Intestinal alterations and mild glucose homeostasis impairments in the offspring born to overweight rats.

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.

Metabolic and molecular effects of dietary extra virgin olive oil in blood and placenta of women with GDM.

Gestational diabetes mellitus (GDM) increases the risks of maternal, placental, and neonatal complications. Previously, we found that a diet enriched in extra virgin olive oil (EVOO) prevents increased maternal triglyceridemia and placental proinflammatory markers in a cohort of GDM patients. The aim of this work was to evaluate maternal circulating markers of insulin resistance, placental collagen, glycogen and lipid levels, and placental levels of proteins, mRNAs, and a microRNA involved in the endocytic pathway in the same cohort of control women and women with GDM who received or did not receive a diet enriched in EVOO (36 g/day) from weeks 24 to 28 of pregnancy until term. Results: At term, the TG/HDL cholesterol ratio, fatty acid binding protein 4 circulating levels, and maternal BMI were increased in the GDM patients, alterations prevented by the maternal diet enriched in EVOO. Although there were no changes in placental lipid levels and lipid profile, GDM placentas were thicker than controls and showed increased glycogen and collagen content, alterations prevented by the EVOO enriched diet. GDM placentas showed increases in megalin levels, in the expression of several genes involved in the endocytic pathway, and in miR-199, which targets these genes, alterations prevented by the maternal diet enriched in EVOO. Conclusions: We identified novel beneficial effects of an EVOO-enriched diet in GDM women, a diet capable of regulating maternal insulin resistance, the structure and metabolism of the placenta, and the placental endocytic pathway, suggesting effects that may be beneficial for fetal development.

Maternal diabetes increases FOXO1 activation during embryonic cardiac development.

Maternal diabetes is known to affect heart development, inducing the programming of cardiac alterations in the offspring's adult life. Previous studies in the heart of adult offspring have shown increased activation of FOXO1 (a transcription factor involved in a wide variety of cellular functions such as apoptosis, cellular proliferation, reactive oxygen species detoxification, and antioxidant and pro-inflammatory processes) and of target genes related to inflammatory and fibrotic processes. In this work, we aimed to evaluate the effects of maternal diabetes on FOXO1 activation as well as on the expression of target genes relevant to the formation of the cardiovascular system during organogenesis (day 12 of gestation). The embryonic heart from diabetic rats showed increased active FOXO1 levels, reduced protein levels of mTOR (a nutrient sensor regulating cell growth, proliferation and metabolism) and reduced mTORC2-SGK1 pathway, which phosphorylates FOXO1. These alterations were related to increases in the levels of 4-hydroxynonenal (an oxidative stress marker) and increased mRNA levels of inducible nitric oxide synthase, angiopoietin-2 and matrix metalloproteinase-2 (MMP2) (all FOXO1 target genes relevant for cardiac development). Results also showed increased extracellular and intracellular immunolocalization of MMP2 in the myocardium and its projection into the lumen of the cavity (trabeculations) together with decreased immunostaining of connexin 43, a protein relevant for cardiac function that is target of MMP2. In conclusion, increases in active FOXO1 induced by maternal diabetes initiate early during embryonic heart development and are related to increases in markers of oxidative stress and of proinflammatory cardiac development, as well to an altered expression of proteolytic enzymes that regulate connexin 43. These alterations may lead to an altered programming of cardiovascular development in the embryonic heart of diabetic rats.

Peroxisome proliferator-activated receptor pathways in diabetic rat decidua early after implantation: regulation by dietary polyunsaturated fatty acids.

