Maternal HF Research Articles

Impact of maternal high-fat diet on offspring gut microbiota during short-term high-fat diet exposure in mice.

Alterations in the gut microbiome have been linked to obesity, with maternal high-fat diet (HF) playing a role in shaping offspring microbiome composition. However, the sex-specific responses to maternal HF diet and the impact of subsequent dietary challenges remain unclear. This study investigated the effects of maternal HF diet on offspring gut microbiota structure and predicted functional profile in response to short-term postnatal HF diet exposure with a focus on sex-specific responses. Female and male offspring of maternal control (C) diet or maternal HF diet were weaned onto C diet or HF diet. Offspring were euthanized at 13 weeks of age and cecal contents were collected for bacterial taxonomic profiling. Maternal HF diet reduced α-diversity, notably in male offspring weaned onto HF diet. Sex-specific differences were observed in the gut microbial composition and predicted functional potential. Furthermore, the influence of maternal diet on bacterial community structure and functional potential varied depending on postnatal diet. Maternal HF diet led to increased relative abundance of Corynebacterium in female offspring and decreased abundance of Akkermansia and Roseburia in male offspring. These findings underscore the sexually dimorphic nature of maternal HF diet effects on gut microbiota composition and function, with implications for developmental programming and metabolic health.

High fat diet consumption and social instability stress impair stress adaptation and maternal care in C57Bl/6 dams

Poor maternal diet and psychosocial stress represent two environmental factors that can significantly impact maternal health during pregnancy. While various mouse models have been developed to study the relationship between maternal and offspring health and behaviour, few incorporate multiple sources of stress that mirror the complexity of human experiences. Maternal high-fat diet (HF) models in rodents are well-established, whereas use of psychosocial stress interventions in female mice are still emerging. The social instability stress (SIS) paradigm, serves as a chronic and unpredictable form of social stress. To evaluate the combined effects of a poor maternal diet and intermittent social stress on maternal health and behaviour, we developed a novel maternal stress model using adult female C57Bl/6 mice. We observed that all HF+ mice demonstrated rapid weight gain, elevated fasting blood glucose levels and impaired glucose tolerance independent of the presence (+) or absence (-) of SIS. Behavioural testing output revealed anxiety-like behaviours remained similar across all groups prior to pregnancy. However, integrated anxiety z-scores revealed a mixed anxious profile amongst HF+/SIS+ females prior to pregnancy. HF+/SIS+ females also did not show reduced plasma ACTH and corticosterone levels that were observed in our other HF+ and HF- stress groups after SIS exposure. Further, HF+/SIS+ females demonstrated significant postpartum maternal neglect, resulting in fewer numbers of live offspring. These findings suggest that prolonged maternal HF diet consumption, coupled with previous exposure to SIS, places a significant burden on the maternal stress response system, resulting in reduced parental investment and negative postpartum behaviour towards offspring.

Maternal High Fat Diet and its Expressions in the Heart and Liver in the Mice Embryogenesis.

