Similar Datasets
Project description:The liver is a major site for synthesis, storage and redistribution of carbohydrates, proteins and lipids. In addition, it is well-known that maternal obesity (MO) increases risk of offspring cardiovascular disease (CVD), diabetes and obesity. However, the mechanisms by which the MO intrauterine environment predisposes offspring to CVD and metabolic dysregulation are unknown. The goal of this study was to assess the impact of MO on primate fetal liver and identify underlying molecular mechanisms by which MO increases disease risk. The goal of this study was to identify candidate molecular mechanisms underlying MO in the near-term non-human primate (NHP) fetal liver. This is the first study of NHP fetal MO livers using unbiased transcriptome analysis to quantify hepatic gene expression, identify dysregulated signaling pathways and potential miRNAs regulating the disrupted metabolic processes. Unbiased gene (arrays) and microRNA (miRNA; small RNA-Seq) abundances were quantified in near-term (0.9 Gestation (0.9G)) baboon fetal livers (control (CON) = 6; MO = 5) and subjected to pathway and network analyses (GeneSifter, Ingenuity® Pathway Analysis (IPA)) to identify a coordinated molecular response to MO. Lipid and glycogen content (CON = 16; MO = 16) were quantified by Computer Assisted Stereology Toolbox (CAST) in 0.9G livers. Pairwise comparisons showed 933 differentially expressed genes between CON and MO livers: 350 genes were upregulated and 583 were downregulated. Pathway analysis revealed upregulation of Wnt/β-catenin signaling and downregulation of tricarboxylic acid (TCA) cycle, proteasome, oxidative phosphorylation and glycolysis pathways in MO fetal livers compared with CON. Inversely expressed miRNAs that target genes in these pathways provide additional support for the importance of these pathways in fetal liver metabolic regulation. Consistent with the observed pathway changes in MO, we found hepatic lipid content was threefold greater in MO than CON fetal livers (p=0.02). Molecular genetic analyses of CON and MO fetal baboon livers revealed dysregulation of Wnt/β-catenin signaling, TCA cycle, proteasome, oxidative phosphorylation and glycolysis pathways in MO livers, all of which are central to fatty acid metabolism and lipid storage. The marked lipid accumulation in MO fetal livers supports our hypothesis that dysregulation of these pathways detrimentally impacts lipid management. Furthermore, our findings demonstrate the detrimental impact of MO on fetal liver development and suggest impaired hepatic function prior to birth.
2018-12-26 | GSE97554 | GEO
Project description:The liver is a major site for synthesis, storage and redistribution of carbohydrates, proteins and lipids. In addition, it is well-known that maternal obesity (MO) increases risk of offspring cardiovascular disease (CVD), diabetes and obesity. However, the mechanisms by which the MO intrauterine environment predisposes offspring to CVD and metabolic dysregulation are unknown. The goal of this study was to assess the impact of MO on primate fetal liver and identify underlying molecular mechanisms by which MO increases disease risk. The goal of this study was to identify candidate molecular mechanisms underlying MO in the near-term NHP fetal liver. This is the first study of NHP fetal MO livers using unbiased transcriptome analysis to quantify hepatic gene expression, identify dysregulated signaling pathways and potential miRNAs regulating the disrupted metabolic processes. Unbiased gene (arrays) and microRNA (miRNA; small RNA-Seq) abundances were quantified in near-term (0.9 Gestation (0.9G)) baboon fetal livers (control (CON) = 6; MO = 5) and subjected to pathway and network analyses (GeneSifter, Ingenuity® Pathway Analysis (IPA)) to identify a coordinated molecular response to MO. Lipid and glycogen content (CON = 16; MO = 16) were quantified by Computer Assisted Stereology Toolbox (CAST) in 0.9G livers.Pairwise comparisons showed 933 differentially expressed genes between CON and MO livers: 350 genes were upregulated and 583 were downregulated. Pathway analysis revealed upregulation of Wnt/β-catenin signaling and downregulation of tricarboxylic acid (TCA) cycle, proteasome, oxidative phosphorylation and glycolysis pathways in MO fetal livers compared with CON. Inversely expressed miRNAs that target genes in these pathways provide additional support for the importance of these pathways in fetal liver metabolic regulation. Consistent with the observed pathway changes in MO, we found hepatic lipid content was threefold greater in MO than CON fetal livers (p=0.02). Molecular genetic analyses of CON and MO fetal baboon livers revealed dysregulation of Wnt/β-catenin signaling, TCA cycle, proteasome, oxidative phosphorylation and glycolysis pathways in MO livers, all of which are central to fatty acid metabolism and lipid storage. The marked lipid accumulation in MO fetal livers supports our hypothesis that dysregulation of these pathways detrimentally impacts lipid management. Furthermore, our findings demonstrate the detrimental impact of MO on fetal liver development and suggest impaired hepatic function prior to birth.