RESEARCH QUESTION: Are peroxisome proliferator-activated receptor (PPAR) pathways and moieties involved in histotrophic nutrition altered in the decidua of diabetic rats? Can diets enriched in polyunsaturated fatty acids (PUFA) administered early after implantation prevent these alterations? Can these dietary treatments improve morphological parameters in the fetus, decidua and placenta after placentation? DESIGN: Streptozotocin-induced diabetic Albino Wistar rats were fed a standard diet or diets enriched in n3- or n6-PUFAs early after implantation. Decidual samples were collected on day 9 of pregnancy. Fetal, decidual and placental morphological parameters were evaluated on day 14 of pregnancy. RESULTS: On gestational day 9, PPARδ levels showed no changes in the diabetic rat decidua compared with controls. In diabetic rat decidua, PPARα levels and the expression of its target genes Aco and Cpt1 had reduced. These alterations were prevented by the n6-PUFA-enriched diet. Levels of PPARγ, the expression of its target gene Fas, lipid droplet number and perilipin 2 and fatty acid binding protein 4 levels increased in the diabetic rat decidua compared with controls. Diets enriched with PUFA prevented PPARγ increase, but not the increased lipid-related PPARγ targets. On gestational day 14, fetal growth, decidual and placental weight reduced in the diabetic group, and alterations prevented by the maternal diets were enriched in PUFAs. CONCLUSION: When diabetic rats are fed diets enriched in n3- and n6-PUFAs early after implantation, PPAR pathways, lipid-related genes and proteins, lipid droplets and glycogen content in the decidua are modulated. This influences decidual histotrophic function and later feto-placental development.

Paternal diabetes programs sex-dependent placental alterations and fetal overgrowth.

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.

Unsaturated Fatty Acid Intake During Periconception and Incidence of Achieving Pregnancy: A Systematic Review and Meta-Analysis.

Background: Previous studies suggest that maternal diets enriched in unsaturated fatty acids may have a positive effect on pregnancy success. The aim of the present study was to conduct a systematic review and meta-analysis to evaluate whether increased dietary intake of polyunsaturated fatty acids (PUFAs) or monounsaturated fatty acids (MUFAs) during the periconception period has beneficial effects on the achievement of pregnancy in women. Methods: The electronic databases PubMed, Medline and Cochrane Central Register, as well as references in related review articles, were searched to find studies assessing the effects of unsaturated fatty acid dietary intake during the periconception period on the achievement of pregnancy in women. Pregnancy was confirmed by high levels of hCG (biochemical means) and ultrasound confirmation of a gestational sac and heartbeat (clinical means). Results: For the meta-analysis evaluating the effects of periconceptional diets enriched in PUFAs on pregnancy, four articles, providing data on 2,121 patients, were included. Results showed that periconceptional intake of PUFAs has no significant effects on achieving pregnancy compared to controls, according to both the fixed effects and random effects models (RR = 0.99, 95% CI 0.98-1.00). Further secondary analysis considering ω-6 and ω-3 PUFAs separately showed no significant effects on achieving pregnancy compared to controls. On the other hand, for the meta-analysis evaluating the effects of periconceptional diets enriched in MUFAs on achieving pregnancy, five articles, providing data on 2,473 patients, were included. Results showed that periconceptional dietary intake of MUFAs has significant effects on achieving pregnancy compared to controls according to the fixed effects model (RR = 1.03, 95% CI 1.01-1.06, p < 0.02) but not to the random effects model, due to heterogeneity. A secondary meta-analysis excluding one study which led to heterogeneity showed significant effects of MUFAs on achieving pregnancy compared to controls, according to both the fixed effects and random effects models (RR = 1.03, 95% CI 1.01-1.05, p < 0.02). Conclusion: The meta-analysis of published clinical studies suggests that diets enriched in MUFAs, although not those enriched in PUFAs, may have a positive effect on pregnancy success as determined by HCG and ultrasonography. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42021239355, identifier: CRD42021239355.

Intrauterine Programming of Cardiovascular Diseases in Maternal Diabetes.

Maternal diabetes is a prevalent pathology that increases the risk of cardiovascular diseases in the offspring, the heart being one of the main target organs affected from the fetal stage until the adult life. Metabolic, pro-oxidant, and proinflammatory alterations in the fetal heart constitute the first steps in the adverse fetal programming of cardiovascular disease in the context of maternal diabetes. This review discusses both human and experimental studies addressing putative mechanisms involved in this fetal programming of heart damage in maternal diabetes. These include cardiac epigenetic changes, alterations in cardiac carbohydrate and lipid metabolism, damaging effects caused by a pro-oxidant and proinflammatory environment, alterations in the cardiac extracellular matrix remodeling, and specific signaling pathways. Putative actions to prevent cardiovascular impairments in the offspring of mothers with diabetes are also discussed.

