Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food.

In utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet (HFD) in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and overexpression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased HFD intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced HFD intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods.

The role of mesenchymal stem cells in early programming of adipose tissue in the offspring of women with obesity.

Maternal obesity is a well-known risk factor for developing premature obesity, metabolic syndrome, cardiovascular disease and type 2 diabetes in the progeny. The development of white adipose tissue is a dynamic process that starts during prenatal life: fat depots laid down in utero are associated with the proportion of fat in children later on. How early this programming takes place is still unknown. However, recent evidence shows that mesenchymal stem cells (MSC), the embryonic adipocyte precursor cells, show signatures of the early setting of an adipogenic committed phenotype when exposed to maternal obesity. This review aims to present current findings on the cellular adaptations of MSCs from the offspring of women with obesity and how the metabolic environment of MSCs could affect the early commitment towards adipocytes. In conclusion, maternal obesity can induce early programming of fetal adipose tissue by conditioning MSCs. These cells have higher expression of adipogenic markers, altered insulin signalling and mitochondrial performance, compared to MSCs of neonates from lean pregnancies. Fetal MSCs imprinting by maternal obesity could help explain the increased risk of childhood obesity and development of further noncommunicable diseases.

Maternal obesity: sex-specific in utero changes in fetal brain autophagy and mTOR.

OBJECTIVE: Maternal obesity affects 39.7% of reproductive-age women in the United States. Emerging research has suggested that in utero exposure to maternal obesity is associated with adverse neurodevelopmental outcomes, but knowledge of underlying mechanisms in human samples is lacking. METHODS: A matched case-control study was performed in women with singleton fetuses who were undergoing elective pregnancy termination at gestational ages 15 to 21 weeks. Maternal adiponectin levels from plasma were measured using ELISA kits. RNA was extracted from fetal brain tissue using RNeasy Mini Kit (QIAGEN). mRNA expression from ADIPOR1, ADIPOR2, MTOR, ATG5, ATG7, BECN1, and MAP1LC3B was quantified through the ΔΔCt method and using GAPDH as a housekeeping gene. RESULTS: We have identified transcription patterns associated with inhibition of autophagy in male fetal brain tissue exposed to maternal obesity (↑MTOR, ↓ATG5, ↓ATG7, and ↓MAP1LC3B), with female fetuses demonstrating either no change in transcription or nonsignificant changes associated with increased autophagy. There was significant downregulation of the autophagy-associated gene BECN1 in both male and female individuals who were exposed to obesity in utero. CONCLUSIONS: We present novel evidence suggesting that in utero exposure to maternal obesity in humans may significantly affect neurodevelopment, especially in male fetuses, through alterations in normal autophagy molecular mechanisms and with adiponectin as a potential mediator.

(-)-epicatechin treatment did not modify the thermogenic pathway in the gastrocnemius muscle of male rat offspring obeses by programming.

The aim of this study was to analyse the expression of genes related to the regulation of energy metabolism in skeletal muscle tissue by comparing male offspring in two age groups [at 110 and 245 postnatal days (pnd)] from a mother with obesity induced by a high-fat diet and (-)-epicatechin (Epi) administration. Four groups of six male offspring from different litters were randomly selected for the control groups [C and offspring of mothers with maternal obesity (MO)] or Epi intervention groups. We evaluated the effect of Epi on gastrocnemius tissue by analysing the mRNA and protein expression levels of Fndc5/irisin, Pgc-1α, Ucp3, and Sln. Epi significantly increased the Pgc-1α protein in the MO group of offspring at 110 pnd (p < 0.036, MO vs. MO+Epi), while at 245 pnd, Epi increased Fndc5/irisin mRNA expression in the MO+Epi group versus the MO group (p = 0.006).No differences were detected in Fndc5/irisin, Ucp3 or Sln mRNA or protein levels (including Pgc-1α mRNA) in the offspring at 110 pnd or in Pgc-1α, Ucp3, or Sln mRNA or protein levels (including Fndc5/irisin protein) at 245 pnd among the experimental groups. In conclusion, (-)-epicatechin treatment increased Fndc5/irisin mRNA expression and Pgc-α protein levels in the gastrocnemius muscle of offspring at postnatal days 110 and 245. Furthermore, it is suggested that the flavonoid effect in a model of obesity and its impact on thermogenesis in skeletal muscle are regulated by a different pathway than Fndc5/irisin.