The developmental biology for the nonalcoholic fatty liver disease and coronary heart disease are known but elaborative ideas of triglycerides phenomenon in the embryo-genesis of the liver and the heart are still not clear. The aim of the study was to relate different triglycerides like LXRα, LPL, LDL R, PPARG-, SREBP-1C expression in the high fat fed mice with the normal fed diet mice in the process of developmental and embryo-genesis biology. Tissue preparation was done by ripalysis. Different protein content was obtained via western blot for the 6 samples namely a-17.5 days mice embryo heart; b- 0th day or the birthday mice infant heart; c-1 week mice infant heart; d-2 weeks mice infant heart; e-3 weeks mice infant heart; f-Adult mice heart. Protein lysates from the heart tissues of the mice was obtained via homegenization and centrifugation. Hematoxylin and Eosin (H and E) was done to see the fat droplets in the liver tissues at the different developmental stages. LXRα,SREBP-1C expression in 17.5 days mice embryo heart and 0th day or the birthday mice infant heart is highly expressed in the high fat diet. LDL-R in the high fat diet mice is increased in 2 weeks mice infant heart but in17.5 days mice embryo heart and in 0th day or the birthday mice infant heart it is low expression but from 1week mice infant heart to the adult mice heart the expression is in decreasing trend. Similarly LPL is highly expressed in17.5 days mice embryo heart and 1 week mice infant heart and thus low expression in decreasing order until adult mice heart.Thus, these results collectively shows that maternal HF diet increases expression of proteins such as LPL, LDLr in the embryo phase and thus getting normal expressions in the adult phase that facilitate Triglycerides (TAG) hydrolysis across the liver and the heart. Also,maternal high fat diet increases the SREBP1c expression, leading to stimulation of LPL Expression. In summary, using a pregnant mice model, we found that maternal high fat diet increases the fetal fat accumulation. Elevated placental LPL activity and expression of genes that facilitate placental lipid transport suggest that enhanced placental lipid transport may play a key role in maternal nutrition and obesity-induced fetal fat accumulation.

Fish oil supplementation during pregnancy decreases liver endocannabinoid system and lipogenic markers in newborn rats exposed to maternal high-fat diet.

Maternal high-fat diet (HF) programs obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), hypertriglyceridemia, and hyperglycemia associated with increased endocannabinoid system (ECS) in the liver of adult male rat offspring. We hypothesized that maternal HF would induce sex specific ECS changes in the liver of newborn rats, prior to obesity onset, and maternal fish oil (FO) supplementation would reprogram the ECS and lipid metabolism markers preventing liver triglycerides (TG) accumulation. Female rats received a control (CT) (10.9% fat) or HF (28.7% fat) diet 8weeks prior to mating and during pregnancy. A subgroup of HF dams received 3% FO supplementation in the HF diet (35.4% fat) during pregnancy (HFFO). Serum hormones and liver TG, ECS, lipid metabolism, oxidative stress and autophagy markers were assessed in male and female newborn offspring. Maternal HF diet increased liver cannabinoid receptor 1 (CB1) in males and decreased CB2 in females, with no effect on liver TG. Maternal FO supplementation reduced liver CB1 regardless of the offspring sex, but reduced TG liver content only in females. FO reduced the liver content of the endocannabinoid anandamide in males, and the content of 2-arachidonoylglycerol in both sexes. Maternal HF increased lipogenic and decreased lipid oxidation markers, and FO induced the opposite regulation in the liver of offspring. Prenatal HF and FO differentially modulate liver ECS in the offspring before obesity and MASLD development. These results suggest that maternal nutrition at critical stages of development can modulate the offspring's ECS, predisposing or preventing the onset of metabolic diseases.

Characterization of milk oligosaccharide and sialic acid content and their influence on brain sialic acid in a lean mouse model for gestational diabetes

Oligosaccharides and sialic acids (Sia) are bioactive components in milk that contribute to newborn development and health. Hyperglycemia in pregnancy (HIP) can have adverse effects on both mother and infant. HIP is associated with low-grade systemic inflammation. Inflammation influenced glycan composition, particularly of Sia-containing structures. We hypothesize that HIP and high-fat diet influence milk oligosaccharide composition, particularly sialylated oligosaccharides. Furthermore, we propose that milk Sia content influences pup brain Sia content. To test these hypotheses we (i) characterize mouse milk oligosaccharides and Sia concentrations in mouse milk of a GDM mouse model with dietary fat intake intervention; and (ii) determine Sia levels in offspring brains.The concentrations of oligosaccharides and Sia in mouse milk and offspring's brains were quantified using UPLC-FLD analysis. Analyses were performed on surplus samples from a previous study, where HIP was induced by combining high-fat diet (HF) feeding and low-dose streptozotocin injections in C57Bl/6NTac female mice. The previous study described the metabolic effects of HIP on dams and offspring.We detected 21 mouse milk oligosaccharides, including 9 neutral and 12 acidic structures using UPLC-MS. A total of 8 structures could be quantified using UPLC-FLD. Maternal HIP and HF diet during lactation influenced sialylated oligosaccharide concentrations in mouse milk and total and free sialic acid concentrations. Sia content in offspring brain was associated with total and free Neu5Gc in mouse milk of dams, but no correlations with HIP or maternal diet were observed.