Intergenerational effects of the antioxidant Idebenone on the placentas of rats with gestational diabetes mellitus.

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.

Diets enriched in PUFAs at an early postimplantation stage prevent embryo resorptions and impaired mTOR signaling in the decidua from diabetic rats.

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.

Sialic acid removal by trans-sialidase modulates MMP-2 activity during Trypanosoma cruzi infection.

Matrix metalloproteinases (MMPs) not only play a relevant role in homeostatic processes but are also involved in several pathological mechanisms associated with infectious diseases. As their clinical relevance in Chagas disease has recently been highlighted, we studied the modulation of circulating MMPs by Trypanosoma cruzi infection. We found that virulent parasites from Discrete Typing Units (DTU) VI induced higher proMMP-2 and MMP-2 activity in blood, whereas both low (DTU I) and high virulence parasites induced a significant decrease in proMMP-9 plasma activity. Moreover, trans-sialidase, a relevant T. cruzi virulence factor, is involved in MMP-2 activity modulation both in vivo and in vitro. It removes α2,3-linked sialyl residues from cell surface glycoconjugates, which then triggers the PKC/MEK/ERK signaling pathway. Additionally, bacterial sialidases specific for this sialyl residue linkage displayed similar MMP modulation profiles and triggered the same signaling pathways. This novel pathogenic mechanism, dependent on sialic acid removal by the neuraminidase activity of trans-sialidase, can be exploited by different pathogens expressing sialidases with similar specificity. Thus, here we present a new pathogen strategy through the regulation of the MMP network.

Inhibition of MTOR signaling impairs rat embryo organogenesis by affecting folate availability.

Mechanistic target of rapamycin (MTOR) is essential for embryo development by acting as a nutrient sensor to regulate cell growth, proliferation and metabolism. Folate is required for normal embryonic development and it was recently reported that MTOR functions as a folate sensor. In this work, we tested the hypothesis that MTOR functions as a folate sensor in the embryo and its inhibition result in embryonic developmental delay affecting neural tube closure and that these effects can be rescued by folate supplementation. Administration of rapamycin (0.5 mg/kg) to rats during early organogenesis inhibited embryonic ribosomal protein S6, a downstream target of MTOR Complex1, markedly reduced embryonic folate incorporation (-84%, P < 0.01) and induced embryo developmental impairments, as shown by an increased resorption rate, reduced embryo somite number and delayed neural tube closure. These alterations were prevented by folic acid administered to the dams. Differently, although an increased rate of embryonic rotation defects was observed in the rapamycin-treated dams, this alteration was not prevented by maternal folic acid supplementation. In conclusion, MTOR inhibition during organogenesis in the rat resulted in decreased folate levels in the embryo, increased embryo resorption rate and impaired embryo development. These data suggest that MTOR signaling influences embryo folate availability, possibly by regulating the transfer of folate across the maternal-embryonic interface.

Prevalence of gestational diabetes mellitus in Argentina according to the Latin American Diabetes Association (ALAD) and International Association of Diabetes and Pregnancy Study Groups (IADPSG) diagnostic criteria and the associated maternal-neonatal complications.

In Argentina, gestational diabetes mellitus (GDM) is diagnosed by the Latin American Diabetes Association (ALAD) diagnostic criterion. In this work, we investigated GDM prevalence according to the ALAD and IADPSG diagnostic criteria, evaluated maternal and fetal outcomes and assessed whether fasting glycemia between 92-99 mg/dL was associated with increased risk of macrosomia and maternal obesity/overweight in an Argentine cohort of pregnant women. GDM prevalence was 9.8% with the ALAD diagnostic criterion and 25% considering the IADPSG criterion. Increased prevalence of maternal obesity/overweight was observed in patients with fasting glycemia over 99 mg/dL. A population of high metabolic risk is identified by the ALAD criterion.

Addition of olive oil to diet of rats with mild pre-gestational diabetes impacts offspring ß-cell development.