2018-12-26 | GSE99717 | GEO
Project description:Primate fetal hepatic response to maternal obesity: epigenetic signaling pathways and lipid accumulation
| PRJNA389405 | ENA
Project description:Background:Maternal obesity and maternal overnutrition, can lead to epigenetic alterations during pregnancy and these alterations can influence fetal and neonatal phenotype which increase the risk of metabolic disorders in later stages of life. Objective:The effects of maternal obesity on fetal programming and potential mechanisms of maternal epigenetic regulation of gene expression which have persistent effects on fetal health and development were investigated. Methods:Review of the literature was carried out in order to discuss the effects of maternal obesity and epigenetic mechanisms in fetal programming of metabolic disorders. All abstracts and full-text articles were examined and the most relevant articles were included in this review. Results:Maternal obesity and maternal overnutrition during fetal period has important overall effects on long-term health. Maternal metabolic alterations during early stages of fetal development can lead to permanent changes in organ structures, cell numbers and metabolism. Epigenetic modifications (DNA methylation, histone modifications, microRNAs) play an important role in disease susceptibility in the later stages of human life. Maternal nutrition alter expression of hypothalamic genes which can increase fetal and neonatal energy intake. Epigenetic modifications may affect the increasing rate of obesity and other metabolic disorders worldwide since the impact of these changes can be passed through generations. Conclusion:Weight management before and during pregnancy, together with healthy nutritional intakes may improve the maternal metabolic environment, which can reduce the risks of fetal programming of metabolic diseases. Further evidence from long-term follow-up studies are needed in order to determine the role of maternal obesity on epigenetic mechanisms.
| S-EPMC7235386 | biostudies-literature
Project description:Undernutrition during pregnancy is implicated in the programming of offspring for the development of obesity and diabetes. We hypothesized that maternal programming causes epigenetic changes in fetal hypothalamic pathways regulating metabolism. This study used sheep to examine the effect of moderate maternal undernutrition (60 d before to 30 d after mating) and twinning to investigate changes in the key metabolic regulators proopiomelanocortin (POMC) and the glucocorticoid receptor (GR) in fetal hypothalami. Methylation of the fetal hypothalamic POMC promoter was reduced in underfed singleton, fed twin, and underfed twin groups (60, 73, and 63% decrease, respectively). This was associated with reduced DNA methyltransferase activity and altered histone methylation and acetylation. Methylation of the hypothalamic GR promoter was decreased in both twin groups and in maternally underfed singleton fetuses (52, 65, and 55% decrease, respectively). This correlated with changes in histone methylation and acetylation and increased GR mRNA expression in the maternally underfed singleton group. Alterations in GR were hypothalamic specific, with no changes in hippocampi. Unaltered levels of OCT4 promoter methylation indicated gene-specific effects. In conclusion, twinning and periconceptional undernutrition are associated with epigenetic changes in fetal hypothalamic POMC and GR genes, potentially resulting in altered energy balance regulation in the offspring.