Multi-Omics Data Integration Reveals Sex-Dependent Hippocampal Programming by Maternal High-Fat Diet during Lactation in Adult Mouse Offspring.

Early-life exposure to high-fat diets (HF) can program metabolic and cognitive alterations in adult offspring. Although the hippocampus plays a crucial role in memory and metabolic homeostasis, few studies have reported the impact of maternal HF on this structure. We assessed the effects of maternal HF during lactation on physiological, metabolic, and cognitive parameters in young adult offspring mice. To identify early-programming mechanisms in the hippocampus, we developed a multi-omics strategy in male and female offspring. Maternal HF induced a transient increased body weight at weaning, and a mild glucose intolerance only in 3-month-old male mice with no change in plasma metabolic parameters in adult male and female offspring. Behavioral alterations revealed by a Barnes maze test were observed both in 6-month-old male and female mice. The multi-omics strategy unveiled sex-specific transcriptomic and proteomic modifications in the hippocampus of adult offspring. These studies that were confirmed by regulon analysis show that, although genes whose expression was modified by maternal HF were different between sexes, the main pathways affected were similar with mitochondria and synapses as main hippocampal targets of maternal HF. The effects of maternal HF reported here may help to better characterize sex-dependent molecular pathways involved in cognitive disorders and neurodegenerative diseases.

303-OR: Maternal High-Fat Diet Alters the Gut Microbiota–Liver Circadian Rhythms and Results In Metabolic Dysfunction in Offspring

Maternal high-fat diet (HF) disturbs the gut microbiota-liver interactions and induces negative effects in the offspring, but its impact on metabolic, gut microbial, and hepatic circadian rhythms in the offspring (F1) are unknown. Here, we tested whether maternal HF could disrupt the metabolic rhythm in the juvenile (postnatal day [PND] 28) and adult offspring (PND112). Metagenomics, transcriptome, and metabolomics throughout the gut microbiota-liver axis were used to investigate the mechanism underpinning metabolic changes in the juvenile offspring. eJTK_Cycle was applied to characterize rhythmic patterns. Both juvenile and adult offspring of HF dams exhibited deteriorated glucose tolerance (P < 0.05) and a gain of the rhythm of serum glucose level (Control [Ctr], adjP > 0.05; HF, adjP < 0.05). Maternal HF altered the compositional and functional circadian rhythms of gut microbiota in the juvenile offspring. The rhythm of capacity for gut microbial synthesis of the short-chain fatty acid acetate was significantly gained in the juvenile offspring of HF dams (Ctr, adjP > 0.05; HF, adjP < 0.05). Consistently, maternal HF induced a rhythm gain of serum and liver acetate in the juvenile offspring (Ctr, adjP > 0.05; HF, adjP < 0.05). Meanwhile, maternal HF resulted in a gain of the rhythm of hepatic G6pc (Ctr, adjP > 0.05; HF, adjP < 0.05), a marker of gluconeogenesis metabolism. G6pc rhythmic expression was significantly correlated with serum acetate (R = 0.58, P < 0.05) and liver acetate (R = 0.64, P < 0.05) in the juvenile offspring. Taken together, we show that maternal HF disrupted the metabolic rhythm and the gut microbiota-liver rhythms, increasing susceptibility to metabolic dysfunction in the offspring. Disclosure L.Ding: None. J.Liu: None. Q.Zhang: None. X.Xiao: None. Funding National Natural Science Foundation of China (81870579)

