A decrease in dkk1, a Wnt inhibitor, contributes to placental and fetal lipid accumulation in an obesity-prone rat model

Placenta, as the sole transport mechanism between mother and fetus, links the maternal physical state and the immediate and life-long outcomes of the offspring. The present study examined the mechanisms behind the effect of maternal obesity on placental lipid accumulation and metabolism. Pregnant Obese Prone (OP) and Obese Resistant (OR) rat strains were fed a control diet throughout gestation. Placentas were collected on gestational d21 for analysis and frozen placental sections were analyzed for fat accumulation as well as β-Catenin and Dkk1 localization. Additionally, DKK1 was overexpressed in JEG3 trophoblast cells, followed by treatment with NEFA and Oil Red O stain quantification and mRNA analysis to determine the relationship between placental DKK1 and lipid accumulation. Maternal plasma and placental NEFA and TG were elevated in OP dams, and offspring of OP dams were smaller than OR. Placental Dkk1 mRNA content was 4-fold lower in OP placentas, and there was a significant increase in β-Catenin accumulation as well as mRNA content of fat transport and TG synthesis enzymes, including Ppar-delta, Fatp1, Fat/Cd36, Lipin1, and Lipin3. There was significant lipid accumulation within the decidual zones in OP but not OR placentas, and the thickness of the decidual and junctional zones was significantly smaller in OP than OR placentas. Overexpression of DKK1 in JEG3 cells decreased lipid accumulation and the mRNA content of PPAR-Delta, FATP1, FAT/CD36, LIPIN1, and LIPIN3. Our results indicate that Dkk1 may be regulating placental lipid metabolism through Wnt-mediated mechanisms. Additionally, recent studies have suggested that maternal obesity may also program early development of non-alcoholic fatty liver disease (NAFLD), rates of which have correlated with the increase in the obesity epidemic. In the current study, livers of OP offspring had significantly increased TG content (P<0.05) and lipid accumulation when compared to offspring of OR dams. Additionally, hepatic Dkk1 mRNA content was significantly decreased in OP livers when compared to OR (P<0.05), and treating H4IIECR rat hepatocyte cells with NEFA showed that Dkk1 mRNA was also decreased in NEFA-treated cells (P<0.05) that also had lipid accumulation. Chromatin Immunoprecipitation (ChIP) analysis of the Dkk1 promoter in fetal livers showed a pattern of histone modifications associated with decreased gene transcription in OP offspring, which agrees with our gene expression data. These results demonstrate that the hepatic Dkk1 gene is epigenetically regulated via histone modification in neonatal offspring in the current model of gestational obesity, and future studies will be needed to determine whether these changes contribute to excessive hepatic lipid accumulation in offspring of obese dams.

Post-shock thermochemistry in hypervelocity CO2 and air flow

This work represents ongoing efforts to study high-enthalpy carbon dioxide flows in anticipation of the upcoming Mars Science Laboratory (MSL) and future missions to the red planet. The work is motivated by observed anomalies between experimental and numerical studies in hypervelocity impulse facilities for high enthalpy carbon dioxide flows. In this work, experiments are conducted in the Hypervelocity Expansion Tube (HET) which, by virtue of its flow acceleration process, exhibits minimal freestream dissociation in comparison to reflected shock tunnels. This simplifies the comparison with computational result as freestream dissociation and considerable thermochemical excitation can be neglected. Shock shapes of the MSL aeroshell and spherical geometries are compared with numerical simulations incorporating detailed CO2 thermochemical modeling. The shock stand-off distance has been identified in the past as sensitive to the thermochemical state and as such, is used here as an experimental measurable for comparison with CFD and two different theoretical models. It is seen that models based upon binary scaling assumptions are not applicable for the low-density, small-scale conditions of the current work. Mars Science Laboratory shock shapes at zero angle of attack are also in good agreement with available data from the LENS X expansion tunnel facility, confi rming results are facility-independent for the same type of flow acceleration, and indicating that the flow velocity is a suitable first-order matching parameter for comparative testing. In an e ffort to address surface chemistry issues arising from high-enthalpy carbon dioxide ground-test based experiments, spherical stagnation point and aeroshell heat transfer distributions are also compared with simulation. Very good agreement between experiment and CFD is seen for all shock shapes and heat transfer distributions fall within the non-catalytic and super-catalytic solutions. We also examine spatial temperature profiles in the non-equilibrium relaxation region behind a stationary shock wave in a hypervelocity air Mach 7.42 freestream. The normal shock wave is established through a Mach reflection from an opposing wedge arrangement. Schlieren images confirm that the shock con guration is steady and the location is repeatable. Emission spectroscopy is used to identify dissociated species and to make vibrational temperature measurements using both the nitric oxide and the hydroxyl radical A-X band sequences. Temperature measurements are presented at selected locations behind the normal shock. LIFBASE is used as the simulation spectrum software for OH temperature-fitting, however the need to access higher vibrational and rotational levels for NO leads to the use of an in-house developed algorithm. For NO, results demonstrate the contribution of higher vibrational and rotational levels to the spectra at the conditions of this study. Very good agreement is achieved between the experimentally measured NO vibrational temperatures and calculations performed using an existing state-resolved, three-dimensional forced harmonic oscillator thermochemical model. The measured NO A-X vibrational temperatures are significantly higher than the OH A-X temperatures.