Paternal obesity predisposes offspring to metabolic dysfunction, but the underlying mechanisms remain unclear. We investigated whether this metabolic dysfunction is associated with changes in placental vascular development and is fueled by endoplasmic reticulum (ER) stress-mediated changes in fetal hepatic development. We also determined whether paternal obesity indirectly affects the in utero environment by disrupting maternal metabolic adaptations to pregnancy. Male mice fed a standard chow or high fat diet (60%kcal fat) for 8–10 weeks were time-mated with female mice to generate pregnancies and offspring. Glucose tolerance was evaluated in dams at mid-gestation (embryonic day (E) 14.5) and late gestation (E18.5). Hypoxia, angiogenesis, endocrine function, macronutrient transport, and ER stress markers were evaluated in E14.5 and E18.5 placentae and/or fetal livers. Maternal glucose tolerance was assessed at E14.5 and E18.5. Metabolic parameters were assessed in offspring at ~60 days of age. Paternal obesity did not alter maternal glucose tolerance but induced placental hypoxia and altered placental angiogenic markers, with the most pronounced effects in female placentae. Paternal obesity increased ER stress-related protein levels (ATF6 and PERK) in the fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Offspring of obese fathers were glucose intolerant and had impaired whole-body energy metabolism, with more pronounced effects in female offspring. Metabolic deficits in offspring due to paternal obesity may be mediated by sex-specific changes in placental vessel structure and integrity that contribute to placental hypoxia and may lead to poor fetal oxygenation and impairments in fetal metabolic signaling pathways in the liver.

Paternal obesity predisposes offspring to metabolic dysfunction, but the underlying mechanisms remain unclear. We investigated whether paternal obesity-induced offspring metabolic dysfunction is associated with placental endoplasmic reticulum (ER) stress and impaired vascular development. We determined whether offspring glucose intolerance is fueled by ER stress-mediated changes in fetal hepatic development. Furthermore, we also determined whether paternal obesity may indirectly affect in utero development by disrupting maternal metabolic adaptations to pregnancy. Male mice fed a standard chow diet (CON; 17% kcal fat) or high fat diet (PHF; 60% kcal fat) for 8-10 weeks were time-mated with control female mice to generate pregnancies and offspring. Glucose tolerance in pregnant females was evaluated at mid-gestation (embryonic day (E) 14.5) and term gestation (E18.5). At E14.5 and E18.5, fetal liver and placentae were collected, and markers of hypoxia, angiogenesis, endocrine function, and macronutrient transport, and unfolded protein response (UPR) regulators were evaluated to assess ER stress. Young adult offspring glucose tolerance and metabolic parameters were assessed at ~60 days of age. Paternal obesity did not alter maternal glucose tolerance or placental lactogen in pregnancy but did induce placental hypoxia, ER stress, and altered placental angiogenesis. This effect was most pronounced in placentae associated with female fetuses. Consistent with this, paternal obesity also activated the ATF6 and PERK branches of the UPR in fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Adult offspring of obese fathers showed glucose intolerance and impaired whole-body energy metabolism, particularly in female offspring. Thus, paternal obesity programs sex-specific adverse placental structural and functional adaptations and alters fetal hepatic development via ER stress-induced pathways. These changes likely underpin metabolic deficits in adult offspring.

It is clear that the gastrointestinal tract influences metabolism and immune function. Most studies to date have used male test subjects, with a focus on effects of obesity and dietary challenges. Despite significant physiological adaptations that occur across gestation, relatively few studies have examined pregnancy-related gut function. In this study, we investigated the impacts of pregnancy and maternal adiposity on the structure of the maternal intestinal epithelium and in vivo intestinal permeability, as well as peripheral blood immunophenotype, using cohorts of control (CTL) and high fat (HF) fed non-pregnant female mice and pregnant mice at mid- (embryonic day (E)14.5) and late (E18.5) gestation. We found that small intestine length increased between non-pregnant mice and dams at late-gestation, but ileum villus length, and ileum and colon crypt depths and goblet cell numbers remained similar. Compared to CTL-fed mice, HF diet reduced small intestine length, as well as ileum crypt depth and villus length, in both non-pregnant and pregnant mice. Goblet cell numbers were only consistently reduced in HF-fed non-pregnant mice. Pregnancy increased in vivo gut permeability, with a greater effect at mid- versus late-gestation. Non-pregnant HF-fed mice had greater gut permeability, and permeability was also increased in HF-fed pregnant dams at mid- but not late-gestation. The loss of maternal gut barrier in HF-fed dams at mid-gestation coincided with changes in maternal blood and bone marrow immune cell composition, including an expansion of circulating inflammatory Ly6Chigh monocytes. In summary, pregnancy has temporal effects on maternal intestinal structure and barrier function, and on peripheral immunophenotype, which are further modified by HF diet-induced maternal adiposity. These data highlight the importance of considering pregnancy as a factor in intestinal modifications and the potential for pregnancy and diet to interact on modifying maternal gut function. Impairments in maternal intestinal and immune adaptations to pregnancy will have long term consequences in the offspring.