IDENTIFICATION OF CRITICAL LACTATION STAGE FOR THE BODY COMPOSITION IN MALE OFFSPRING OF HIGH-FAT FED DAMS

Each stage (early, middle and late) of lactation is a critical period during which maternalmalnutritional can negatively effects on the offspring's body development. We investigatedthe effects of a maternal high fat diet (HF) during the different stages of lactation on bodyweight of male offspring at weaning. Female Wistar rats were fed either a HF diet only duringthe first week (HF1-7 group), second week (HF7-14 group), third week (HF14-21 group) andthroughout lactation (group HF1-21) or standard diet during all lactation. Biometricparameters of dams and male offspring were evaluated. HF fed dams did not have a differencein body weight, food intake and fat pad compared with the control dams. Regarding theoffspring, a higher final body weight was observed in males from the HF7-14 and HF14-21and HF21 groups compared to the control. There was an increase in retroperitoneal andmesenteric fat in HF21 and HF14-21 compared with control groups. Higher perigonadal fatpat was only observed in HF21. Consumption of maternal HF diet throughout lactation causeshigh body weight in male offspring. Interestingly, each isolated phase also causes importantbody weight accumulation, mainly the second and third week.

Offspring NAFLD liver phospholipid profiles are differentially programmed by maternal high-fat diet and maternal one carbon supplement

Little is known if and how maternal diet affects the liver phospholipid profiles that contribute to non-alcoholic fatty liver disease (NAFLD) development in offspring. We examined NAFLD phenotypes in male offspring mice of either maternal normal-fat diet (NF group), maternal high-fat diet (HF group), maternal methionine supplement (H1S group), or complete one-carbon supplement (H2S group) added to the maternal HF diet during gestation and lactation. HF offspring displayed worsened NAFLD phenotypes induced by post-weaning HF diet, however, maternal one-carbon supplement prevented such outcome. HF offspring also showed a distinct phospholipid profile from the offspring exposed to H1S or H2S diet. Whole genome bisulfite sequencing (WGBS) analysis further identified five pathways involved in phospholipid metabolism altered by different maternal diet interventions. Furthermore, differential methylated regions (DMRs) on Prkca, Dgkh, Plcb1 and Dgki were identified comparing between HF and NF offspring; most of these DMRs were recovered in H2S offspring. These methylation pattern changes were associated with gene expression changes: HF diet significantly reduced while H1S and H2S diet recovered their levels. Maternal HF diet disrupted offspring phospholipid profiles contributing to worsened hepatic steatosis. The maternal one-carbon supplement prevented such effects, probably through DNA methylation modification.

Effects of maternal HF diet and absence of TRPC1 gene on mouse placental growth and fetal intrauterine growth retardation (IUGR)

Placental tissue intracellular calcium (Ca2+) regulates placental development and growth. Maternal high-fat diet (HFD) results in placental lipid accumulation, increased inflammation, reduced nutrient transport expression, and intrauterine growth restriction (IUGR). Currently, whether maternal HFD differentially affects placental and fetal growth and development under reduced Ca2+ influx is not yet known. We hypothesized that maternal HFD feeding decreases placental growth and development resulting in IUGR and that reduction of Ca2+ influx in the placenta worsens maternal HFD-induced placental dysfunction and IUGR. Three-week-old female B6129SF2/J wild type (WT) and transient receptor potential canonical 1 (TRPC1) protein deficient (KO) mice were fed normal fat (NF, 16 kcal % fat) and high fat (HF, 45 kcal % fat) diets for 12 weeks prior to mating with NF diet fed male mice. Fetuses and placentae were examined at mid- (D12) and late- (D18) gestation. At D12, maternal HFD had no effects on placental or fetal weight changes in WT and TRPC1 KO mice while absence of TRPC1 resulted in decreased placental and fetal weights. At D18, maternal HFD increased placental weights in both TRPC1 KO and WT mice, in part, by moderately increasing placental tissue triacylglyceride (TAG, P=.0632). At D12, mRNA expression of key placental growth factors including IGF1, PLGF, and VEGF were increased in WT compared to TRPC1 KO mice while IGF2 and VEGF mRNA expression were increased at D18. Results presented in our study demonstrated that maternal HFD increased placental weight, in part, due to increased lipid concentration resulting in IUGR and via an additive adverse effect of genotype and maternal HFD. Future studies are needed to determine the signaling mechanism underlying Ca2+ influx reduction-induced placental dysfunction and IUGR.

