Maternal High Fat Research Articles

Synergism between maternal and offspring high fat diet feeding in the non-human primate neuroactive metabolome

The microbiome produces small molecules, including neuroactive metabolites crucial for normal lifelong behavior. In a non-human primate (NHP) model, offspring exposed to maternal high fat diet (mHFD) display physiological changes compared to offspring exposed to maternal control diet (mCTR). To investigate the relationship between maternal diet and offspring post-weaning diet, we hypothesized that mHFD exposure plus a post-weaning high fat diet (HFD) will produce a persistently altered gut metabolome profile in vivo compared to mCTR exposure.

Maternal high fat diet exposure persistently alters the non-human primate neurometabolome independent of offspring diet

Our microbiome produces metabolites required for lifelong health. In a non-human primate (NHP) model, we have shown that offspring exposed to maternal high fat diet (mHFD) display persistent anxiety and a persistently altered gut microbiome, even when weaned onto a control diet for 2.5 years. Since the gut and its microbes influence behavior/neuroactivity, we hypothesized that mHFD exposure influences offspring behavior years after birth via a persistently altered gut metabolome in vivo.

Deletion of Npas2 in the liver alters the functional gut microbiome at light/dark timepoints

In utero exposure of a maternal high fat diet (mHFD) results in the targeted epigenetic reprograming and disruption of circadian clock genes in the fetal liver. However, it is unclear if this disruption of the circadian clock exacerbates the effect of the offspring’s post-weaning high fat diet (oHFD) on the function of its gut microbiome. To understand the interaction of the circadian clock and the offspring gut microbiome with HFD feeding, we disrupted liver Npas2 expression and analyzed the resultant microbiome in light and dark cycles of feeding.

Maternal Obesity Related to High Fat Diet Induces Placenta Remodeling and Gut Microbiome Shaping That Are Responsible for Fetal Liver Lipid Dysmetabolism.

Background: Maternal obesity in utero may affect fetal development and cause metabolic problems during childhood and even adulthood. Diet-induced maternal obesity can impair gut barrier integrity and change the gut microbiome, which may contribute to adverse placental adaptations and increase the obesity risk in offspring. However, the mechanism through which maternal obesity causes offspring metabolic disorder must be identified.Methods: Eight-week-old female rats received a control diet or high-fat (HF) diet for 11 weeks before conception and during gestation. The placentas were collected on gestational day 21 before offspring delivery. Placental tissues, gut microbiome, and short-chain fatty acids of dams and fetal liver tissues were studied.Results: Maternal HF diet and obesity altered the placental structure and metabolism-related transcriptome and decreased G protein–coupled receptor 43 expression. HF diet and obesity also changed the gut microbiome composition and serum propionate level of dams. The fetal liver exhibited steatosis, enhanced oxidative stress, and increased expression of acetyl-CoA carboxylase 1 and lipoprotein lipase with changes in maternal HF diet and obesity.Conclusions: Maternal HF diet and obesity shape gut microbiota and remodel the placenta of dams, resulting in lipid dysmetabolism of the fetal liver, which may ultimately contribute to the programming of offspring obesity.

Maternal high fat diets based on olive oil protect offspring against nafld features through epigenetic alterations

Rationale: Dietary fatty liver composition plays a role in nonalcoholic fatty liver disease (NAFLD) pathogenesis, being the main hepatic manifestation of metabolic syndrome. Maternal obesogenic diet exposure contributes to NAFLD susceptibility. We examined if a maternal high fat diet (HFD) based on extra virgin olive oil (EVOO), rich in monounsaturated fatty acids, reduces the risk of offspring NAFLD through epigenetic microRNA changes.

Sex Differences in Early Programming by Maternal High Fat Diet Induced-Obesity and Fish Oil Supplementation in Mice.

