Objective: 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 . 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.
Methods: Here we use null alleles to induce obesity in the parental generation and then score both metabolic parameters and genome-wide transcriptional responses in heterozygote F1 progeny and genetically wild-type F2 progeny.
Results: Unexpectedly, we observe elevated glycogen levels and changes in gene expression in heterozygotes due to haploinsufficiency at this locus. We also show that genetic manipulation of parental metabolism using mutations results in significant physiological changes in F2 wild-type offspring of the grandpaternal/maternal lineage.
Conclusions: Our results demonstrate that genetic manipulation of parental metabolism in 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.
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| http://dx.doi.org/10.1016/j.molmet.2017.03.012 | DOI Listing |
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