ABSTRACT
The gut plays a crucial role in metabolism by regulating the passage of nutrients, water and microbial-derived substances to the portal circulation. Additionally, it produces incretins, such as glucose-insulinotropic releasing peptide (GIP) and glucagon-like derived peptide 1 (GLP1, encoded by gcg gene) in response to nutrient uptake. We aimed to investigate whether offspring from overweight rats develop anomalies in the barrier function and incretin transcription. We observed pro-inflammatory related changes along with a reduction in Claudin-3 levels resulting in increased gut-permeability in fetuses and offspring from overweight rats. Importantly, we found decreased gip mRNA levels in both fetuses and offspring from overweight rats. Differently, gcg mRNA levels were upregulated in fetuses, downregulated in female offspring and unchanged in male offspring from overweight rats. When cultured with high glucose, intestinal explants showed an increase in gip and gcg mRNA levels in control offspring. In contrast, offspring from overweight rats did not exhibit any response in gip mRNA levels. Additionally, while females showed no response, male offspring from overweight rats did exhibit an upregulation in gcg mRNA levels. Furthermore, female and male offspring from overweight rats showed sex-dependent anomalies when orally challenged with a glucose overload, returning to baseline glucose levels after 120 min. These results open new research questions about the role of the adverse maternal metabolic condition in the programming of impairments in glucose homeostasis, enteroendocrine function and gut barrier function in the offspring from overweight mothers and highlight the importance of a perinatal maternal healthy metabolism.
Subject(s)
Gastric Inhibitory Polypeptide , Overweight , Rats , Male , Female , Animals , Overweight/metabolism , Gastric Inhibitory Polypeptide/metabolism , Incretins/metabolism , Glucagon-Like Peptide 1/metabolism , Glucose/metabolism , Peptides/metabolism , Homeostasis , RNA, Messenger/geneticsABSTRACT
The aim of this study was to evaluate the paternal programming of sex-dependent alterations in fetoplacental growth and placental lipid metabolism regulated by peroxisome proliferator-activated receptor (PPAR) target genes in F1 diabetic males born from F0 pregestational diabetic rats. F1 control and diabetic male rats were mated with control female rats. On day 21 of gestation, F2 male and female fetoplacental growth, placental lipid levels, and protein and mRNA levels of genes involved in lipid metabolism and transport were evaluated. Fetal but not placental weight was increased in the diabetic group. Triglyceride, cholesterol and free fatty acid levels were increased in placentas of male fetuses from the diabetic group. The mRNA levels of Pparα and Pparγ coactivator 1α (Pgc-1α) were increased only in placentas of male fetuses from the diabetic group. Protein levels of PPARα and PGC-1α were decreased only in placentas of male fetuses from the diabetic group. No differences were found in Pparγ mRNA and protein levels in placentas from the diabetic group. The mRNA levels of genes involved in lipid synthesis showed no differences between groups, whereas the mRNA levels of genes involved in lipid oxidation and transport were increased only in placentas of male fetuses from the diabetic group. In conclusion, paternal diabetes programs fetal overgrowth and sex-dependent effects on the regulation of lipid metabolism in the placenta, where only placentas of male fetuses show an increase in lipid accumulation and mRNA expression of enzymes involved in lipid oxidation and transport pathways.
Subject(s)
Diabetes Mellitus, Experimental , Diabetes, Gestational , Animals , Diabetes Mellitus, Experimental/metabolism , Diabetes, Gestational/genetics , Diabetes, Gestational/metabolism , Female , Fetal Macrosomia/metabolism , Humans , Male , PPAR alpha/genetics , PPAR alpha/metabolism , PPAR gamma/genetics , PPAR gamma/metabolism , Placenta/metabolism , Pregnancy , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Wistar , Triglycerides/metabolismABSTRACT
Experimental models of maternal diabetes lead to the intrauterine programming of Gestational Diabetes Mellitus (GDM) in the offspring, together with an intrauterine proinflammatory environment, feto-placental metabolic alterations and fetal overgrowth. The aim of this work was to evaluate the effect of the mitochondrial antioxidant Idebenone given to F0 mild pregestational diabetic rats on the development of GDM in their F1 offspring and the intergenerational programming of a pro-oxidant/proinflammatory environment that affects the placentas of F2 fetuses. Control and mild pregestational diabetic female rats (F0) were mated with control males, and Idebenone or vehicle was administered to diabetic rats from day 1 of gestation to term. The F1 female offspring were mated with control males and maternal and fetal plasma samples were obtained for metabolic determinations at term. The F2 fetuses and placentas were weighed, and placental protein levels and peroxynitrite-induced damage (immunohistochemistry), mRNA levels (PCR), nitric oxide production (Griess reaction), and number of apoptotic cells (TUNEL) were evaluated. The F1 offspring of F0 diabetic rats (treated or not with Idebenone) developed GDM. The placentas of GDM rats showed a decrease in the mRNA levels of manganese superoxide dismutase and an increase in the production of nitric oxide, peroxynitrite-induced damage, and connective tissue growth factor levels, alterations that were prevented by the maternal Idebenone treatment in F0 rats. In conclusion, the maternal treatment with Idebenone in pregestational diabetic F0 rats ameliorates the pro-oxidant/proinflammatory environment that affects the placentas of F2 fetuses, although it does not prevent F1 rats from developing GDM.
