠环境而导致表型的连续繁殖。在这里，我们试图区分这些可能性，使用母体肥胖的A（vy）小鼠模型。在该模型中，肥胖母鼠的F1子代显示出对肝胰岛素抵抗的易感性，其保持潜伏，除非后代用西方饮食进行挑战。我们发现肥胖母鼠的F2孙子和F3曾孙也具有代谢功能障碍的潜在倾向，但在健康饮食下保持代谢正常。考虑到产生F2和F3的育种动物保持健康饮食，表型的潜伏期允许排除连续编程;我们还证实F1雌性在妊娠期间保持代谢健康。对雄性后代的分子分析确定了肝脏Apoa 4的上调是所有世代中潜伏表型的一致特征。我们的研究结果排除了串行编程作为一个因素，在传输的代谢表型诱导的祖先母亲肥胖，并表明通过种系遗传，可能通过某种形式的表观遗传。
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(vy) mouse model of maternal obesity. In this model, Fl 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 programing; we also confirmed that Fl 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.