Parental obesity predisposes offspring to kidney dysfunction and increased susceptibility to ischemia-reperfusion injury in a sex-dependent manner.

Although obesity is recognized as a risk factor for cardiorenal and metabolic diseases, the impact of parental obesity on the susceptibility of their offspring to renal injury at adulthood is unknown. We examined the impact of parental obesity on offspring kidney function, morphology, and markers of kidney damage after acute kidney injury (AKI). Offspring from normal (N) diet-fed C57BL/6J parents were fed either N (NN) or a high-fat (H) diet (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were fed N (HN) or H diet (HH) after weaning. All offspring groups were submitted to bilateral AKI by clamping the left and right renal pedicles for 30 min. Compared with male NH and NN offspring from lean parents, male HH and HN offspring from obese parents exhibited higher kidney injury markers such as urinary, renal osteopontin, plasma creatinine, urinary albumin excretion, and neutrophil gelatinase-associated lipocalin (NGAL) levels, and worse histological injury score at 22 wk of age. Only albumin excretion and NGAL were elevated in female HH offspring from obese parents compared with lean and obese offspring from lean parents. We also found an increased mortality rate and worse kidney injury scores after AKI in male offspring from obese parents, regardless of the diet consumed after weaning. Female offspring were protected from major kidney injury after AKI. These results indicate that parental obesity leads to increased kidney injury in their offspring after ischemia-reperfusion in a sex-dependent manner, even when their offspring remain lean.NEW & NOTEWORTHY Offspring from obese parents are more susceptible to kidney injury and worse outcomes following an acute ischemia-reperfusion insult. Male, but not female, offspring from obese parents exhibit increased blood pressure early in life. Female offspring are partially protected against major kidney injury induced by ischemia-reperfusion.

Melatonin supplementation in obese mothers reduces hypothalamic inflammation and enhances thermogenesis in mice progeny.

Maternal obesity might induce obesity and metabolic alterations in the progeny. The study aimed to determine the effect of supplementing obese mothers with Mel (Mel) on thermogenesis and inflammation. C57BL/6 female mice (mothers) were fed from weaning to 12 weeks control diet (C, 17% kJ as fat) or a high-fat diet (HF, 49% kJ as fat) and then matted with male mice fed the control diet. Melatonin (10 mg/kg daily) was supplemented to mothers during gestation and lactation, forming the groups C, CMel, HF, and HFMel (n = 10/group). Twelve-week male offspring were studied (plasma biochemistry, immunohistochemistry, protein, and gene expressions at the hypothalamus - Hyp, subcutaneous white adipose tissue - sWAT, and interscapular brown adipose tissue - iBAT). Comparing HFMel vs. HF offspring, fat deposits and plasmatic proinflammatory markers decreased. Also, HFMel showed decreased Hyp proinflammatory markers and neuropeptide Y (anabolic) expression but improved proopiomelanocortin (catabolic) expression. Besides, HFMel sWAT adipocytes changed to a beige phenotype with-beta-3 adrenergic receptor and uncoupling protein-1 activation, concomitant with browning genes activation, triggering the iBAT thermogenic activity. In conclusion, compelling evidence indicated the beneficial effects of supplementing obese mothers with Mel on the health of their mature male offspring. Mel led to sWAT browning-related gene enhancement, increased iBAT thermogenis, and mitigated hypothalamic inflammation. Also, principal component analysis of the data significantly separated the untreated obese mother progeny from the progeny of treated obese mothers. If confirmed in humans, the findings encourage a future guideline recommending Mel supplementation during pregnancy and breastfeeding.

Maternal obesity and placental function: impaired maternal-fetal axis.