Maternal diabetes impairs fetal development and increases the risk of metabolic diseases in the offspring. Previously, we demonstrated that maternal dietary supplementation with 6% of olive oil prevents diabetes-induced embryo and fetal defects, in part, through the activation of peroxisome proliferator-activated receptors (PPARs). In this study, we examined the effects of this diet on neonatal and adult pancreatic development in male and female offspring of mothers affected with pre-gestational diabetes. A mild diabetic model was developed by injecting neonatal rats with streptozotocin (90 mg/kg). During pregnancy, these dams were fed a chow diet supplemented or not with 6% olive oil. Offspring pancreata was examined at day 2 and 5 months of age by immunohistochemistry followed by morphometric analysis to determine number of islets, α and ß cell clusters and ß-cell mass. At 5 months, male offspring of diabetic mothers had reduced ß-cell mass that was prevented by maternal supplementation with olive oil. PPARα and PPARγ were localized mainly in α cells and PPARß/δ in both α and ß cells. Although Pparß/δ and Pparγ RNA expression showed reduction in 5-month-old male offspring of diabetic rats, Pparß/δ expression returned to control levels after olive-oil supplementation. Interestingly, in vitro exposure to oleic acid (major component of olive oil) and natural PPAR agonists such as LTB4, CPC and 15dPGJ2 also significantly increased expression of all Ppars in αTC1-6 cells. However, only oleic acid and 15dPGJ2 increased insulin and Pdx-1 expression in INS-1E cells suggesting a protective role in ß-cells. Olive oil may be considered a dietary supplement to improve islet function in offspring of affected mothers with pre-gestational diabetes.

Olive oil supplementation prevents extracellular matrix deposition and reduces prooxidant markers and apoptosis in the offspring´s heart of diabetic rats.

Maternal diabetes induces fetal programming of cardiovascular diseases. Diabetes induced-cardiac fibrosis is a process that may start in utero and may be related to the prooxidant/proinflammatory environment. The aim of this study was to investigate the effect of a maternal diet enriched in olive oil on the levels of components and regulators of the extracellular matrix, on prooxidant markers and on apoptosis rate in the heart of 21-day-old offspring of diabetic rats. Maternal diabetes was induced by neonatal administration of streptozotocin. During pregnancy, diabetic and control rats were fed with diets supplemented or not with 6% olive oil. The heart of the offspring was studied at 21 days of age. We found increased deposition of collagen IV and fibronectin in the offspring´s heart of diabetic rats, which was prevented by the maternal diets enriched in olive oil. Increases in connective tissue growth factor were also prevented by the maternal diets enriched in olive oil. Prooxidant markers as well as apoptosis, which were increased in the heart of the offspring of diabetic rats, were prevented by the maternal olive oil dietary treatment. Our findings identified powerful effects of a maternal diet enriched in olive oil on the prevention of increased extracellular matrix deposition and increased prooxidant markers in the heart of 21-day-old offspring of diabetic rats.

An extra virgin olive oil-enriched diet improves maternal, placental, and cord blood parameters in GDM pregnancies.

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.

The offspring from rats fed a fatty diet display impairments in the activation of liver peroxisome proliferator activated receptor alpha and features of fatty liver disease.

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.

Proinflammation in maternal and fetal livers and circulating miR-122 dysregulation in a GDM rat model induced by intrauterine programming.

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.

Maternal diets enriched in olive oil regulate lipid metabolism and levels of PPARs and their coactivators in the fetal liver in a rat model of gestational diabetes mellitus.

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.

Altered FOXO1 activation in the programming of cardiovascular alterations by maternal diabetes.

Maternal diabetes programs cardiovascular alterations in the adult offspring but the mechanisms involved remain unclarified. Here, we addresed whether maternal diabetes programs cardiac alterations related to extracellular matrix remodeling in the adult offspring, as well as the role of forkhead box transcription factor 1 (FOXO1) in the induction of these alterations. The heart from adult offspring from control and streptozotocin-induced diabetic rats was evaluated. Increased glycemia, triglyceridemia and insulinemia and markers of cardiomyopathy were found in the offspring from diabetic rats. In the heart, an increase in active FOXO1 and mRNA levels of its target genes, Mmp-2 and Ctgf, genes related to an altered extracellular matrix remodeling, together with an increase in collagen deposition and a decrease in the connexin43 levels, were found in the offspring from diabetic rats. Altogether, these results suggest an important role of FOXO1 activation in the cardiac alterations induced by intrauterine programming in maternal diabetes.