Maternal high-fat diet alters lung development and function in the offspring.

The effects of maternal obesity on lung development have been recognized, and speculation is that these diseases are not simply because of accelerated pulmonary decline with aging but with a failure to achieve optimal lung development during early life. These studies tested the hypothesis that maternal obesity alters signaling pathways during the course of lung development that may affect life-long pulmonary health. Adult female mice were fed 60% fat [high-fat diet (HFD)] or 10% fat [control diet (CD)] for 8 wk before mating and through weaning. Pup lung tissues were collected at postnatal days (PN) 7, 21, and 90 (after receiving HFD or CD as adults). At PN7, body weights from HFD were greater than CD but lung weight-to-body weight ratios were lower. In lung tissues, NFκB-mediated inflammation was greater in HFD pups at PN21 and phospho-/total STAT3, phospho-/total VEGF receptor 2, and total AKT protein levels were lower with maternal HFD and protein tyrosine phosphatase B1 levels were increased. Decreased platelet endothelial cell adhesion molecule levels were observed at PN21 and at PN90 in the pups exposed to maternal HFD. Morphometry indicated that the pups exposed to maternal or adult HFD had fewer alveoli, and the effect was additive. Decreases in pulmonary resistance, elastance, and compliance were observed because of adult HFD diet and decreases in airway resistance and increases in inspiratory capacity because of maternal HFD. In conclusion, maternal HFD disrupts signaling pathways in the early developing lung and may contribute to deficiencies in lung function and increased susceptibility in adults.

Maternal high fat diet exposure is associated with increased hepcidin levels, decreased myelination, and neurobehavioral changes in male offspring.

Maternal obesity induces chronic inflammatory responses that impact the fetus/neonate during the perinatal period. Inflammation, iron regulation, and myelination are closely interconnected and disruptions in these processes may have deleterious effects on neurodevelopment. Hepcidin levels are increased in response to inflammation causing subsequent decreases in ferroportin and available iron needed for myelination. Our current studies were designed to test the hypotheses that: 1) maternal high fat diet (HFD) prior to and during pregnancy is sufficient to induce inflammation and alter iron regulation in the brain of the offspring, and 2) HFD exposure is associated with altered myelination and neurobehavioral deficits in the offspring. Our data revealed modest increases in inflammatory cytokines in the serum of dams fed HFD prior to pregnancy compared to dams fed a control diet (CD). Early increases in IL-5 and decreases in IL-10 were observed in serum at PN7 while IL-5 remained elevated at PN21 in the HFD-exposed pups. At PN0, most cytokine levels in whole brain homogenates were higher in the pups born to HFD-fed dams but were not different or were lower than in pups born to CD-fed dams at PN21. Conversely, the inflammation mediated transcription factor Nurr77 remained elevated at PN21. At birth, brain hepcidin, ferroportin, and l-ferritin levels were elevated in pups born to HFD-fed dams compared to pups born to CD-fed dams. Hepcidin levels remained elevated at PN7 and PN21 while ferroportin and l-ferritin levels were lower at PN7 and were not different at PN21. Decreases in myelination in the medial cortex were observed in male but not in female pups born to maternal HFD-fed dams at PN21. These structural changes correlated with changes in behavior (novel object recognition) in at 4months in males only. Our data indicate that maternal obesity (HFD) results in disruption of iron regulation in the brains of the offspring with structural and neurobehavioral deficits in males.

Nurr1 expression is modified by inflammation in microglia.

Advances in neonatal care have allowed premature infants to survive at earlier gestational ages, but they are often afflicted with neurological delays or deficits. Maternal inflammation has been identified as a major risk factor for premature birth and once born, infants often require supplemental oxygen for survival. Nurr1 (NR4A2) is an orphan nuclear receptor with no known binding site and is essential for the growth of midbrain dopamine neurons. Others have reported that Nurr1 can act as an anti-inflammatory transcription factor in microglia and astrocytes and respond lipopolysaccharide (LPS). We have previously reported decreased numbers of oligodendrocytes and increased numbers of microglia in the mice exposed to both maternal inflammation and neonatal hyperoxia in the perinatal period. These studies tested the hypothesis that the combined exposures to inflammation and hyperoxia would increase Nurr1 expression in microglia in our mouse model and in an immortalized microglia cell line, BV2 cells. Our data indicate that Nurr1 protein expression is increased at postnatal day 0 and postnatal day 28 in whole-brain homogenates from mice exposed to LPS and hyperoxia. Alternatively, Nurr1 message is decreased at postnatal day 60 in isolated microglia, indicating that the increases in whole-brain homogenates may be due to other cell types. In BV2 cells, Nurr1 message in increased by exposure to hyperoxia, but this increase is attenuated in cells exposed to both LPS and hyperoxia. Although Nurr1 regulation is not straightforward, these data indicate that Nurr1 expression is increased in whole-brain homogenates in response to inflammation, but is decreased in isolated primary microglia and BV2 cells in response to similar inflammation. Our data support the hypothesis that Nurr1 expression may play a significant role in regulating inflammation in the brain and understanding the complex regulation of Nurr1 could lead to new therapeutic strategies.