Pre-pregnancy obesity is a contributing factor for impairments in offspring metabolic health. Interventional strategies during pregnancy are a potential approach to alleviate and/or prevent obesity and obesity related metabolic alterations in the offspring. Fish oil (FO), rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) exerts metabolic health benefits. However, the role of FO in early life remains still unknown. Hence, this study objective was to determine the effect of FO supplementation in mice from pre-pregnancy through lactation, and to study the post-natal metabolic health effects in gonadal fat and liver of offspring fed high fat (HF) diet with or without FO. Female C57BL6J mice aged 4–5 weeks were fed a HF (45% fat) diet supplemented with or without FO (30 g/kg of diet) and low fat (LF; 10% fat) pre-pregnancy through lactation. After weaning, offspring (male and female) from HF or FO dams either continued the same diet (HF-HF and FO-FO) or switched to the other diet (HF-FO and FO-HF) for 13 weeks, creating four groups of treatment, and LF-LF was used as a control group. Serum, gonadal fat and liver tissue were collected at termination for metabolic analyses. Offspring of both sexes fed HF with or without fish oil gained (p < 0.05) more weight post weaning, compared to LF-LF-fed mice. All the female offspring groups supplemented with FO had reduced body weight compared to the respective male groups. Further, FO-FO supplementation in both sexes (p < 0.05) improved glucose clearance and insulin sensitivity compared to HF-HF. All FO-FO fed mice had significantly reduced adipocyte size compared to HF-HF group in both male and females. Inflammation, measured by mRNA levels of monocyte chemoattractant protein 1 (Mcp1), was reduced (p < 0.05) with FO supplementation in both sexes in gonadal fat and in the liver. Markers of fatty acid synthesis, fatty acid synthase (Fasn) showed no sex specific differences in gonadal fat and liver of mice supplemented with HF. Female mice had lower liver triglycerides than male counterparts. Supplementation of FO in mice improved metabolic health of offspring by lowering markers of lipid synthesis and inflammation.

132 Early Establishment of the Human Gut Microbiome—a Tale of Moms, Their Diets, and Babes Guts

Abstract Human microbial communities are characterized by their metagenomic and metabolic diversity, which varies by distinct body sites and influences human physiology. We are only beginning to characterize the complex set of interactions which alters both community membership and function in early development. With respect to the potential source of microbiota at birth, it has been generally assumed that the majority of seeding microbes originate from the maternal lower genital tract, with microbiota ascending into the otherwise sterile intrauterine. However, we and subsequently others have recently demonstrated that (1) the vaginal and gut microbiome communities are distinctly structured in pregnancy, and (2) the intrauterine environment and the fetus is in fact not sterile, but rather harbors a low-abundance microbiome which varies by several measured exposures, and (3) the maternal diet during both gestation and lactation, and notably a high fat diet, has a particularly strong impact on the developing and early in life microbial community structure. We have taken two dynamic approaches to answering these questions in our studies. First, we use large and robust longitudinal cohorts of maternal-infant dyads collected across gestation and into infancy to gain deeper insight into both source and sink of the early developmental microbiome and its role on determining length of gestation. Second, we utilize our well established primate models of maternal high fat dietary exposure, both in the absence and presence of maternal obesity, to determine the impact of maternal diet on both the microbiome and the resultant offspring metabolic phenotype.

Maternal Metformin Treatment during Gestation and Lactation Improves Skeletal Muscle Development in Offspring of Rat Dams Fed High-Fat Diet.

Maternal high-fat (HF) diet is associated with offspring metabolic disorder. This study intended to determine whether maternal metformin (MT) administration during gestation and lactation prevents the effect of maternal HF diet on offspring’s skeletal muscle (SM) development and metabolism. Pregnant Sprague-Dawley rats were divided into four groups according to maternal diet {CHOW (11.8% fat) or HF (60% fat)} and MT administration {control (CT) or MT (300 mg/kg/day)} during gestation and lactation: CH-CT, CH-MT, HF-CT, HF-MT. All offspring were weaned on CHOW diet. SM was collected at weaning and 18 weeks in offspring. Maternal metformin reduced plasma insulin, leptin, triglyceride and cholesterol levels in male and female offspring. Maternal metformin increased MyoD expression but decreased Ppargc1a, Drp1 and Mfn2 expression in SM of adult male and female offspring. Decreased MRF4 expression in SM, muscle dysfunction and mitochondrial vacuolization were observed in weaned HF-CT males, while maternal metformin normalized them. Maternal metformin increased AMPK phosphorylation and decreased 4E-BP1 phosphorylation in SM of male and female offspring. Our data demonstrate that maternal metformin during gestation and lactation can potentially overcome the negative effects of perinatal exposure to HF diet in offspring, by altering their myogenesis, mitochondrial biogenesis and dynamics through AMPK/mTOR pathways in SM.

A Maternal High Fat Diet Leads to Sex-Specific Programming of Mechanical Properties in Supraspinatus Tendons of Adult Rat Offspring.

