Maternal obesity heritably perturbs offspring metabolism for three generations without serial programming.

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.

Maternal undernutrition during the first week after conception results in decreased expression of glucocorticoid receptor mRNA in the absence of GR exon 17 hypermethylation in the fetal pituitary in late gestation.

Exposure to maternal undernutrition during the periconceptional period results in an earlier prepartum activation of the fetal hypothalamo-pituitary-adrenal (HPA) axis and altered stress responsiveness in the offspring. It is not known whether such changes are a consequence of exposure of the oocyte and/or the early embryo to maternal undernutrition in the periconceptional period. We have compared the effects of 'periconceptional' undernutrition (PCUN: maternal undernutrition imposed from at least 45 days before until 6 days after conception), and 'early preimplantation' undernutrition (PIUN: maternal undernutrition imposed for only 6 days after conception) on the expression of genes in the fetal anterior pituitary that regulate adrenal growth and steroidogenesis, proopiomelanorcortin (POMC), prohormone convertase 1 (PC1), 11ß-hydroxysteroid dehydrogenase type 1 and 2 (11ßHSD1 and 2) and the glucocorticoid receptor (GR) in fetal sheep at 136-138 days of gestation. Pituitary GR mRNA expression was significantly lower in the PCUN and PIUN groups in both singletons and twins compared with controls, although this suppression of GR expression was not associated with hypermethylation of the exon 17 region of the GR gene. In twin fetuses, the pituitary 11ßHSD1 mRNA expression was significantly higher in the PIUN group compared with the PCUN but not the control group. Thus, exposure of the single or twin embryo to maternal undernutrition for only 1 week after conception is sufficient to cause a suppression of the pituitary GR expression in late gestation. These changes may contribute to the increased stress responsiveness of the HPA axis in the offspring after exposure to poor nutrition during the periconceptional period.