The prevalence of maternal obesity rapidly increases, which represents a major public health concern worldwide. Maternal obesity is characteristic by metabolic dysfunction and chronic inflammation. It is associated with health problems in both mother and offspring. Increasing evidence indicates that the placenta is an axis connecting maternal obesity with poor outcomes in the offspring. In this brief review, we have summarized the current data regarding deregulated placental function in maternal obesity. The data show that maternal obesity induces numerous placental defects, including lipid and glucose metabolism, stress response, inflammation, immune regulation and epigenetics. These placental defects affect each other and result in a stressful intrauterine environment, which transduces and mediates the adverse effects of maternal obesity to the fetus. Further investigations are required to explore the exact molecular alterations in the placenta in maternal obesity, which may pave the way to develop specific interventions for preventing epigenetic and metabolic programming in the fetus.

Sex-specific regulation of miR-22 and ERα in white adipose tissue of obese dam's female offspring impairs the early postnatal development of functional beige adipocytes in mice.

During inguinal adipose tissue (iWAT) ontogenesis, beige adipocytes spontaneously appear between postnatal 10 (P10) and P20 and their ablation impairs iWAT browning capacity in adulthood. Since maternal obesity has deleterious effects on offspring iWAT function, we aimed to investigate its effect in spontaneous iWAT browning in offspring. Female C57BL/6 J mice were fed a control or obesogenic diet six weeks before mating. Male and female offspring were euthanized at P10 and P20 or weaned at P21 and fed chow diet until P60. At P50, mice were treated with saline or CL316,243, a ß3-adrenoceptor agonist, for ten days. Maternal obesity induced insulin resistance at P60, and CL316,243 treatment effectively restored insulin sensitivity in male but not female offspring. This discrepancy occurred due to female offspring severe browning impairment. During development, the spontaneous iWAT browning and sympathetic nerve branching at P20 were severely impaired in female obese dam's offspring but occurred normally in males. Additionally, maternal obesity increased miR-22 expression in the iWAT of male and female offspring during development. ERα, a target and regulator of miR-22, was concomitantly upregulated in the male's iWAT. Next, we evaluated miR-22 knockout (KO) offspring at P10 and P20. The miR-22 deficiency does not affect spontaneous iWAT browning in females and, surprisingly, anticipates iWAT browning in males. In conclusion, maternal obesity impairs functional iWAT development in the offspring in a sex-specific way that seems to be driven by miR-22 levels and ERα signaling. This impacts adult browning capacity and glucose homeostasis, especially in female offspring.

Sex-Dependent Variations in Hypothalamic Fatty Acid Profile and Neuropeptides in Offspring Exposed to Maternal Obesity and High-Fat Diet.

Maternal obesity and/or high-fat diet (HF) consumption can disrupt appetite regulation in their offspring, contributing to transgenerational obesity and metabolic diseases. As fatty acids (FAs) play a role in appetite regulation, we investigated the maternal and fetal levels of FAs as potential contributors to programmed hyperphagia observed in the offspring of obese dams. Female mice were fed either a control diet (CT) or HF prior to mating, and fetal and maternal blood and tissues were collected at 19 days of gestation. Elevated levels of linoleic acid were observed in the serum of HF dams as well as in the serum of their fetuses. An increased concentration of eicosadienoic acid was also detected in the hypothalamus of female HF-O fetuses. HF-O male fetuses showed increased hypothalamic neuropeptide Y (Npy) gene expression, while HF-O female fetuses showed decreased hypothalamic pro-opiomelanocortin (POMC) protein content. Both male and female fetuses exhibited reduced hypothalamic neurogenin 3 (NGN-3) gene expression. In vitro experiments confirmed that LA contributed to the decreased gene expression of Pomc and Ngn-3 in neuronal cells. During lactation, HF female offspring consumed more milk and had a higher body weight compared to CT. In summary, this study demonstrated that exposure to HF prior to and during gestation alters the FA composition in maternal serum and fetal serum and hypothalamus, particularly increasing n-6, which may play a role in the switch from POMC to NPY neurons, leading to increased weight gain in the offspring during lactation.

Preconception Diet Interventions in Obese Outbred Mice and the Impact on Female Offspring Metabolic Health and Oocyte Quality.