Background: Over half of women of reproductive age are now overweight or obese. The impact of maternal high-fat diet (HFD) is emerging as an important factor in the development and health of musculoskeletal tissues in offspring, however there is a paucity of evidence examining its effects on tendon. Alterations in the early life environment during critical periods of tendon growth therefore have the potential to influence tendon health that cross the lifespan. We hypothesised that a maternal HFD would alter biomechanical, morphological and gene expression profiles of adult offspring rotator cuff tendon.Materials and Methods: Female Sprague-Dawley rats were randomly assigned to either: control diet (CD; 10% kcal or 43 mg/g from fat) or HFD (45% kcal or 235 mg/g from fat) 14 days prior to mating and throughout pregnancy and lactation. Eight female and male offspring from each maternal diet group were weaned onto a standard chow diet and then culled at postnatal day 100 for tissue collection. Supraspinatus tendons were used for mechanical testing and histological assessment (cellularity, fibre organisation, nuclei shape) and tail tendons were collected for gene expression analysis.Results: A maternal HFD increased the elasticity (Young's Modulus) in the supraspinatus tendon of male offspring. Female offspring tendon biomechanical properties were not affected by maternal HFD. Gene expression of SCX and COL1A1 were reduced in male and female offspring of maternal HFD, respectively. Despite this, tendon histological organisation were similar between maternal diet groups in both sexes.Conclusion: An obesogenic diet during pregnancy increased tendon elasticity in male, but not female, offspring. This is the first study to demonstrate that maternal diet can modulate the biomechanical properties of offspring tendon. A maternal HFD may be an important factor in regulating adult offspring tendon homeostasis that may predispose offspring to developing tendinopathies and adverse tendon outcomes in later life.

Postnatal exercise protects offspring from high-fat diet-induced reductions in subcutaneous adipocyte beiging in C57Bl6/J mice

Maternal low-protein and postnatal high-fat (HF) diets program offspring obesity and type 2 diabetes mellitus (T2DM) risk by epigenetically reducing beige adipocytes (BAs) via increased G9a protein expression (Histone3 Lysine9 dimethyl transferase), an inhibitor of the BA marker fibroblast growth factor 21 (FGF21). Conversely, offspring exercise reduces fat mass and white adipocytes, but the mechanisms are not yet understood. This work investigated whether exercise reduces offspring obesity and T2DM risk caused by a maternal HF diet via regulation of G9a and FGF21 expression that would convert white to BA. Two-month-old female C57Bl/6J mice (F0) were fed a 16% (normal fat; NF) or a 45% HF diet for 3 months prior to breeding, and subsequent gestation and lactation. Male offspring (F1) were fed the same NF and HF diets and further divided into either sedentary (S) or voluntary wheel running (Ex) groups for an additional 3 months yielding eight groups: NF (maternal treatment condition)-NF-S (postweaning treatment conditions), NF-HF-S, NF-NF-Ex, NF-HF-Ex, HF-NF-S, HF-HF-S, HF-NF-Ex, and HF-HF-Ex. Subcutaneous adipose tissue was collected for protein and mRNA analysis of FGF21, peroxisome proliferator-activated receptor-gamma coactivator (PGC-1 alpha, inducer of FGF21), G9a, E4BP4 (G9a coactivator), and protein expression of H3K9 demethylases (KDM4C). Postnatal HF diet decreased FGF21 positive BA numbers regardless of maternal diets and postnatal exercise. Under sedentary conditions, postnatal HF diet increased protein expression of FGF21 transcription inhibitors G9a and E4BP4 compared to NF diet resulting in decreased FGF21 expression. In contrast, postnatal HF diet and exercise decreased G9a and E4BP4 protein expression while decreasing FGF21 expression compared to NF diet. Under exercised condition, postnatal HF diet-induced KDM4C protein expression while no changes in KDM4C protein expression were induced by postnatal HF diet under sedentary conditions. These findings suggest that the postnatal diet exerts a greater impact on offspring adiposity and BA numbers than maternal diets. These data also suggest that offspring exercise induces KDM4C to counter the increase in G9a that was triggered by maternal and postnatal HF diets. Future studies need to determine whether KDM4C induces methylation status of G9a to alter thermogenic function of BA.