| S-EPMC3316895 | biostudies-other
Project description:OBJECTIVE:To utilize a nonhuman primate model to examine the impact of maternal high-fat diet (HFD) consumption and pre-pregnancy obesity on offspring intake of palatable food and to examine whether maternal HFD consumption impaired development of the dopamine system, critical for the regulation of hedonic feeding. METHODS:The impact of exposure to maternal HFD and obesity on offspring consumption of diets of varying composition was assessed after weaning. The influence of maternal HFD consumption on the development of the prefrontal cortex-dopaminergic system at 13 months of age was also examined. RESULTS:During a preference test, offspring exposed to maternal HFD consumption and obesity displayed increased intake of food high in fat and sugar content relative to offspring from lean control mothers. Maternal HFD consumption suppressed offspring dopamine signaling (as assessed by immunohistochemistry) relative to control offspring. Specifically, there was decreased abundance of dopamine fibers and of dopamine receptor 1 and 2 proteins. CONCLUSIONS:This study reveals that offspring exposed to both maternal HFD consumption and maternal obesity during early development are at increased risk for obesity due to overconsumption of palatable energy-dense food, a behavior that may be related to reduced central dopamine signaling.
| S-EPMC4636015 | biostudies-literature
Project description:BackgroundAlcohol abuse and alcoholism lead to alcohol liver disease such as alcoholic fatty liver. Parkin is a component of the multiprotein E3 ubiquitin ligase complex and is associated with hepatic lipid accumulation. However, the role of parkin in ethanol-induced liver disease has not been reported. Here, we tested the effect of parkin on ethanol-induced fatty liver in parkin knockout (KO) mice with chronic ethanol feeding.MethodsMale wild type (WT) and parkin KO mice (10-12?weeks old, n =?10) were fed on a Lieber-DeCarli diet containing 6.6% ethanol for 10?days. Liver histological, biochemical, and gene-expression studies were performed.ResultsParkin KO mice exhibited lower hepatosteatosis after ethanol consumption. Because several studies reported that ?-catenin is a critical factor in ethanol metabolism and protects against alcohol-induced hepatosteatosis, we investigated whether parkin changes ?-catenin accumulation in the liver of ethanol-fed mice. Our results show that ?-catenin was greatly accumulated in the livers of ethanol-fed parkin KO mice compared to ethanol-fed WT mice, and that parkin binds to ?-catenin and promotes its degradation it by ubiquitination. Moreover, the ?-catenin inhibitor IWR-1 abrogated the attenuation of ethanol-induced hepatic lipid accumulation by parkin deficiency in the livers of parkin KO mice and parkin siRNA-transfected human hepatic cell line.ConclusionsParkin deficiency prevents ethanol-induced hepatic lipid accumulation through promotion of ?-catenin signaling by failure of ?-catenin degradation.
| S-EPMC6704582 | biostudies-literature
Project description:OBJECTIVE:Recent evidence indicates that the adult hematopoietic system is susceptible to diet-induced lineage skewing. It is not known whether the developing hematopoietic system is subject to metabolic programming via in utero high-fat diet (HFD) exposure, an established mechanism of adult disease in several organ systems. We previously reported substantial losses in offspring liver size with prenatal HFD. As the liver is the main hematopoietic organ in the fetus, we asked whether the developmental expansion of the hematopoietic stem and progenitor cell (HSPC) pool is compromised by prenatal HFD and/or maternal obesity. METHODS:We used quantitative assays, progenitor colony formation, flow cytometry, transplantation, and gene expression assays with a series of dietary manipulations to test the effects of gestational high-fat diet and maternal obesity on the day 14.5 fetal liver hematopoietic system. RESULTS:Maternal obesity, particularly when paired with gestational HFD, restricts physiological expansion of fetal HSPCs while promoting the opposing cell fate of differentiation. Importantly, these effects are only partially ameliorated by gestational dietary adjustments for obese dams. Competitive transplantation reveals compromised repopulation and myeloid-biased differentiation of HFD-programmed HSPCs to be a niche-dependent defect, apparent in HFD-conditioned male recipients. Fetal HSPC deficiencies coincide with perturbations in genes regulating metabolism, immune and inflammatory processes, and stress response, along with downregulation of genes critical for hematopoietic stem cell self-renewal and activation of pathways regulating cell migration. CONCLUSIONS:Our data reveal a previously unrecognized susceptibility to nutritional and metabolic developmental programming in the fetal HSPC compartment, which is a partially reversible and microenvironment-dependent defect perturbing stem and progenitor cell expansion and hematopoietic lineage commitment.