Subject(s)
Antioxidants/pharmacology , Ubiquinone/analogs & derivatives , Animals , Diabetes Mellitus, Experimental/metabolism , Diabetes, Gestational/metabolism , Female , Fetal Macrosomia/metabolism , Fetal Macrosomia/physiopathology , Fetus/metabolism , Male , Nitric Oxide/metabolism , Placenta/metabolism , Pregnancy , Pregnancy Proteins , Rats , Rats, Wistar , Ubiquinone/pharmacologyABSTRACT
Maternal diabetes increases the risk of embryo resorptions and impairs embryo development. Decidualization is crucial for embryo development and regulated by mTOR signaling. However, little is known about how maternal diabetes affects the decidua at early postimplantation stages and whether dietary treatments enriched in polyunsaturated fatty acids (PUFAs) can prevent decidual alterations. Here, we determined resorption rates, decidual mTOR pathways and markers of decidual function and remodeling in diabetic rats fed or not with diets enriched in PUFAs exclusively during the early postimplantation period. Pregestational streptozotocin-induced diabetic Albino Wistar rats and controls were fed or not with diets enriched in 6% sunflower oil or 6% chia oil (enriched in n-6 or n-3 PUFAs, respectively) on days 7, 8 and 9 of pregnancy and evaluated on day 9 of pregnancy. Maternal diabetes induced an 11-fold increase in embryo resorptions, which was prevented by both PUFAs-enriched diets despite no changes in maternal glycemia. The activity of mTOR pathway was decreased in the decidua from diabetic rats, an alteration prevented by the PUFAs-enriched diets. PUFAs-enriched diets prevented increased expression of Foxo1 (a negative regulator of mTOR) and reduced expression of miR-21 (a negative regulator of Foxo1). These diets also prevented reduced markers of decidual function (leukemia inhibitory factor and IGFBP1 expression and MMPs activity) in diabetic rat decidua. We identified the early post implantation as a crucial stage for pregnancy success, in which dietary PUFAs can protect diabetic pregnancies from embryo resorptions, decidual mTOR signaling impairments, and altered markers of decidual function and remodeling.
Subject(s)
Decidua/metabolism , Dietary Fats/administration & dosage , Embryo Loss/prevention & control , Fatty Acids, Unsaturated/pharmacology , Prenatal Nutritional Physiological Phenomena , TOR Serine-Threonine Kinases/metabolism , Animal Nutritional Physiological Phenomena , Animals , Blood Glucose , Decidua/drug effects , Fatty Acids, Unsaturated/administration & dosage , Female , Gene Expression Regulation/drug effects , Insulin-Like Growth Factor Binding Protein 1/genetics , Insulin-Like Growth Factor Binding Protein 1/metabolism , Leukemia Inhibitory Factor/genetics , Leukemia Inhibitory Factor/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Pregnancy , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , TOR Serine-Threonine Kinases/geneticsABSTRACT
AIMS: To address the effect of a diet enriched in extra virgin olive oil (EVOO) on maternal metabolic parameters and placental proinflammatory markers in Gestational diabetes mellitus (GDM) patients. METHODS: Pregnant women at 24-28 weeks of gestation were enrolled: 33 GDM patients which were randomly assigned or not to the EVOO-enriched group and 17 healthy controls. Metabolic parameters were determined. Peroxisome proliferator activated receptor (PPAR) γ and PPARα protein expression, expression of microRNA (miR)-130a and miR-518d (which respectively target these PPAR isoforms) and levels of proinflammatory markers were evaluated in term placentas. Matrix metalloproteinases (MMPs) activity was evaluated in term placentas and umbilical cord blood. RESULTS: GDM patients that received the EVOO-enriched diet showed reduced pregnancy weight gain (GDM-EVOO:10.3 ± 0.9, GDM:14.2 ± 1.4, P = .03) and reduced triglyceridemia (GDM-EVOO:231 ± 14, GDM:292 ± 21, P = .02) compared to the non-EVOO-enriched GDM group. In GDM