Effect of a maternal high-fat diet with vegetable substitution on fetal brain transcriptome

Maternal dietary conditions play a major role in fetal growth and brain development. The primary aim of this study was to determine the effects of 5% of energy substitution by vegetables in a maternal dietary fat on placental and fetal weight and on fetal brain gene expression. Two-month-old female C57BL/6 mice were fed 16% (normal-fat, NF), 45% fat (HF), or HF substituted with vegetables (5% energy, HF+VS) diets for 12 weeks. Dams were then bred with NF diet-fed male mice. Placenta and fetal weights were measured at gestational age 19 (D19). RNA was isolated from fetal whole brains and sequenced using Illumina HiSeq. HF+VS diet prevented maternal HF diet-induced decreases in placental weight at D19. Feeding of a maternal HF diet was associated with 79 differentially expressed genes (DEGs), while maternal vegetable substitution was associated with 131 DEGs. The vegetable substitution diet decreased Apold1 (P=.0319), Spata2l (P=.0404), and Celsr1 (P<.03) expression compared to HF diet. Enrichment analysis of HF vs. HF+VS DEGs identified that synapse organization and regulation of embryonic development were significantly represented. KEGG enrichment analysis identified a significant representation of DEGs in the ubiquitin mediated proteolysis pathway in HF vs. HF+VS, and chemokine signaling pathway in NF vs. HF. These findings suggest that at D19, in a rodent model, a maternal HF diet alters placental and fetal growth, and that vegetable supplementation renders a protective effect against these changes.

Maternal high‐fat diet disrupted one‐carbon metabolism in offspring, contributing to nonalcoholic fatty liver disease

AbstractBackground &amp; AimsPregnant women may transmit their metabolic phenotypes to their offspring, enhancing the risk for nonalcoholic fatty liver disease (NAFLD); however, the molecular mechanisms remain unclear.MethodsPrior to pregnancy female mice were fed either a maternal normal‐fat diet (NF‐group, “no effectors”), or a maternal high‐fat diet (HF‐group, “persistent effectors”), or were transitioned from a HF to a NF diet before pregnancy (H9N‐group, “effectors removal”), followed by pregnancy and lactation, and then offspring were fed high‐fat diets after weaning. Offspring livers were analysed by functional studies, as well as next‐generation sequencing for gene expression profiles and DNA methylation changes.ResultsThe HF, but not the H9N offspring, displayed glucose intolerance and hepatic steatosis. The HF offspring also displayed a disruption of lipid homeostasis associated with an altered methionine cycle and abnormal one‐carbon metabolism that caused DNA hypermethylation and L‐carnitine depletion associated with deactivated AMPK signalling and decreased expression of PPAR‐α and genes for fatty acid oxidation. These changes were not present in H9N offspring. In addition, we identified maternal HF diet‐induced genes involved in one‐carbon metabolism that were associated with DNA methylation modifications in HF offspring. Importantly, the DNA methylation modifications and their associated gene expression changes were reversed in H9N offspring livers.ConclusionsOur results demonstrate for the first time that maternal HF diet disrupted the methionine cycle and one‐carbon metabolism in offspring livers which further altered lipid homeostasis. CpG islands of specific genes involved in one‐carbon metabolism modified by different maternal diets were identified.