Obese individuals often suffer from metabolic health disorders and reduced oocyte quality. Preconception diet interventions in obese outbred mice restore metabolic health and oocyte quality and mitochondrial ultrastructure. Also, studies in inbred mice have shown that maternal obesity induces metabolic alterations and reduces oocyte quality in offspring (F1). Until now, the effect of maternal high-fat diet on F1 metabolic health and oocyte quality and the potential beneficial effects of preconception dietary interventions have not been studied together in outbred mice. Therefore, we fed female mice a high-fat/high-sugar (HF/HS) diet for 7 weeks and switched them to a control (CONT) or caloric-restriction (CR) diet or maintained them on the HF/HS diet for 4 weeks before mating, resulting in three treatment groups: diet normalization (DN), CR, and HF/HS. In the fourth group, mice were fed CONT diet for 11 weeks (CONT). HF/HS mice were fed an HF/HS diet from conception until weaning, while all other groups were then fed a CONT diet. After weaning, offspring were kept on chow diet and sacrificed at 11 weeks. We observed significantly elevated serum insulin concentrations in female HF/HS offspring and a slightly increased percentage of mitochondrial ultrastructural abnormalities, mitochondrial size, and mitochondrial mean gray intensity in HF/HS F1 oocytes. Also, global DNA methylation was increased and cellular stress-related proteins were downregulated in HF/HS F1 oocytes. Mostly, these alterations were prevented in the DN group, while, in CR, this was only the case for a few parameters. In conclusion, this research has demonstrated for the first time that a maternal high-fat diet in outbred mice has a moderate impact on female F1 metabolic health and oocyte quality and that preconception DN is a better strategy to alleviate this compared to CR.

Long-term impact of maternal obesity on the gliovascular unit and ephrin signaling in the hippocampus of adult offspring.

BACKGROUND: Children born to obese mothers are at increased risk of developing mood disorders and cognitive impairment. Experimental studies have reported structural changes in the brain such as the gliovascular unit as well as activation of neuroinflammatory cells as a part of neuroinflammation processing in aged offspring of obese mothers. However, the molecular mechanisms linking maternal obesity to poor neurodevelopmental outcomes are not well established. The ephrin system plays a major role in a variety of cellular processes including cell-cell interaction, synaptic plasticity, and long-term potentiation. Therefore, in this study we determined the impact of maternal obesity in pregnancy on cortical, hippocampal development, vasculature and ephrin-A3/EphA4-signaling, in the adult offspring in mice. METHODS: Maternal obesity was induced in mice by a high fat/high sugar Western type of diet (HF/HS). We collected brain tissue (prefrontal cortex and hippocampus) from 6-month-old offspring of obese and lean (control) dams. Hippocampal volume, cortical thickness, myelination of white matter, density of astrocytes and microglia in relation to their activity were analyzed using 3-D stereological quantification. mRNA expression of ephrin-A3, EphA4 and synaptic markers were measured by qPCR in the brain tissue. Moreover, expression of gap junction protein connexin-43, lipocalin-2, and vascular CD31/Aquaporin 4 were determined in the hippocampus by immunohistochemistry. RESULTS: Volume of hippocampus and cortical thickness were significantly smaller, and myelination impaired, while mRNA levels of hippocampal EphA4 and post-synaptic density (PSD) 95 were significantly lower in the hippocampus in the offspring of obese dams as compared to offspring of controls. Further analysis of the hippocampal gliovascular unit indicated higher coverage of capillaries by astrocytic end-feet, expression of connexin-43 and lipocalin-2 in endothelial cells in the offspring of obese dams. In addition, offspring of obese dams demonstrated activation of microglia together with higher density of cells, while astrocyte cell density was lower. CONCLUSION: Maternal obesity affects brain size, impairs myelination, disrupts the hippocampal gliovascular unit and decreases the mRNA expression of EphA4 and PSD-95 in the hippocampus of adult offspring. These results indicate that the vasculature-glia cross-talk may be an important mediator of altered synaptic plasticity, which could be a link between maternal obesity and neurodevelopmental/neuropsychiatric disorders in the offspring.