placentas, the EVOO-enriched diet did not regulate PPARγ protein expression or miR-130a expression, but prevented the reduced PPARα protein expression (P = .02 vs GDM) and the increased miR-518d expression (P = .009 vs GDM). Increased proinflammatory markers (interleukin-1ß, tumour necrosis factor-α and nitric oxide overproduction) in GDM placentas were prevented by the EVOO-enriched diet (respectively P = .001, P = .001 and P = .01 vs GDM). MMPs overactivity was prevented in placenta and umbilical cord blood in the EVOO-enriched GDM group (MMP-9: respectively P = .01 and P = .001 vs GDM). CONCLUSIONS: A diet enriched in EVOO in GDM patients reduced maternal triglyceridemia and weight gain and has antiinflammatory properties in placenta and umbilical cord blood, possibly mediated by the regulation of PPAR pathways.
Subject(s)
Biomarkers/blood , Blood Glucose/analysis , Diabetes, Gestational/diet therapy , Diet , Fetal Blood/metabolism , Olive Oil/pharmacology , Placenta/metabolism , Adult , Case-Control Studies , Diabetes, Gestational/metabolism , Diabetes, Gestational/pathology , Female , Follow-Up Studies , Glycated Hemoglobin/analysis , Humans , Olive Oil/administration & dosage , Pregnancy , PrognosisABSTRACT
Maternal obesity programs liver derangements similar to those of NAFLD. Our main goal was to evaluate whether these liver anomalies were related to aberrant PPARα function. Obesity was induced in female Albino-Wistar rats by a fatty diet (FD rats). Several parameters related to NAFLD were evaluated in both plasma and livers from fetuses of 21 days of gestation and 140-day-old offspring. FD fetuses and offspring developed increased levels of AST and ALT, signs of inflammation and oxidative and nitrative stress-related damage. FD offspring showed dysregulation of Plin2, CD36, Cyp4A, Aco, Cpt-1, Hadha and Acaa2 mRNA levels, genes involved in lipid metabolism and no catabolic effect of the PPARα agonist clofibrate. These results suggest that the FD offspring is prone to develop fatty liver, a susceptibility that can be linked to PPARα dysfunction, and that this could in turn be related to the liver impairments programmed by maternal obesity.
Subject(s)
Diet, High-Fat , Liver/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , PPAR alpha/metabolism , Animals , Clofibrate/pharmacology , Female , Fetus/pathology , Gene Expression Regulation/drug effects , Lipid Metabolism/drug effects , Lipid Metabolism/genetics , Liver/embryology , Liver/pathology , Liver/physiopathology , Male , PPAR alpha/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, WistarABSTRACT
In gestational diabetes mellitus (GDM) pregnancies, a compromised fetal liver may impact offspring's metabolic health. Here, we aimed to address prooxidant, proinflammatory and profibrotic markers in the livers from GDM rats and their fetuses, and to analyze the expression of miR-122 (a relevant microRNA in liver pathophysiology) in fetal and maternal plasma of GDM rats, as well as in the fetal livers of neonatal streptozotocin-induced (nSTZ) diabetic rats, the rats that generate GDM through intrauterine programming. GDM and nSTZ rats were evaluated on day 21 of pregnancy. We found increased nitric oxide production and lipoperoxidation in the livers from GDM rats and their fetuses compared to controls. Livers from GDM fetuses also showed increased levels of connective tissue growth factor and matrix metalloproteinase-2. The expression of miRNA-122 was downregulated in the plasma from GDM rats and their male fetuses, as well as in the livers from male fetuses of nSTZ diabetic rats. miR-122 levels were regulated both in vitro through PPARγ activation and in vivo through a maternal diet enriched in PPAR ligands. Our findings revealed a prooxidant/proinflammatory environment in the livers from GDM rats and their fetuses and a dysregulation of miR-122, likely relevant in the programming of offspring's diseases.