Maternal and offspring high-fat diet leads to platelet hyperactivation in male mice offspring

Maternal over-nutrition increases the risk of diabetes and cardiovascular events in offspring. While prominent effects on cardiovascular health are observed, the impact on platelet physiology has not been studied. Here, we examined whether maternal high-fat diet (HF) ingestion affects the platelet function in lean and obese offspring. C57BL6/N mice dams were given a HF or control (C) diet for 8 weeks before and during pregnancy. Male and female offspring received C or HF diets for 26 weeks. Experimental groups were: C/C, dam and offspring fed standard laboratory diet; C/HF dam fed standard laboratory diet and offspring fed HF diet; HF/C and HF/HF. Phenotypic and metabolic tests were performed and blood collected for platelet studies. Compared to C/C, offspring HF groups were obese, with fat accumulation, hyperglycaemia and insulin resistance. Female offspring did not present platelet hyperactivity, hence we focused on male offspring. Platelets from HF/HF mice were larger, hyperactive and presented oxidative stress when compared to C/C. Maternal and offspring HF diet results in platelet hyperactivation in male mouse offspring, suggesting a novel ‘double-hit’ effect.

Maternal diet intervention before pregnancy primes offspring lipid metabolism in liver

Nonalcoholic fatty liver disease (NAFLD) has a developmental origin and is influenced in utero. We aimed to evaluate if maternal diet intervention before pregnancy would be beneficial to reduce the risk of offspring NAFLD. In our study, female mice were either on a normal-fat diet (NF group), or a high-fat diet for 12 weeks and continued on this diet throughout pregnancy and lactation (HF group), or switched from HF-to-NF diet 1 week (H1N group), or 9 weeks (H9N group) before pregnancy. Compared with the NF offspring, the H1N and HF, but not the H9N offspring, displayed more severe hepatic steatosis and glucose intolerance. More specifically, an abnormal blood lipid panel was seen in the H1N offspring and abnormal hepatic free fatty acid composition was present in both the HF and H1N offspring, while the H9N offspring displayed both at normal levels. These physiological changes were associated with desensitized hepatic insulin/AKT signaling, increased expression of genes and proteins for de novo lipogenesis and cholesterol synthesis, decreased expression of genes and proteins for fatty acid oxidation, increased Pcsk9 expression, and hypoactivation of 5′ AMP-activated protein kinase (AMPK) signaling in the HF and H1N offspring. However, these effects were completely or partially rescued in the H9N offspring. In summary, we found that early maternal diet intervention is effective in reducing the risk of offspring NAFLD caused by maternal HF diet. These findings provide significant support to develop effective diet intervention strategies and policies for prevention of obesity and NAFLD to promote optimal health outcomes for mothers and children.

Maternal Exposure to Bisphenol A Combined with High-Fat Diet-Induced Programmed Hypertension in Adult Male Rat Offspring: Effects of Resveratrol.

Maternal exposure to endocrine disrupting chemicals (EDCs) and a high-fat intake may induce the developmental programming of hypertension in adult offspring. Bisphenol A (BPA) is one of the most commonly environmental EDCs. As the nitric oxide (NO) and aryl hydrocarbon receptor (AHR) signaling pathways both contribute to the pathogenesis of hypertension, we evaluated whether resveratrol, an antioxidant and an AHR antagonist, can prevent hypertension programmed by a maternal BPA and HF diet. Sixteen-week-old male rat offspring were assigned to six groups (n = 8 per group): Control, HF (D12331, Research Diets), BPA (50 μg/kg/day), HF + BPA, BPA + R (resveratrol 50mg/L in drinking water throughout pregnancy and lactation), and HF + BPA + R. Maternal BPA exposure exacerbated hypertension programmed by HF consumption in adult male offspring, which was protected by maternal resveratrol therapy. The BPA and HF diet synergistically induced oxidative stress in offspring kidneys, which resveratrol treatment prevented. We observed that HF + BPA-induced programmed hypertension was associated with a decreased NO bioavailability, increased oxidative stress, and an activated AHR signaling pathway. The beneficial effects of resveratrol are relevant to restoring NO bioavailability, reducing oxidative stress, and antagonizing the AHR signaling pathway. Our results cast a new light on resveratrol as a reprogramming strategy to protect against hypertension programmed by combined BPA and HF exposure, but this strategy has yet to be translated into clinical applications.