The role of maternal high fat diet on mouse pup metabolic endpoints following perinatal PFAS and PFAS mixture exposure

Per- and polyfluoroalkyl substances (PFAS) are a family of chemicals that are ubiquitous in the environment. Some of these chemicals, such as perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonate (PFHxS) and perfluorooctanoic acid (PFOA), are found in human sera and have been shown to cause liver steatosis and reduce postnatal survival and growth in rodents. The purpose of this work is to evaluate the impact of diet and PFAS exposure to mouse dam (mus musculus) on the risk to pup liver and metabolism endpoints later in life, as well as evaluate PFAS partitioning to pups. Timed-pregnant dams were fed a standard chow diet or 60 % kcal high fat diet (HFD). Dams were administered either vehicle, 1 mg/kg PFOA, 1 mg/kg PFOS, 1 mg/kg PFHxS, or a PFAS mixture (1 mg/kg of each PFOA, PFOS, and PFHxS) daily via oral gavage from gestation day 1 until postnatal day (PND) 20. At PND 21, livers of dams and 2 pups of each sex were evaluated for lipid changes while remaining pups were weaned to the same diet as the dam for an additional 10 weeks. Dam and pup serum at PND 21 and PND 90 were also evaluated for PFAS concentration, alanine aminotransferase (ALT), leptin and adiponectin, and glycosylated hemoglobin A1c. Perinatal exposure to a HFD, as expected, increased pup body weight, maternal liver weight, pup liver triglycerides, pup serum ALT, and pup serum leptin. PFOA and the PFAS mixture increased liver weights, and. treatment with all three compounds increased liver triglycerides. The maternal HFD increased dam and pup serum PFAS levels, however, was protective against PFOA-induced increase in serum ALT and observed increases in liver triglycerides. The PFAS mixture had very distinct effects when compared to single compound treatment, suggesting some cumulative effects, particularly when evaluating PFAS transfer from dam to pup. This data highlights the importance of diet and mixtures when evaluating liver effect of PFAS and PFAS partitioning.

Associations between mother-child dyad dietary patterns and child anthropometric measures among 6-year-old children.

The goals of this study were to study relationships between maternal and children's dietary patterns (DPs) and to assess how children's DP was associated with child anthropometry. This cross-sectional study included 788 pairs of 6-year-old girls and mothers in health centers in Tehran, Iran. Information on dietary intake was collected with a 168-item food frequency questionnaire. Principal component factor analysis was performed to label different data-driven dietary patterns. Three different binary logistic regression models were used to evaluate the associations between child's DPs and child anthropometry. A positive correlation was found between all maternal patterns and child's Western DP (p < 0.001). Maternal prudent and Western DPs were correlated with child's high-protein DP (p < 0.001). Children's high-protein DP was negatively correlated with maternal high fat DP (p < 0.001). Maternal prudent and high fat DPs were correlated with prudent DP in children (p < 0.001). In adjusted models, a child being in the highest compared to the first quartile of the high-protein DP was associated with decreased odds of underweight and wasting (OR 0.43; 95% CI 0.23-0.80).Conclusion: The present study showed inverse associations between a high-protein DP in children and being underweight and wasted. Also, a positive correlation was found between all maternal DPs and children's Western DPs. This correlation should be taken into account while managing child nutrition by means of educating parents on the influence of their own dietary pattern on their children. Moreover, getting enough protein through a balanced diet should be considered in children. What is Known: • Some research exists on the intake of specific foods in relation to risk of abnormal growth in children. • Less is known about the relationship between mothers' and children's food intake. What is New: • Better adherence to a high-protein dietary pattern was significantly associated with lower risk of being both underweight and wasted. • This study suggests that correlation between mothers' and their children's dietary patterns exists, which should be taken into consideration when managing child nutrition.

Absence of TRPC1 Ca2+-permeable Channel Causes Placental and Fetal Growth Restriction in Mice