Programming of cardiac metabolism by miR-15b-5p, a miRNA released in cardiac extracellular vesicles following ischemia-reperfusion injury.

OBJECTIVE: We investigated the potential involvement of miRNAs in the developmental programming of cardiovascular diseases (CVD) by maternal obesity. METHODS: Serum miRNAs were measured in individuals from the Helsinki Birth Cohort (with known maternal body mass index), and a mouse model was used to determine causative effects of maternal obesity during pregnancy and ischemia-reperfusion on offspring cardiac miRNA expression and release. RESULTS: miR-15b-5p levels were increased in the sera of males born to mothers with higher BMI and in the hearts of adult mice born to obese dams. In an ex-vivo model of perfused mouse hearts, we demonstrated that cardiac tissue releases miR-15b-5p, and that some of the released miR-15b-5p was contained within small extracellular vesicles (EVs). We also demonstrated that release was higher from hearts exposed to maternal obesity following ischaemia/reperfusion. Over-expression of miR-15b-5p in vitro led to loss of outer mitochondrial membrane stability and to repressed fatty acid oxidation in cardiomyocytes. CONCLUSIONS: These findings suggest that miR-15-b could play a mechanistic role in the dysregulation of cardiac metabolism following exposure to an in utero obesogenic environment and that its release in cardiac EVs following ischaemic damage may be a novel factor contributing to inter-organ communication between the programmed heart and peripheral tissues.

Vernix caseosa reveals mechanistic clues linking maternal obesity to atopic dermatitis pathogenesis.

BACKGROUND: Maternal overweight and obesity have been associated with an increased risk of atopic dermatitis (AD) in the offspring, but the underlying mechanisms are unclear. Vernix caseosa (VC) is a proteolipid material covering the fetus produced during skin development. However, whether maternal prepregnancy weight excess influences fetal skin development is unknown. Characterizing the VC of newborns from mothers with prepregnancy overweight and obesity might reveal AD-prone alterations during fetal skin development. OBJECTIVE: We sought to explore AD biomarkers and staphylococcal loads in VC from the offspring of mothers who were overweight/obese (O/O) before pregnancy versus in those from offspring of normal weight mothers. METHODS: The VC of newborns of 14 O/O and 12 normal weight mothers were collected immediately after birth. Biomarkers were determined by ELISA and staphylococcal species by quantitative PCR. RESULTS: The VC from the O/O group showed decreased expression of skin barrier proteins (filaggrin and loricrin) and increased levels of proinflammatory biomarkers (IgA, thymic stromal lymphopoietin [TSLP], S100A8, IL-25, and IL-33). No differences in concentrations of antimicrobial peptides and enzymes were detected. The VC from the O/O group had a lower Staphylococcus epidermidis and Staphylococcus hominis commensal bacterial load, whereas Staphylococcus aureus bacterial load was not significantly different between the 2 groups. Maternal body mass index was negatively correlated with VC filaggrin expression and S epidermidis load and was positively associated with TSLP concentration. One-year follow-up established that the offspring of O/O mothers had a higher incidence of AD that was specifically linked with decreased VC filaggrin expression and lower S epidermidis load. CONCLUSIONS: VC from neonates of mothers with prepregnancy overweight and obesity exhibit skin barrier molecular alterations and staphylococcal dysbiosis that suggest early mechanistic clues to this population's increased risk of AD.

Maternal obesity impacts fetal liver androgen signalling in a sex-specific manner.