Subject(s)
Diabetes Mellitus, Experimental/genetics , Diabetes, Gestational/genetics , Fetus/embryology , Gene Expression Regulation , Inflammation/genetics , Liver/embryology , MicroRNAs/blood , Uterus/pathology , Animals , Biomarkers/metabolism , Circulating MicroRNA/blood , Circulating MicroRNA/genetics , Connective Tissue Growth Factor/metabolism , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/metabolism , Diabetes, Gestational/blood , Diabetes, Gestational/metabolism , Disease Models, Animal , Female , Inflammation/blood , Lipid Peroxidation , Male , Matrix Metalloproteinase 2/metabolism , MicroRNAs/genetics , Nitric Oxide/biosynthesis , Olive Oil , Oxidants/metabolism , Pregnancy , Rats, Wistar , StreptozocinABSTRACT
In a rat model of gestational diabetes mellitus (GDM) programmed in the offspring of neonatal streptozotocin-induced (nSTZ) diabetic rats, lipids are accumulated in the fetal liver in a sex-dependent way. Here, we evaluated whether maternal diets enriched in olive oil in rats that will develop GDM ameliorate lipid metabolic impairments in the fetal livers. Pregnant offspring of control and nSTZ diabetic rats (F0) were fed a 6% olive oil-supplemented diet throughout the F1 gestation. We evaluated maternal metabolic parameters as well as lipid content, expression of lipid metabolizing enzymes and protein expression of PLIN2, PPARs and PPAR coactivators in the fetal livers. The offspring of nSTZ diabetic rats developed GDM regardless of the maternal treatment. Hypertriglyceridemia in GDM rats was prevented by the olive oil-enriched maternal treatment. In the livers of male fetuses of GDM rats, the maternal olive oil-supplemented diet prevented lipid overaccumulation and prevented the increase in PPARγ and PPARδ levels. In the livers of female fetuses of GDM rats, the maternal olive oil supplementation prevented the increase in PPARδ levels and the reduction in PGC1α levels, but did not prevent the reduced lipid content. Control and GDM rats showed a reduction of lipid metabolic enzymes in the fetal livers, which was associated with reduced levels of the PPAR coactivators PGC-1α and SRC-1 in males and of SRC-1 in females. These results suggest powerful effects of a maternal olive oil-supplemented diet in the fetal liver, possibly providing benefits in the fetuses and offspring from GDM rats.
Subject(s)
Diabetes Mellitus, Experimental/diet therapy , Diabetes, Gestational/diet therapy , Diet , Lipid Metabolism , Liver/embryology , Olive Oil/administration & dosage , PPAR gamma/metabolism , Animals , Dietary Supplements , Female , Ligands , Lipids/chemistry , Liver/metabolism , Male , Perilipin-2/metabolism , Pregnancy , Pregnancy, Animal , Rats , Rats, Wistar , Sex FactorsABSTRACT
SCOPE: Offspring from rats with mild diabetes develop gestational diabetes mellitus (GDM). We tested the hypothesis that an olive oil-supplemented diet attenuates placental oxidative stress/inflammation, activation of mTOR signaling, and inhibition of peroxisome proliferator-activated receptor γ (PPARγ) and fetal overgrowth in GDM offspring from mild diabetic rats. METHODS AND RESULTS: Female offspring from rats with mild diabetes (group that developed GDM) and controls were fed with either a standard diet or a 6% olive oil-supplemented diet during pregnancy. On day 21 of pregnancy, plasma glucose levels in mothers and fetuses were increased in the GDM group independently of the diet. Fetal overgrowth and activation of placental mTOR signaling were partially prevented in the olive oil-treated GDM group. Placental PPARγ protein expression was decreased in GDM rats, independently of the diet. However, increases in placental lipoperoxidation, connective tissue growth factor, and matrix metalloproteinase 2 levels were prevented by the olive oil-enriched diet. CONCLUSION: Diets enriched with olive oil attenuate placental dysfunction and fetal overgrowth in rats with GDM induced by intrauterine programming.