ObjectivesPlacental tissue intracellular calcium (Ca2+) regulates placental development and growth (e.g., blastocyst development through branching morphogenesis). Maternal high-fat (HF) diet results in placental lipid accumulation, increase in inflammation, reduction in nutrient transport expression and intra uterine growth restriction (IUGR). Currently, whether maternal HF diet affects placental and fetal growth and development differentially under reduction in Ca2 + influx is not known. Thus, we hypothesized that maternal HF diet feeding decreases placental growth and development resulting in IUGR. We further hypothesized that reduction of Ca2 + influx in placenta worsens the maternal HF-induced placental dysfunction. MethodsTwo-month old female B6129SF2/J wild type (WT) and transient receptor potential canonical 1 (TRPC1) protein deficient (KO) mice were fed normal fat (NF, 16% fat) and high fat (HF, 45%) diets for 12 weeks. Fetuses and placentae were examined at mid- (D12) and late- (D19) gestation. ResultsPlacental length, width, and weight as well as fetal weight were decreased in the TRPC1KO mice at D12 and D19 compared to that of WT mice. Expression of placental growth factor (PLGF) mRNA was decreased at D12 in TRPC1 KO mice while vascular endothelial growth factor (VEGF) mRNA levels were increased at D19 compared to WT mice. ConclusionsThese findings suggest that genotypic differences rather than maternal HF diet alter placental size and weight as well as fetal weight. Decreased in PLGF mRNA may be responsible for the placental and fetal growth restriction while increase in VEGF mRNA indicates compensatory adaptation to decreased PLGF-associated placental and fetal growth restriction. Future studies are needed to determine the signaling mechanism underlying Ca2 + influx reduction- induced placental dysfunction and IUGR. Funding SourcesUSDA Agricultural Research Service Project #3062–51,000-054–00D.

Choline Supplementation in Obese Mouse Dams Alters Offspring DNA Methylation in a Time-Specific Manner

ObjectivesMaternal obesity has long-term influence on metabolic health of offspring, partly through an epigenetic mechanism. Choline is a methyl donor which provides methyl groups for epigenetic modification such as DNA methylation. In this study, we examined the effect of maternal choline supplementation (MCS) on DNA methylation of offspring born to high-fat (HF) fed obese mouse dams. MethodsC57BL/6J mice were fed either a 10% kcal normal fat (NF) or a 60% kcal HF diet with either 25 mM choline supplement or control drinking water from 4 weeks prior to mating until the end of gestation. The offspring were fed the HF diet for 6 weeks after weaning. We measured both global DNA methylation and site-specific methylation of several metabolic genes in the liver, visceral adipose tissue, and brain at both embryonic day E17.5 and after the post-weaning HF feeding. ResultsAt E17.5, HF-MCS led to higher global DNA methylation in both fetal liver and brain. Methylation of one of the CpGs in the promoter region of Srebp1f (a gene that regulates lipogenesis) was also upregulated in the fetal liver by HF-MCS, accordingly there was lower expression of this gene (p < 0.05). However, HF-MCS had opposite effects on global DNA methylation after 6 weeks of post weaning HF feeding than during the fetal period. At this time point, HF-MCS led to hypomethylation of liver and visceral adipose tissue (p < 0.05). Global DNA methylation of the brain was decreased by post-weaning HF feeding but was not affected by maternal HF or MCS (p < 0.01). ConclusionsIn conclusion, MCS during maternal obesity in the perinatal period influences offspring DNA methylation in a time-specific manner. The epigenetic programming effect of MCS needs to be evaluated in both short and long term in the offspring. Funding SourcesNIGMS.

Maternal high fat diet interacts with the maternal microbiome to expand IL-17 producing type 3 innate lymphoid cells in offspring.

Abstract Introduction: Previously, we demonstrated that maternal high fat diet (mHFD) exposure results in a unique pattern of microbial colonization in offspring and subsequent expansion of IL-17 producing type 3 innate lymphoid cells (ILC3). We hypothesized that in utero mechanisms involving the maternal microbiome were responsible for the phenotype in offspring. Methods: To assess if the maternal microbiome was responsible for altering the mHFD offspring phenotype, we delivered mHFD and regular diet (RD)-exposed pups at birth by C-section (CS) and exposed mHFD mothers to broad-spectrum antibiotics (ABX) throughout pregnancy. We cross-fostered the offspring to RD mothers at birth. Microbial colonization in 2-week-old offspring was determined by 16s-based rRNA analysis, intestinal cytokines were quantified by qRT-PCR and lamina propria cells (LP) were profiled by flow cytometry. To determine if innate immunity is altered prenatally by maternal diet, we delivered mHFD and RD offspring by CS and examined the small intestine (SI) at birth for cytokine expression, TLR signaling and LP profiling. Global MyD88 KO mice on mHFD or RD were also examined for the same endpoints. Results: mHFD offspring at 2-weeks showed an expansion of Firmicutes and IL-17 producing ILC3, independent of the mode of delivery. ABX in mHFD mothers ameliorated the mHFD offspring phenotype, with microbial colonization and ILC3 similar to controls. mHFD offspring had altered TLR signaling at birth in SI. ILC3 were expanded at birth in mHFD offspring (14.2% vs 9.5%). MyD88−/− offspring exposed to mHFD did not have an expansion of ILC3. Conclusion: mHFD prenatally alters the offspring microbiome and ILC3 and this effect is dependent on the maternal microbiome and TLR signaling.

