Abstract
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 Avy 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.
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Acknowledgements
JEC is supported by an Australian Research Council DECRA (DE120100723). CMS was supported by an Australian Research Council Future Fellowship (FT120100097). This study was supported in part by a Diabetes Australia Research Trust grant-in-aid.
Author contributions
SAE designed and performed experiments, analysed data and drafted the manuscript. AJA performed experiments. PEY performed experiments and analysed data. JWKH analysed data. JEC conceived and designed experiments, analysed and interpreted data and drafted the manuscript. CMS conceived and designed experiments, interpreted data and drafted the manuscript. All authors critically revised the paper and approved the final version.
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Supplementary Information accompanies this paper on International Journal of Obesity website
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Eaton, S., Aiken, A., Young, P. et al. Maternal obesity heritably perturbs offspring metabolism for three generations without serial programming. Int J Obes 42, 911–914 (2018). https://doi.org/10.1038/ijo.2017.247
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DOI: https://doi.org/10.1038/ijo.2017.247