Maternal Genistein Intake Mitigates the Deleterious Effects of High-Fat Diet on Glucose and Lipid Metabolism and Modulates Gut Microbiota in Adult Life of Male Mice.

Adverse early-life exposures program increased risk of chronic metabolic diseases in adulthood. However, the effects of genistein supplementation in early life on metabolic health in later life are largely unclear. Our objective was to investigate whether maternal genistein intake could mitigate the deleterious influence of a maternal high-fat diet on glucose and lipid metabolism in offspring and to explore the role of gut microbiota in mediating the transgenerational effects. C57BL/6 female mice were fed either a high-fat diet (HF), high-fat diet with genistein (0.6 g/kg diet) (HFG) or normal control diet (C) for 3 weeks before pregnancy and throughout pregnancy and lactation. The male offspring had ad libitum access to normal chow diet from weaning to 24 weeks of age. Then the content of inguinal subcutaneous adipose tissue (SAT) and epididymal visceral adipose tissue (VAT) were weighed. Glucose tolerance test (GTT), the level of serum insulin and lipid profiles were analyzed. The caecal contents were collected for 16S rDNA sequencing. The results showed that maternal genistein intake could significantly reduce blood glucose levels during GTT, fasting insulin levels, VAT mass and serum triglyceride levels as well as increase high-density lipoprotein cholesterol in adult male offspring. Significant decrease of germs from the Tenericutes phylum and enrichment of Rikenella as well as SCFA (short-chain fatty acid)-producing bacteria, including Alloprevotella, Odoribacter, and Clostridium XlVa, in offspring of genistein fed dams might play crucial roles in the improvement of glucose and lipid metabolism. Overall, early-life genistein intake attenuated the harmful effects of maternal HF on metabolism in adult offspring and the protective effects were associated with the alterations in gut microbiota, which provides new evidence and targets for mitigate the poor effects of adverse early-life exposures on metabolic health in later life.

Maternal and Post-weaning High-Fat Diets Produce Distinct DNA Methylation Patterns in Hepatic Metabolic Pathways within Specific Genomic Contexts.

Calorie-dense high-fat diets (HF) are associated with detrimental health outcomes, including obesity, cardiovascular disease, and diabetes. Both pre- and post-natal HF diets have been hypothesized to negatively impact long-term metabolic health via epigenetic mechanisms. To understand how the timing of HF diet intake impacts DNA methylation and metabolism, male Sprague–Dawley rats were exposed to either maternal HF (MHF) or post-weaning HF diet (PHF). At post-natal week 12, PHF rats had similar body weights but greater hepatic lipid accumulation compared to the MHF rats. Genome-wide DNA methylation was evaluated, and analysis revealed 1744 differentially methylation regions (DMRs) between the groups with the majority of the DMR located outside of gene-coding regions. Within differentially methylated genes (DMGs), intragenic DNA methylation closer to the transcription start site was associated with lower gene expression, whereas DNA methylation further downstream was positively correlated with gene expression. The insulin and phosphatidylinositol (PI) signaling pathways were enriched with 25 DMRs that were associated with 20 DMGs, including PI3 kinase (Pi3k), pyruvate kinase (Pklr), and phosphodiesterase 3 (Pde3). Together, these results suggest that the timing of HF diet intake determines DNA methylation and gene expression patterns in hepatic metabolic pathways that target specific genomic contexts.

Maternal Diet Transition Before Pregnancy Plays a Transgenerational Effect on Offspring Lipid Homeostasis in Liver (P11-143-19)