Enhanced Steatosis and Fibrosis in Liver of Adult Offspring Exposed to Maternal High-Fat Diet.

Early life exposures can increase the risk of developing chronic diseases including nonalcoholic fatty liver disease. Maternal high-fat diet increases susceptibility to development of steatosis in the offspring. We determined the effect of maternal high-fat diet exposure in utero and during lactation on offspring liver histopathology, particularly fibrosis. Female C57Bl/6J mice were fed a control or high-fat diet (HFD) for 8 weeks and bred with lean males. Nursing dams were continued on the same diet with offspring sacrificed during the perinatal period or maintained on either control or high-fat diet for 12 weeks. Increased hepatocyte proliferation and stellate cell activation were observed in the liver of HFD-exposed pups. Offspring exposed to perinatal high-fat diet and high-fat diet postweaning showed extensive hepatosteatosis compared to offspring on high-fat diet after perinatal control diet. Offspring exposed to perinatal high-fat diet and then placed on control diet for 12 weeks developed steatosis and pericellular fibrosis. Importantly, we found that exposure to perinatal high-fat diet unexpectedly promotes more rapid disease progression of nonalcoholic fatty liver disease, with a sustained fibrotic phenotype, only in adult offspring fed a postweaning control diet.

Perinatal inflammation results in decreased oligodendrocyte numbers in adulthood.

AIMS: Maternal inflammation is a risk factor for preterm birth, and premature infants are often exposed to supplemental oxygen as a life-sustaining therapy. While more immature neonates are surviving, rates of neurodevelopmental impairment are not improving. We developed a novel mouse model with clinically relevant exposures to test the hypothesis that systemic maternal inflammation with transient neonatal hyperoxia exposure will induce a phenotype similar to diffuse periventricular leukomalacia (PVL) like that observed in premature human infants. MAIN METHODS: Timed-pregnant C3H/HeN mice received intraperitoneal injections of lipopolysaccharide (LPS) or saline on embryonic day 16. Newborn pups were placed in room air (RA) or 85% oxygen (O2) for 14 days, followed by 14 days in RA recovery. Oligodendroglial and microglial populations were evaluated at 14 and 28 days. KEY FINDINGS: Brain weight to body weight ratios were lower in mice exposed to LPS. Oligodendrocyte numbers were decreased significantly in the cerebral cortex and hippocampus in groups exposed to LPS or LPS/O2 at 14 days, and persisted in the cerebral cortex at 28 days for LPS/O2 mice. At day 14, cleaved caspase 3 was increased and numbers of microglia were elevated in the cerebral cortex and hippocampus of LPS/O2 animals. SIGNIFICANCE: These data indicate that combining systemic maternal LPS and neonatal hyperoxic exposure impairs myelination, and suggests that this novel mouse model may represent a subtle, diffuse form of periventricular white matter injury that could provide a clinically relevant platform for further study of perinatal brain injury.

Associations between maternal and infant morbidities and sRAGE within the first week of life in extremely preterm infants.

BACKGROUND: Soluble RAGE (sRAGE) has been associated with multiple inflammatory responses including maternal chorioamnionitis and preeclampsia. Analysis of umbilical cord blood levels have also indicated that sRAGE levels in the infant are affected by maternal inflammation. S100b is a ligand for RAGE and increases in circulating S100b levels are associated with poor neurological outcome in preterm infants. The objective of this study was to determine whether sRAGE or s100b levels in plasma samples from extremely preterm infants at the end of the first week of life were correlated with infant morbidities and whether sRAGE and s100b levels at this time point were still associated with maternal inflammation. METHODS: Plasma samples were collected from 130 preterm infants (≤28 weeks) at days of life 5, 6, or 7. sRAGE and s100b levels were measured by ELISA and data were analyzed by Pearson's correlation or Generalized Estimating Equations. RESULTS: sRAGE was negatively correlated with development of sepsis (p=0.024), the FiO2 requirement of the infant at the time of sampling (p=0.030), as well as maternal preeclampsia (p=0.046), and positively correlated with maternal chorioamnionitis (p=0.006). s100b levels were positively associated with maternal chorioamnionitis (p=0.039). No correlations were observed with other infant morbidities. CONCLUSION: These data indicate that sRAGE could potentially be a biomarker of early severe inflammatory responses in the preterm infant. However, more studies are needed to confirm the present findings.