| S-EPMC4314531 | biostudies-literature
Project description:Obesity is a major public health problem worldwide. In the United States, one-third of women of reproductive age are obese. Human studies show that maternal obesity (MO) predisposes offspring to cardiovascular disease. However, the underlying mechanisms remain unclear. Given the similarities between pregnancy in sheep and humans, we studied sheep to examine the impact of MO on fetal cardiomyocyte contractility at term. We observed that MO impaired cardiomyocyte contractility by reducing peak shortening and shortening/relengthening velocity, prolonging time to relengthening. MO disrupted Ca2+ homeostasis in fetal cardiomyocytes, increasing intracellular Ca2+ and inducing cellular Ca2+ insensitivity. The Ca2+-release channel was impaired, but Ca2+ uptake was unaffected by MO. The upstream kinases that phosphorylate the Ca2+-release channel-ryanodine receptor-2, PKA, and calmodulin-dependent protein kinase II-were activated in MO fetuses. Contractile dysfunction was associated with an increased ratio of myosin heavy chain (MHC)-β to MHC-α and upregulated cardiac troponin (cTn)-T and tropomyosin, as well as cTn-I phosphorylation. In summary, this is the first characterization of the effects of MO on fetal cardiomyocyte contractility. Our findings indicate that MO impairs fetal cardiomyocyte contractility through altered intracellular Ca2+ handling, overloading fetal cardiomyocyte intracellular Ca2+ and aberrant myofilament protein composition. These mechanisms may contribute to developmental programming by MO of offspring cardiac function and predisposition to later life cardiovascular disease in the offspring.-Wang, Q., Zhu, C., Sun, M., Maimaiti, R., Ford, S. P., Nathanielsz, P. W., Ren, J., Guo, W. Maternal obesity impairs fetal cardiomyocyte contractile function in sheep.
| S-EPMC6338653 | biostudies-literature
Project description:IntroductionPlacentas of obese women have higher lipid content compared to lean women. We have previously shown that supplementation of overweight and obese women with omega-3 fatty acids decreases placental esterification pathways and total lipid content in a mid-western population (Ohio). We hypothesized that placental lipid accumulation and inflammation would be similar between lean and obese women living in a region of high omega-3 intake, such as Hawaii.MethodsFifty-five healthy, normal glucose tolerant women from Honolulu Hawaii, dichotomized based on pre-pregnancy BMI into lean (BMI <25 kg/m2, n = 29) and obese (BMI >30 kg/m2, n = 26), were recruited at scheduled term cesarean delivery. Maternal plasma DHA levels were analyzed by mass spectrometry. Expression of key genes involved in fatty acid oxidation and esterification were measured in placental tissue using qPCR. Total lipids were extracted from placental tissue via the Folch method. TNF-α concentration was measured by enzyme-linked immunosorbent assay in placental lysates.ResultsDHA levels were higher in lean women compared to obese women (P = 0.02). However, DHA levels in obese women in Hawaii were eight times higher compared to obese Ohioan women (P=<0.0001). Placental lipid content and expression of key genes involved in fatty acid oxidation and esterification were similar (P > 0.05) between lean and obese women in Hawaii. Furthermore, TNF-α placental lysates were not different between lean and obese women.ConclusionsThough obese women in Hawaii have lower DHA levels compared to their lean counterparts, these levels remain over eight times as high as obese Ohioan women. These relatively high plasma omega-3 levels in obese women in Hawaii may suppress placental lipid esterification/storage and inflammation to the same levels of lean women, as seen previously in vitro.
| S-EPMC8439553 | biostudies-literature