ObjectivesIt is now clear that non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has a developmental origin. Thus, we aims on to evaluate if a maternal diet intervention before pregnancy would be beneficial to reduce the risk for offspring NAFLD. MethodsIn our study, female mice were either on an NF diet (NF group), or a HF diet (HF group), for 9 weeks and continued on such diet through pregnancy and gestation, or switched from the 9-week HF to an NF diet for 1 week (H1N group) or 9 weeks (H9N group) before pregnancy. After weaning, the male offspring were given the HF diet for 12 weeks to promote NAFLD. ResultsComparing to the NF offspring, the H1N and HF but not the H9N offspring, displayed more severe hepatic steatosis and glucose intolerance. More specifically, the H1N and HF offspring had abnormal blood lipid panel and abnormal free fatty acid composition in liver, while the H9N offspring displayed normal. These physiological changes were associated with a desensitized hepatic insulin/AKT signaling, an increased expression of genes and proteins for de novo lipogenesis, a decreased expression of genes and proteins for fatty acid oxidation, increased Pcsk9 expression and the AMPK signaling hypoactivation in the HF and H1N offspring. However, these effects were either completely or partially avoided in the H9N offspring. ConclusionsIn summary, we showed that an early maternal diet intervention is efficient to reduce the risk for offspring NAFLD caused by the maternal HF diet. These information will provide significant support for setting up guidelines that women at childbearing age could follow to select the ideal diets, prior to and during pregnancy, which not only immediately benefit the pregnant outcome but also give a long-term beneficial effect on offspring health. Funding SourcesThis project is supported by grants from the National Institutes of Health (NIDDK 1R01DK112368-01 to LX and KZ) and the USDA National Institute of Food and Agriculture, [Hatch] project [1010406] to LX.

Maternal high-fat diet consumption induces sex-dependent alterations of the endocannabinoid system and redox homeostasis in liver of adult rat offspring

Maternal diet plays a critical role in health development. Perinatal overnutrition induces metabolic dysfunctions and obesity in the offspring. Obesity is associated with endocannabinoid system (ECS) over activation and oxidative stress. Liver ECS activation induces hepatic steatosis, inflammation and fibrosis while the antagonism of cannabinoid receptors ameliorates these alterations. Here, we investigated the effect of perinatal maternal high-fat diet (HF, 29% of calories as fat) on the ECS and antioxidant system in liver of male and female adult rat offspring (180 days old). Maternal HF diet increased hepatic cannabinoid receptors, ECS metabolizing enzymes and triglyceride content, with male offspring more affected. ECS changes are likely independent of estradiol serum levels but associated with increased hepatic content of estrogen receptor, which can stimulate the expression of ECS components. Differently, maternal HF diet decreased the activity of the antioxidant enzymes glutathione peroxidase, superoxide dismutase and catalase, and increased oxidative stress markers in both sexes. Alterations in the redox homeostasis were associated with mitochondria damage but not with liver fibrosis. Our data suggest that maternal HF diet induces ECS over activation in adulthood, and that male offspring are at higher risk to develop liver disease compared with female rats.

Perinatal high fat diet and early life methyl donor supplementation alter one carbon metabolism and DNA methylation in the brain.

One carbon metabolism is regulated by the availability of nutrients known as methyl donors, and disruption of this pathway can affect multiple physiological systems. DNA methylation, critical for the regulation of gene expression, is linked to one carbon metabolism, and can be altered by perinatal diet. In this study, dams (n=12/group) were fed HF or standard control (SC) diet through pregnancy and lactation, and male and female offspring were then fed either SC or methyl donor-supplemented diet (MDS) between 3 and 6weeks of age (n=20-26/group). Concentration of one carbon intermediates and other related metabolites were assessed within brain tissue (prefrontal cortex, PFC) through the use of mass spectrometry at 6weeks of age. In addition, the expression of target genes and enzymes that participate in DNA methylation or are relevant to one carbon metabolism were measured. We found that MDS increases the concentration of folate intermediates in the PFC, and that this increase is blunted in male offspring from dams fed a HF diet. In addition, perinatal HF diet increased the concentration of cysteine in the PFC of both male and female offspring, consistent with oxidative stress. Furthermore, both maternal HF diet and postnatal MDS altered global DNA methylation in the PFC in males but not females. Collectively, these data demonstrate sex differences in changes in one carbon metabolites in the prefrontal cortex in response to early life high fat diet and methyl donor supplementation. Read the Editorial Highlight for this article on page 358.