BACKGROUND: Maternal obesity (MO) increases fetal androgen concentrations, the prevalence of macrosomia, and predisposes offspring to metabolic dysfunction in later life, especially males. These risks may be, in part, the result of increased liver-specific androgen signalling pathway activity in utero. Androgen signalling activity can be suppressed by androgen metabolism via cytochrome P450 (CYP) isoenzymes (CYP2B6, CYP3A) or through inhibition of the full-length androgen receptor (AR-FL) via the antagonistic isoform, AR-45. We hypothesised MO impairs CYP enzyme activity and AR-45 expression in male fetal livers, thereby enhancing activity of androgen signalling pathways. METHODS: Nine months prior to pregnancy, nulliparous female baboons were assigned to either ad libitum control or high fat diet. At 165 day (d) gestation (term, 180 d) fetal liver was collected (n = 6/sex/group). CYP activity was quantified using functional assays; subcellular AR expression was measured using Western blot. RESULTS: CYP2B6 and CYP3A activity, and nuclear expression of AR-45, was reduced in MO males only. Nuclear AR-45 expression was inversely related with fetal body weight of MO males only. CONCLUSIONS: Reduced CYP2B6 and CYP3A activity in conjunction with decreased nuclear AR-45 expression may enhance liver androgen signalling in males from MO pregnancies, thereby increasing the risk of macrosomia, as well as metabolic dysfunction in later life.

Bdnf-Nrf-2 crosstalk and emotional behavior are disrupted in a sex-dependent fashion in adolescent mice exposed to maternal stress or maternal obesity.

Maternal obesity has been recognized as a stressor affecting the developing fetal brain, leading to long-term negative outcomes comparable to those resulting from maternal psychological stress, although the mechanisms have not been completely elucidated. In this study, we tested the hypothesis that adverse prenatal conditions as diverse as maternal stress and maternal obesity might affect emotional regulation and stress response in the offspring through common pathways, with a main focus on oxidative stress and neuroplasticity. We contrasted and compared adolescent male and female offspring in two mouse models of maternal psychophysical stress (restraint during pregnancy - PNS) and maternal obesity (high-fat diet before and during gestation - mHFD) by combining behavioral assays, evaluation of the hypothalamic-pituitary-adrenal (HPA) axis reactivity, immunohistochemistry and gene expression analysis of selected markers of neuronal function and neuroinflammation in the hippocampus, a key region involved in stress appraisal. Prenatal administration of the antioxidant N-acetyl-cysteine (NAC) was used as a strategy to protect fetal neurodevelopment from the negative effects of PNS and mHFD. Our findings show that these two stressors produce overlapping effects, reducing brain anti-oxidant defenses (Nrf-2) and leading to sex-dependent impairments of hippocampal Bdnf expression and alterations of the emotional behavior and HPA axis functionality. Prenatal NAC administration, by restoring the redox balance, was able to exert long-term protective effects on brain development, suggesting that the modulation of redox pathways might be an effective strategy to target common shared mechanisms between different adverse prenatal conditions.

Obesity in pregnancy-Long-term effects on offspring hypothalamic-pituitary-adrenal axis and associations with placental cortisol metabolism: A systematic review.

Obesity, affecting one in three pregnant women worldwide, is not only a major obstetric risk factor. The resulting low-grade inflammation may have a long-term impact on the offspring's HPA axis through dysregulation of maternal, placental and fetal corticosteroid metabolism, and children born of obese mothers have increased risk of diabetes and cardiovascular disease. The long-term effects of maternal obesity on offspring neurodevelopment are, however, undetermined and could depend on the specific effects on placental and fetal cortisol metabolism. This systematic review evaluates how maternal obesity affects placental cortisol metabolism and the offspring's HPA axis. Pubmed, Embase and Scopus were searched for original studies on maternal BMI, obesity, and cortisol metabolism and transfer. Fifteen studies were included after the screening of 4556 identified records. Studies were small with heterogeneous exposures and outcomes. Two studies found that maternal obesity reduced placental HSD11ß2 activity. In one study, umbilical cord blood cortisol levels were affected by maternal BMI. In three studies, an altered cortisol response was consistently seen among offspring in childhood (n = 2) or adulthood (n = 1). Maternal BMI was not associated with placental HSD11ß1 or HSD11ß2 mRNA expression, or placental HSD11ß2 methylation. In conclusion, high maternal BMI is associated with reduced placental HSD11ß2 activity and a dampened cortisol level among offspring, but the data is sparse. Further investigations are needed to clarify whether the HPA axis is affected by prenatal factors including maternal obesity and investigate if adverse effects can be ameliorated by optimising the intrauterine environment.