Sexual dimorphism in rats exposed to maternal high fat diet: alterations in medullary sympathetic network.

Exposure to high fat diet during perinatal period (PHFD) leads to neuroplastic changes in autonomic circuits, however, the role of gender has been incompletely understood. This study aims to investigate (i) short, and (ii) long-term effects of PHFD on autonomic outflow, and (iii) sexual dimorphic variations emerge at adulthood. Male and female rats were fed a control diet (13.5 % kcal from fat) or PHFD (60 % kcal from fat) from embryonic day-14 to postnatal day-21. To assess changes in autonomic outflow, heart rate variability (HRV) was analyzed at 10- and 20-week-old ages. Expressions of tyrosine hydroxylase (TH), metabotropic glutamate2/3 receptor (mGlu2/3R), N-methyl-D-aspartate1 receptor (NMDA1R), and gamma aminobutyric acidA receptor (GABAAR) were evaluated by immunohistochemistry. PHFD did not affect the body weight of 4-, 10-or 20-week-old male or female offsprings. PHFD significantly increased the sympathetic marker low frequency (LF) component, and sympatho-vagal balance (LF:HF) only in 10-week-old PHFD males. Compared with control, the propranolol-induced (4mg·kg- 1, ip) decline in LF was observed more prominently in PHFD rats, however, these changes were found to be restored at the age of 20 weeks. In caudal ventrolateral medulla and nucleus tractus solitarius, expression of mGlu2/3R was downregulated in PHFD males, whereas no change was detected in NMDA1R. The number of GABAAR-expressing TH-immunoreactive cells was decreased in rostral ventrolateral medulla of PHFD males. The findings of this study suggest that exposure to maternal high-fat diet could lead to autonomic imbalance with increased sympathetic tone in the early adulthood of male offspring rats without developing obesity.

Maternal high sugar and fat diet benefits offspring brain function via targeting on the gut-brain axis.

A recent study showed that a gestational high fat diet protects 3xTg-AD offspring from memory impairments, synaptic dysfunction, and brain pathology. However, it is unknown whether this diet exerts the same effects on normal mice or on other functions, and if so, how. In the present study, mother mice were pre-fed a high sugar and high fat (HSHF) diet for 1 month and then fertilized; the HSHF diet was continued until birth and then mother mice were returned to a standard diet. The gut microbiota, and intestinal and brain functions of the offspring were dynamically monitored at 7, 14, 28, and 56 days old until 16 months of age. Results showed that the HSHF diet significantly affected the gut microbiota structure of the offspring, especially during the early life stage. In addition, in the HSHF diet offspring, there were influenced on various types of neurons, including cholinergic and GABAergic neurons, on autophagy levels in the brain, and on inflammation levels in the intestinal tract. When the offspring grew older (16 months), we found that some genes of benefit against nervous system disease were activated, such as Lhx8, GPR88, RGS9, CD4, DRD2, RXRG, and Syt6, and the expression of cholinergic and GABAergic neurons biomarker protein increased. Although the inflammation levels in the nervous and peripheral systems showed no obvious differences, the AFP level of individuals on the HSHF diet was much higher than those on the standard diet, suggesting that more accurate and/or personalized nutrition is needed. Taken together, the results show that a maternal HSHF diet benefits the offspring by reducing the risk of nervous diseases, which might depend on LHX8 activation to modulate cholinergic and GABAergic neurons via the gut–brain axis, but still need much more deep studies.

Developing Brain Glucose Transporters, Serotonin, Serotonin Transporter, and Oxytocin Receptor Expression in Response to Early-Life Hypocaloric and Hypercaloric Dietary, and Air Pollutant Exposures