Subject(s)
Diabetes, Gestational/diet therapy , Olive Oil/pharmacology , Placenta/physiopathology , Animals , Diabetes Mellitus, Experimental/diet therapy , Diabetes, Gestational/physiopathology , Dietary Supplements , Female , Organ Size/drug effects , Oxidative Stress/drug effects , PPAR gamma/metabolism , Placenta/drug effects , Placenta/metabolism , Pregnancy , Rats, Wistar , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolismABSTRACT
Gestational diabetes mellitus (GDM) is a prevalent disease that impairs fetal metabolism and development. We have previously characterized a rat model of GDM induced by developmental programming. Here, we analyzed lipid content, the levels of the three PPAR isotypes and the expression of microRNAs that regulate PPARs expression in the liver of male and female fetuses of control and GDM rats on day 21 of pregnancy. We found increased levels of triglycerides and cholesterol in the livers of male fetuses of GDM rats compared to controls, and, oppositely, reduced levels of triglycerides, cholesterol, phospholipids and free fatty acids in the livers of female fetuses of GDM rats compared to controls. Although GDM did not change PPARα levels in male and female fetal livers, PPARγ was increased in the liver of male fetuses of GDM rats, a change that occurred in parallel to a reduction in the expression of miR-130, a microRNA that targets PPARγ. In livers of female fetuses of GDM rats, no changes in PPARγ and miR-130 were evidenced, but PPARδ was increased, a change that occurred in parallel to a reduction in the expression of miR-9, a microRNA that targets PPARδ, and was unchanged in the liver of male fetuses of GDM and control rats. These results show clear sex-dependent changes in microRNAs that target different PPAR isotypes in relation to changes in the levels of their targets and the differential regulation of lipid metabolism evidenced in fetal livers of GDM pregnancies.
Subject(s)
Diabetes, Gestational/metabolism , Fetus/metabolism , Lipid Metabolism , Liver/embryology , MicroRNAs/metabolism , Peroxisome Proliferator-Activated Receptors/metabolism , Sex Characteristics , Animals , Female , Gene Expression Regulation , Lipid Metabolism/genetics , Lipids/biosynthesis , Male , MicroRNAs/genetics , Pregnancy , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, WistarABSTRACT
Maternal diabetes impairs fetoplacental development and programs metabolic diseases in the offspring. We have previously reported that female offspring of pregnant rats with mild diabetes develop gestational diabetes mellitus (GDM) when they become pregnant. Here, we studied the effects of supplementation with polyunsaturated fatty acids (PUFAs) in pregnant mild diabetic rats (F0) by feeding a 6% safflower-oil-enriched diet from day 1 to 14 followed by a 6% chia-oil-enriched diet from day 14 of pregnancy to term. We analyzed maternal metabolic parameters and placental signaling at term in pregnant offspring (F1). The offspring of both PUFAs-treated and untreated mild diabetic rats developed GDM. Although gestational hyperglycemia was not prevented by dietary PUFAs treatment in F0, triglyceridemia and cholesterolemia in F1 mothers were normalized by F0 PUFAs dietary treatment. In the placenta of F1 GDM rats, PPARγ levels were reduced and lipoperoxidation was increased, changes that were prevented by the maternal diets enriched in PUFAs in the F0 generation. Moreover, fetal overgrowth and placental activation of mTOR signaling pathways were reduced in F1 GDM rats whose mothers were treated with PUFAs diets. These results suggest that F0 PUFAs dietary treatment in pregnancies with mild diabetes improves maternal dyslipidemia, fetal overgrowth and placental signaling in female offspring when they become pregnant. We speculate that an increased PUFAs intake in pregnancies complicated by diabetes may prove effective to ameliorate metabolic programming in the offspring, thereby improving the health of future generations.
Subject(s)
Diabetes, Gestational/metabolism , Fatty Acids, Unsaturated/pharmacology , PPAR gamma/metabolism , Placenta/drug effects , TOR Serine-Threonine Kinases/metabolism , Animals , Diabetes Mellitus, Experimental/diet therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes, Gestational/diet therapy , Diabetes, Gestational/etiology , Dietary Supplements , Female , Male , Placenta/metabolism , Pregnancy , Rats, WistarABSTRACT
Maternal diabetes programs metabolic and cardiovascular diseases in the offspring. Here, we demonstrated increased pro-oxidant/pro-inflammatory markers in the heart of 2-day-old offspring of diabetic rats, previous to the induction of metabolic alterations. At a pre-pubertal stage, sex-dependent changes were evidenced in the diabetic group, as only males showed increased glycemia as well as increased concentrations of nitrated proteins, matrix metalloproteinase-9 and peroxisome proliferator activated receptor α (PPARα) in the heart. Differently, the heart of male and female offspring of diabetic rats showed increased levels of connective tissue growth factor (CTGF). Maternal treatments with idebenone, a mitochondrial antioxidant, led to reductions in all the pro-oxidant and pro-inflammatory markers evaluated and in PPARα protein expression in the heart of the offspring of diabetic rats. The results of the present study highlight the gender dependence and the role of oxidative stress in the diabetes-induced intrauterine programming of heart alterations.