Placental dysfunction in obese women and antenatal surveillance.

Obesity is a significant health concern worldwide and is associated with numerous health complications, including placental dysfunction during pregnancy. Placental dysfunction can lead to adverse outcomes for both the mother and the foetus, such as preeclampsia, gestational diabetes, preterm birth, and foetal growth restriction. Studies have shown that maternal obesity can lead to placental dysfunction through various mechanisms, including chronic inflammation, oxidative stress, and dysregulation of metabolic pathways. These factors can contribute to changes in the placenta's structure and function, impairing nutrient and oxygen exchange between the mother and foetus. Recent research has also suggested that alteration of gene expression in the placenta due to epigenetic changes, such as DNA methylation, may play a role in placental dysfunction associated with maternal obesity. These changes can affect altering foetal growth and development. Prevention and management of maternal obesity are crucial in reducing the risk of placental dysfunction and associated adverse outcomes during pregnancy. This can be achieved through lifestyle modifications, such as diet and exercise, and early detection and management of underlying health conditions. In conclusion, maternal obesity is a significant risk factor for placental dysfunction during pregnancy, which can lead to adverse outcomes for both the mother and the foetus. Further research is needed to understand the relationship and mechanisms to develop effective interventions to prevent and manage placental dysfunction in obese pregnant women.

Fetal sex differences in placental LCPUFA ether and plasmalogen phosphatidylethanolamine and phosphatidylcholine contents in pregnancies complicated by obesity.

BACKGROUND: We have previously reported that maternal obesity reduces placental transport capacity for lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA), a preferred form for transfer of DHA (omega 3) to the fetal brain, but only in male fetuses. Phosphatidylethanolamine (PE) and phosphatidylcholine (PC), have either sn-1 ester, ether or vinyl ether (plasmalogen) linkages to primarily unsaturated and monounsaturated fatty acids and DHA or arachidonic acid (ARA, omega 6) in the sn-2 position. Whether ether and plasmalogen PC and PE metabolism in placenta impacts transfer to the fetus is unexplored. We hypothesized that ether and plasmalogen PC and PE containing DHA and ARA are reduced in maternal-fetal unit in pregnancies complicated by obesity and these differences are dependent on fetal sex. METHODS: In maternal, umbilical cord plasma and placentas from obese women (11 female/5 male infants) and normal weight women (9 female/7 male infants), all PC and PE species containing DHA and ARA were analyzed by LC-MS/MS. Placental protein expression of enzymes involved in phospholipid synthesis, were determined by immunoblotting. All variables were compared between control vs obese groups and separated by fetal sex, in each sample using the Benjamini-Hochberg false discovery rate adjustment to account for multiple testing. RESULTS: Levels of ester PC containing DHA and ARA were profoundly reduced by 60-92% in male placentas of obese mothers, while levels of ether and plasmalogen PE containing DHA and ARA were decreased by 51-84% in female placentas. PLA2G4C abundance was lower in male placentas and LPCAT4 abundance was lower solely in females in obesity. In umbilical cord, levels of ester, ether and plasmalogen PC and PE with DHA were reduced by 43-61% in male, but not female, fetuses of obese mothers. CONCLUSIONS: We found a fetal sex effect in placental PE and PC ester, ether and plasmalogen PE and PC containing DHA in response to maternal obesity which appears to reflect an ability of female placentas to adapt to maintain optimal fetal DHA transfer in maternal obesity.