Perturbed maternal diet and prenatal exposure to air pollution (AP) affect the fetal brain, predisposing to postnatal neurobehavioral disorders. Glucose transporters (GLUTs) are key in fueling neurotransmission; deficiency of the neuronal isoform GLUT3 culminates in autism spectrum disorders. Along with the different neurotransmitters, serotonin (5-HT) and oxytocin (OXT) are critical for the development of neural connectivity. Serotonin transporter (SERT) modulates synaptic 5-HT levels, while the OXT receptor (OXTR) mediates OXT action. We hypothesized that perturbed brain GLUT1/GLUT3 regulated 5-HT-SERT imbalance, which serves as a contributing factor to postnatal neuropsychiatric phenotypes, with OXT/OXTR providing a counterbalance. Employing maternal diet restriction (intrauterine growth restriction [IUGR]), high-fat (HF) dietary modifications, and prenatal exposure to simulated AP, fetal (E19) murine brain 5-HT was assessed by ELISA with SERT and OXTR being localized by immunohistochemistry and measured by quantitative Western blot analysis. IUGR with lower head weights led to a 48% reduction in male and female fetal brain GLUT3 with no change in GLUT1, when compared to age- and sex-matched controls, with no significant change in OXTR. In addition, a ∼50% (p = 0.005) decrease in 5-HT and SERT concentrations was displayed in fetal IUGR brains. In contrast, despite emergence of microcephaly, exposure to a maternal HF diet or AP caused no significant changes. We conclude that in the IUGR during fetal brain development, reduced GLUT3 is associated with an imbalanced 5-HT-SERT axis. We speculate that these early changes may set the stage for altering the 5HT-SERT neural axis with postnatal emergence of associated neurodevelopmental disorders.

Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet.

BackgroundMaternal high fat diet (HFD) promotes chronic kidney disease (CKD) in offspring. This is in accordance with the theory of fetal programming, which suggests adverse conditions occurring in utero predispose offspring to chronic conditions later in life. DNA methylation has been proposed as a key mechanism by which fetal programming occurs and is implicated in CKD progression. DNA demethylating drugs may interrupt the fetal programming of CKD by maternal obesity. Hydralazine, an antihypertensive agent, demethylates DNA at low doses which do not reduce blood pressure. We used a mouse model of maternal obesity to determine whether gestational administration of low-dose hydralazine to mothers can prevent CKD in offspring.MethodsC57BL/6 dams received HFD or chow from 6 weeks prior to mating and were administered subcutaneous hydralazine (5mg/kg) or saline thrice weekly during gestation. Male offspring were weaned to chow and were sacrificed at either postnatal week 9 or week 32. Biometric and metabolic parameters, renal global DNA methylation, renal structural and functional changes and markers of fibrosis, oxidative stress and inflammation were measured in offspring at weeks 9 and 32.ResultsIn week 9 offspring, maternal HFD consumption did not significantly alter anthropometric or metabolic parameters, or renal global DNA methylation. Week 32 offspring had increased renal global DNA methylation, together with albuminuria, glomerulosclerosis, renal fibrosis and oxidative stress. Administration of low-dose hydralazine to obese mothers during gestation reduced renal global DNA methylation and renal fibrotic markers in week 32 offspring.ConclusionGestational hydralazine reduced renal global DNA methylation in offspring of obese mothers and attenuated maternal obesity-induced renal fibrosis. These data support the use of low-dose hydralazine as a demethylating agent to prevent CKD arising in offspring due to maternal HFD consumption.

Maternal High Fat Diet Consumption Exaggerates Metabolic Disorders in Mice With Cigarette-Smoking Induced Intrauterine Undernutrition.

Objectives: Maternal smoking causes fetal underdevelopment and results in births which are small for gestation age due to intrauterine undernutrition, leading to various metabolic disorders in adulthood. Furthermore, postnatal high fat diet (HFD) consumption is also a potent obesogenic factor, which can interact with maternal smoking. In this study, we aimed to determine whether maternal HFD consumption during pregnancy can reverse the adverse impact of maternal smoking and change the response to postnatal HFD consumption.Methods: Female mice were exposed to cigarette smoke (SE, 2 cigarettes/day) or sham exposed for 5 weeks before mating, with half of the SE dams fed HFD (43% fat, SE+HFD). The same treatment continued throughout gestation and lactation. Male offspring from each maternal group were fed the same HFD or chow after weaning and sacrificed at 13 weeks.Results: Maternal SE alone increased body weight and fat mass in HFD-fed offspring, while SE+HFD offspring showed the highest energy intake and glucose metabolic disorder in adulthood. In addition, postnatal HFD increased the body weight and aggravated the metabolic disorder caused by maternal SE and SE+HFD.Conclusions: Maternal HFD consumption could not ameliorate the adverse effect of maternal SE but exaggerate metabolic disorders in adult offspring. Smoking cessation and a healthy diet are needed during pregnancy to optimize the health outcome in the offspring.