Subject(s)
Diabetes Mellitus, Experimental/metabolism , Myocardium/metabolism , Animals , Antioxidants/pharmacology , Connective Tissue Growth Factor/metabolism , Female , Male , Maternal-Fetal Exchange , Matrix Metalloproteinase 9/metabolism , Mitochondria , Nitric Oxide/metabolism , Oxidative Stress , PPAR alpha/metabolism , Pregnancy , Rats, Wistar , Ubiquinone/analogs & derivatives , Ubiquinone/pharmacologyABSTRACT
During the passage of sperm through the oviduct, spermatozoa bind to the oviductal epithelium and form the oviductal reservoir. This interaction keeps the fertilizing capacity of sperm until ovulation-associated signals induce sperm release from the oviductal epithelium, allowing the transit of spermatozoa to the fertilization site. Fibronectin is a glycoprotein from the extracellular matrix that binds to α5ß1 receptors. Fibronectin has been found to be expressed in the oviduct, whereas α5ß1 has been found to be expressed in the sperm of different species. Fibronectin is involved through α5ß1 in sperm functions. The aim of this work was to study the participation of oviductal fibronectin in the regulation of the sperm-oviduct interaction in cattle. We found that oviductal epithelial cells differentially expressed all mRNA splice variants of fibronectin during the estrous cycle. Fibronectin was localized in the apical region of oviductal epithelial cells and fibronectin levels in the oviductal fluid fluctuated during the estrous cycle. Also, bovine spermatozoa expressed α5ß1. Using in vitro sperm-oviduct co-cultures, we found that spermatozoa were attached to the oviductal epithelium through α5ß1. The incubation of co-cultures with fibronectin induced sperm release from the oviductal cells through α5ß1. The sperm population released from oviductal cells by fibronectin was enriched in motile and capacitated spermatozoa. Based on our in vitro culture system results, we propose that fibronectin and α5ß1 are involved in the sperm-oviduct interaction. Also, an increase in fibronectin levels in the oviductal fluid during the pre-ovulatory period may promote sperm release from the oviductal epithelium in cattle. J. Cell. Biochem. 118: 4095-4108, 2017. © 2017 Wiley Periodicals, Inc.
Subject(s)
Cell Communication/physiology , Epithelial Cells/metabolism , Estrous Cycle/physiology , Fibronectins/metabolism , Oviducts/metabolism , Spermatozoa/metabolism , Animals , Cattle , Epithelial Cells/cytology , Female , Male , Oviducts/cytology , Spermatozoa/cytologyABSTRACT
A family history of diabetes predisposes to gestational diabetes mellitus (GDM). We hypothesized that female offspring of rats with pre-gestational diabetes will develop GDM, a pathology associated with fetal overgrowth and altered placental signaling. We found normal glycemia and insulinemia in the offspring from pre-gestational diabetic rats at three months of age. However, consistent with GDM, maternal hyperglycemia and hyperinsulinemia and increased fetal weight were evident when compared to controls. In this intrauterine programmed GDM model, the placentas showed alterations in mTOR pathway: unchanged phosphorylation of 4EBP-1 and PKCα despite reduced total expression of 4EBP-1 and PKCα, and increased phosphorylation of SGK1. GDM placentas also showed reduced expression of PPARα and PPARγ, and increased lipoperoxidation, nitric oxide production and peroxynitrite-induced damage. We conclude that exposure of maternal diabetes in utero programs GDM in the female offspring, leading to a GDM model associated with impaired placental signaling pathways, increased pro-oxidant/pro-inflammatory environment and fetal overgrowth.