Docosahexaenoic acid (DHA) is a critical omega 3 long chain polyunsaturated fatty acid (LCPUFA) for fetal brain development. We have recently reported that maternal obesity reduces placental transport capacity for LysophosPhatidylCholine-DHA (LPC-DHA), a preferred form for transfer of DHA to the fetal brain, but only in male fetuses. Other important lipids, the plasmalogen phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are considered DHA reservoirs, but its roles in the maternal­fetal unit are largely unexplored. We examined these lipid species in maternal and fetal circulation and in placental tissue to uncover potential novel roles for ether and plasmalogen lipids in the regulation of placenta delivery of these vital nutrients in pregnancies complicated by obesity depending of fetal sex. We demonstrated for the first time, that female fetuses of obese mothers decrease placental ether and plasmalogen PE containing DHA and arachidonic acid (ARA, omega 6), and show a high fetal­placental adaptability and placental reserve capacity that can maintain the PC-LCPUFA synthesis and the transfer of these crucial species to the fetus to preserve brain development. Our study also demonstrated that male fetuses, in response to maternal obesity, reduce the placental ester PC species containing DHA and ARA and reduce the ether and plasmalogen PE reservoir of DHA and ARA in fetal circulation. Our findings support a fetal sex effect in placental ester, ether and plasmalogen PE and PC containing DHA in response to maternal obesity which appears to reflect an ability of female placentas to adapt to maintain optimal fetal DHA transfer in maternal obesity.

Sex-specific impact of maternal obesity on fetal placental macrophages and cord blood triglycerides.

INTRODUCTION: Maternal obesity is associated with increased risk of offspring obesity and cardiometabolic disease. Altered fetoplacental immune programming is a potential candidate mechanism. Differences in fetal placental macrophages, or Hofbauer cells (HBCs), have been observed in maternal obesity, and lipid metabolism is a key function of resident macrophages that may be deranged in inflammation/immune activation. We sought to test the following hypotheses: 1) maternal obesity is associated with altered HBC density and phenotype in the term placenta and 2) obesity-associated HBC changes are associated with altered placental lipid transport to the fetus. The impact of fetal sex was evaluated in all experiments. METHODS: We quantified the density and morphology of CD163-and CD68-positive HBCs in placental villi in 34 full-term pregnancies undergoing cesarean delivery (N = 15, maternal BMI ≥30 kg/m2; N = 19, BMI <30 kg/m2). Antibody-positive cells in terminal villi were detected and cell size and circularity analyzed using a semi-automated method for thresholding of bright-field microscopy images (ImageJ). Placental expression of lipid transporter genes was quantified using RTqPCR, and cord plasma triglycerides (TGs) were profiled using modified Wahlefeld method. The impact of maternal obesity and fetal sex on HBC features, lipid transporters, and cord TGs were evaluated by two-way ANOVA. Spearman correlations of cord TGs, HBC metrics and gene expression levels were calculated. RESULTS: Maternal obesity was associated with significantly increased density of HBCs, with male placentas most affected (fetal sex by maternal obesity interaction p = 0.04). CD163+ HBCs were larger and rounder in obesity-exposed male placentas. Sexually dimorphic expression of placental FATP4, FATP6, FABPPM, AMPKB1 and AMPKG and cord TGs was noted in maternal obesity, such that levels were higher in males and lower in females relative to sex-matched controls. Cord TGs were positively correlated with HBC density and FATP1 expression. DISCUSSION: Maternal obesity is associated with sex-specific alterations in HBC density and placental lipid transporter expression, which may impact umbilical cord blood TG levels and offspring cardiometabolic programming.

Fetoplacental endothelial dysfunction in gestational diabetes mellitus and maternal obesity: A potential threat for programming cardiovascular disease.

Gestational diabetes mellitus (GDM) and maternal obesity (MO) increase the risk of adverse fetal outcomes, and the incidence of cardiovascular disease later in life. Extensive research has been conducted to elucidate the underlying mechanisms by which GDM and MO program the offspring to disease. This review focuses on the role of fetoplacental endothelial dysfunction in programming the offspring for cardiovascular disease in GDM and MO pregnancies. We discuss how pre-existing maternal health conditions can lead to vascular dysfunction in the fetoplacental unit and the fetus. We also examine the role of fetoplacental endothelial dysfunction in impairing fetal cardiovascular system development and the involvement of nitric oxide and hydrogen sulfide in mediating fetoplacental vascular dysfunction. Furthermore, we suggest that the L-Arginine-Nitric Oxide and the Adenosine-L-Arginine-Nitric Oxide (ALANO) signaling pathways are pertinent targets for research. Despite significant progress in this area, there are still knowledge gaps that need to be addressed in future research.