Maternal High-Fat Diet Effects on Third-Generation Female Body Size via the Paternal Lineage

The health consequences of in utero exposure to maternal obesity on future generations are concerning because they contribute to increased rates of diabetes, cardiovascular disease, and metabolic syndrome. We previously reported that maternal high-fat diet exposure in mice resulted in an increase in body size and reduced insulin sensitivity that persisted across two generations via both maternal and paternal lineages. However, because the first generation's primordial germ cells may be affected by gestational exposure, analysis of phenotype transmission into a third generation (F3) is necessary to determine whether stable epigenetic programming has occurred. Therefore, we have examined the body size and insulin sensitivity of male and female F3 offspring. We found that only females displayed the increased body size phenotype, and this effect was only passed on via the paternal lineage. The finding of a paternally transmitted phenotype to F3 female offspring supports a stable germline-based transgenerational mode of inheritance; thus we hypothesized that imprinted genes may be involved in this epigenetic programming. Using a quantitative TaqMan Array for imprinted genes to examine paternally or maternally expressed loci in F3 female livers, we detected a potential dynamic pattern of paternally expressed genes from the paternal lineage that was not noted in the maternal lineage. These findings suggest that the environmental influence on developmental regulation of growth and body size may be the result of broad programming events at imprinted loci, thereby providing sex specificity to both the transmission and inheritance of traits related to disease predisposition. (Endocrinology 152: 2228-2236, 2011)