Subject(s)
Diabetes, Gestational/etiology , Diabetes, Gestational/metabolism , Fetal Development , Placenta/metabolism , TOR Serine-Threonine Kinases/metabolism , Animals , Female , Gene Expression Regulation, Developmental , Lipid Peroxidation , Pregnancy , Pregnancy Proteins/metabolism , Rats , Signal TransductionABSTRACT
We aimed to analyze if an overload of saturated fat in maternal diet induced lipid metabolic impairments in livers from rat fetuses that persist in the offspring and to identify potential mechanisms involving fetal leptin resistance. Female rats were fed either a diet enriched in 25% of saturated fat (SFD rats) or a regular diet (controls). Fetuses of 21days of gestation and offspring of 21 and 140days of age were obtained and plasma and liver were kept for further analysis. Livers from a group of control and SFD fetuses were cultured in the presence or absence of leptin. Leptin or vehicle was administered to control fetuses during the last days of gestation and, on day 21, fetal livers and plasma were obtained. Lipid levels were assessed by thin-layer chromatography and mRNA gene expression of CPT1, ACO and PPARα by RT-PCR. Liver lipid levels were increased and CPT1 and ACO were down-regulated in fetuses and offspring from SFD rats compared to controls. After the culture with leptin, control fetal livers showed increased ACO and CPT1 expression and decreased lipid levels, while fetal livers from SFD rats showed no changes. Fetal administration of leptin induced a decrease in ACO and no changes in CPT1 expression. In summary, our results suggest that a saturated fat overload in maternal diet induces fetal leptin resistance in liver lipid catabolism, which might be contributing to liver lipid alterations that are sustained in the offspring.
Subject(s)
Dietary Fats/administration & dosage , Leptin/physiology , Liver/embryology , Animals , Female , Homeostasis , Liver/metabolism , Male , Rats , Rats, WistarABSTRACT
SCOPE: Maternal diabetes can program metabolic and cardiovascular diseases in the offspring. The aim of this work was to address whether an olive oil supplemented diet during pregnancy can prevent lipid metabolic alterations in the heart of the offspring of mild diabetic rats. METHODS AND RESULTS: Control and diabetic Wistar rats were fed during pregnancy with either a standard diet or a 6% olive oil supplemented diet. The heart of adult offspring from diabetic rats showed increases in lipid concentrations (triglycerides in males and phospholipids, cholesterol, and free fatty acids in females), which were prevented with the maternal diets enriched in olive oil. Maternal olive oil supplementation increased the content of unsaturated fatty acids in the hearts of both female and male offspring from diabetic rats (possibly due to a reduction in lipoperoxidation), increased the expression of Δ6 desaturase in the heart of male offspring from diabetic rats, and increased the expression of peroxisome proliferator activated receptor α in the hearts of both female and male offspring from diabetic rats. CONCLUSION: Relevant alterations in cardiac lipid metabolism were evident in the adult offspring of a mild diabetic rat model, and regulated by maternal diets enriched in olive oil.
Subject(s)
Lipid Metabolism/drug effects , Myocardium/metabolism , Olive Oil/pharmacology , Pregnancy in Diabetics/diet therapy , Animals , Body Weight/drug effects , Diabetes Mellitus, Experimental/diet therapy , Diabetes Mellitus, Experimental/metabolism , Dietary Supplements , Fatty Acids/metabolism , Female , Heart/drug effects , Linoleoyl-CoA Desaturase/metabolism , Lipid Peroxidation/drug effects , Male , Nitric Oxide/metabolism , PPAR alpha/metabolism , Pregnancy , Pregnancy in Diabetics/metabolism , Rats, WistarABSTRACT
Peroxisome proliferator activated receptors (PPARs) are ligand activated transcription factors with crucial functions in lipid homeostasis, anti-inflammatory processes and placental development. Maternal diabetes induces a pro-inflammatory environment and alters placental development. We investigated whether PPARs regulate lipid metabolism and nitric oxide (NO) production in placental explants from healthy and type 2 diabetic (DM2) patients. We found decreased PPARα and PPARγ concentrations, no changes in PPARδ concentrations, and increased lipids, lipoperoxides and NO production in placentas from DM2 patients. PPARα agonists reduced placental concentrations of triglycerides and both PPARα and PPARδ agonists reduced concentrations of phospholipids, cholesteryl esters and cholesterol. PPARγ agonists increased lipid concentrations in placentas from DM2 patients and more markedly in placentas from healthy patients. Endogenous ligands for the three PPAR isotypes reduced NO production and lipoperoxidation in placentas from DM2 patients. We conclude that PPARs play a role in placental NO and lipid homeostasis and can regulate NO production, lipid concentrations and lipoperoxidation in placentas from DM2 patients.
Subject(s)
Diabetes Mellitus, Type 2/metabolism , Lipid Metabolism , Lipid Peroxidation , Nitric Oxide/biosynthesis , Peroxisome Proliferator-Activated Receptors/metabolism , Placenta/metabolism , Adult , Blotting, Western , Densitometry , Female , Humans , Ligands , Peroxisome Proliferator-Activated Receptors/agonists , Pregnancy , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
The fetal lung is affected by maternal diabetes. Nuclear receptor PPARα regulates nitric oxide (NO) overproduction in different tissues. We aimed to determine whether fetal lung PPARα expression is altered by maternal diabetes, and if there are gender-dependent changes in PPARα regulation of NO production in the fetal lung. Fetal lungs from control and diabetic rats were explanted on day 21 of gestation and evaluated for PPARα expression and NO production. Fetuses were injected with the PPARα ligand LTB(4) on days 19, 20 and 21, and the fetal lung explanted on day 21 to evaluate PPARα and the inducible isoform of NO synthase (iNOS). Besides, pregnant rats were fed with olive oil- and safflower oil-supplemented diets, enriched in PPAR ligands, for evaluation of fetal lung NO production and PPARα expression. We found reduced PPARα concentrations only in the lung from male fetuses from the diabetic group when compared to controls, although maternal diabetes led to NO overproduction in both male and female fetal lungs. Fetal activation of PPARα led to changes in lung PPARα expression only in female fetuses, although this treatment increased iNOS expression in both male and female fetuses in the diabetic group. Diets supplemented with olive oil and not with safflower oil led to a reduction in NO production in male and female fetal lungs. In conclusion, there are gender-dependent changes in PPARα expression and signaling in the fetal lung from diabetic rats, although PPARα activation prevents maternal diabetes-induced lung NO overproduction in both male and female fetuses.
Subject(s)
Diabetes Mellitus, Experimental/metabolism , Fetus/metabolism , Lung/metabolism , Nitric Oxide/metabolism , PPAR alpha/metabolism , Pregnancy in Diabetics/metabolism , Animals , Blood Glucose , Diet , Female , Fetal Blood/metabolism , Fetal Weight , Fetus/drug effects , Fetus/pathology , Gene Expression Regulation, Developmental , Leukotriene B4/administration & dosage , Lung/pathology , Male , Maternal-Fetal Exchange , Olive Oil , Organ Size , PPAR alpha/genetics , Plant Oils/administration & dosage , Pregnancy , Prenatal Nutritional Physiological Phenomena , Rats , Rats, Wistar , Safflower Oil/administration & dosage , Sex Factors , Signal Transduction , Triglycerides/bloodABSTRACT
This work deals with the study of how porphyrinogenic drugs modeling acute porphyrias interfere with the status of carbohydrate-regulating hormones in relation to key glucose enzymes and to porphyria, considering that glucose modulates the development of the disease. Female Wistar rats were treated with 2-allyl-2-isopropylacetamide (AIA) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) using different doses of AIA (100, 250 and 500mg/kg body weight) and a single dose of DDC (50mg DDC/kg body weight). Rats were sacrificed 16h after AIA/DDC administration. In the group treated with the highest dose of AIA (group H), hepatic 5-aminolevulinic acid synthase (ALA-S) increased more than 300%, phosphoenolpyruvate carboxykinase (PEPCK) and glycogen phosphorylase (GP) activities were 43% and 46% lower than the controls, respectively, plasmatic insulin levels exceeded normal values by 617%, and plasmatic glucocorticoids (GC) decreased 20%. GC results are related to a decrease in corticosterone (CORT) adrenal production (33%) and a significant reduction in its metabolization by UDP-glucuronosyltransferase (UGT) (62%). Adrenocorticotropic hormone (ACTH) stimulated adrenal production 3-fold and drugs did not alter this process. Thus, porphyria-inducing drugs AIA and DDC dramatically altered the status of hormones that regulate carbohydrate metabolism increasing insulin levels and reducing GC production, metabolization and plasmatic levels. In this acute porphyria model, gluconeogenic and glycogenolytic blockages caused by PEPCK and GP depressed activities, respectively, would be mainly a consequence of the negative regulatory action of insulin on these enzymes. GC could also contribute to PEPCK blockage both because they were depressed by the treatment and because they are positive effectors on PEPCK. These disturbances in carbohydrates and their regulation, through ALA-S de-repression, would enhance the porphyria state promoted by the drugs on heme synthesis and destruction. This might be the mechanism underlying the "glucose effect" observed in hepatic porphyrias. The statistical correlation study performed showed association between all the variables studied and reinforce these conclusions.