Metabolic Outcomes In Offspring Research Articles

The P300-ARRDC3 axis participates in maternal subclinical hypothyroidism and is involved in abnormal hepatic insulin sensitivity in adult offspring

Numerous studies have suggested potential associations between maternal subclinical hypothyroidism (SCH) and adverse metabolic outcomes in offspring, however, the underlying mechanism remains unclear. In this study, we generated a maternal SCH mouse model by administering 50 ppm 6-propyl-2-thiouracil (PTU) in the drinking water of pregnant mice until delivery. This model was used to investigate the mechanisms influencing glucose metabolism in offspring. RNA sequencing (RNA-seq) revealed a substantial increase in ARRDC3 expression in the livers of the offspring of the SCH model mice, which may contribute to insulin resistance. Additionally, the phosphorylation levels of key proteins in the insulin signalling pathway, such as protein kinase B (Akt), glycogen synthase kinase 3 beta (GSK-3β), and Forkhead box protein O1 (FoxO1), were correspondingly reduced in the SCH offspring. Moreover, overexpression of ARRDC3 in Hepa1‒6 cells suppressed the Akt/GSK-3β/FoxO1 signalling pathway and increased the expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), which was consistent with the molecular changes observed in SCH offspring. Our results also indicated that the upregulation of ARRDC3 in SCH offspring may result from increased H3K27 acetylation of the ARRDC3 promoter region, driven by elevated expression of P300. Importantly, adequate L-T4 supplementation during pregnancy improved insulin sensitivity and reversed the molecular alterations in the insulin signalling pathway observed in SCH offspring. In conclusion, exposure to intrauterine SCH resulted in altering the P300-ARRDC3 axis in offspring and impaired insulin sensitivity by disrupting the Akt/GSK-3β/FoxO1 signalling pathway. Timely L-T4 supplementation during pregnancy is an effective strategy to prevent insulin resistance in offspring of SCH mothers. This study elucidates potential molecular mechanisms behind insulin resistance in SCH offspring and suggests novel therapeutic targets for treating metabolic disorders related to maternal SCH.

Maternal hypothyroidism and subsequent metabolic outcomes in children: a systematic review and meta-analysis

IntroductionAs the fetus relies on maternal thyroid hormones in early pregnancy, maternal hypothyroidism plays an important role in fetal development. However, the association between maternal hypothyroidism and metabolic disease in offspring is unclear.ObjectiveTo examine the association between maternal hypothyroidism in pregnancy and metabolic outcomes (obesity, hypertension, type 2 diabetes mellitus, and dyslipidemia) in children < 18 years.MethodsWe systematically searched 5 databases from inception to May 2023. Eligible studies included cohort, case-control, and randomized controlled trials involving children born to mothers with or without hypothyroidism in pregnancy. Data were pooled across studies using random-effects models for outcomes reported in at least three studies. Quality assessment was performed using the ROBINS-E tool for observational studies and the Cochrane Risk of Bias tool for trials.ResultsThe search identified 3221 articles, of which 7 studies were included (1 trial, 6 observational). All studies were conducted outside of North America and ranged in size from 250 to > 1 million children. The follow-up time ranged from 6 to 20 years. Included studies support an increased risk of hypertension and glucose dysregulation in offspring exposed to maternal hypothyroidism (hypertension: OR 1.08, 95% CI 0.75, 1.57 and HR 1.81, 95% CI 1.21, 2.69; diabetes: RR 2.7, 95% CI 0.7, 10). In the pooled analysis, maternal hypothyroidism was not associated with obesity in offspring (OR 1.04, 95% CI 0.64, 1.70).ConclusionThis study found inconsistent evidence on the association between maternal hypothyroidism in pregnancy and metabolic outcomes in offspring, though associations with hypertension and glucose dysregulation are possible.

Long-term Neurobehavioral and Metabolic Outcomes in Offspring of Mothers With Diabetes During Pregnancy: A Large, Population-Based Cohort Study in Ontario, Canada.

Offspring of women with diabetes are at increased risk of developing neurobehavioral and cardiometabolic disorders, but there is scant evidence regarding the association between glycemic level during pregnancy and these long-term offspring outcomes. We conducted a population-based, cohort study of deliveries in Ontario between April 1991 and March 2018. Women had preexisting diabetes, gestational diabetes, or no diabetes. We applied a Cox proportional hazard model to examine the risk of developing attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and cardiometabolic outcomes in offspring and assessed the association between pregnancy HbA1c levels and risk of outcomes, adjusting for confounders. A total of 3,407,961 mother/infant pairs were followed up to 29 years. Using a Cox proportional hazard model, offspring of women with type 1 diabetes had the highest risk of ADHD (adjusted hazard ratio [aHR] 1.43 [95% CI 1.36-1.49]), ASD (aHR 1.94 [1.80-2.09]), diabetes (aHR 4.73 [4.34-5.16]), hypertension (aHR 2.32 [2.07-2.61]), and cardiovascular disease (CVD) (aHR 1.72 [1.56-1.90]), followed by offspring of women with type 2 diabetes and gestational diabetes compared with those unexposed. Among women with preexisting diabetes, there was an association between level of pregnancy HbA1c and offspring diabetes (aHR 1.22 [95% CI 1.12-1.32]), hypertension (aHR 1.42 [1.29-1.57]), and CVD (aHR 1.20 [1.11-1.29]) but no statistically significant association with neurobehavioral outcomes. In utero exposure to maternal diabetes was associated with an increase in ADHD, ASD, and cardiometabolic outcomes in offspring, with differences seen across diabetes subtypes. Pregnancy glycemia was associated with cardiometabolic outcomes, but not neurobehavioral outcomes, and provides a potentially modifiable risk factor to decrease cardiometabolic outcomes in offspring.

Transcriptomics integrated with metabolomics reveals perfluorobutane sulfonate (PFBS) exposure effect during pregnancy and lactation on lipid metabolism in rat offspring

Emerging epidemiological evidence indicates potential associations between gestational perfluorobutane sulfonate (PFBS) exposure and adverse metabolic outcomes in offspring. However, the underlying mechanisms remain unclear. Our study aimed to investigate PFBS exposure effects during pregnancy and lactation on rat offspring lipid profiles and the possible underlying mechanisms. Although the biochemical index difference including total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), alanine amino transaminase (ALT), aspartate amino transferase (AST), and fasting blood glucose between exposed groups and the control group was not significant, transcriptome analyses showed that the differentially expressed genes (DEGs) in the 50 mg/kg/day PFBS exposure group were significantly related to protein digestion and absorption, peroxisome proliferator activated-receptor (PPAR) signaling pathway, xenobiotic metabolism by cytochrome P450, glycine, serine and threonine metabolism, β-alanine metabolism, bile secretion, unsaturated fatty acid (FA) biosynthesis, and alanine, aspartate and glutamate metabolism. Untargeted metabolomics analyses identified 17 differential metabolites in the 50 mg/kg/day PFBS exposure group. Among these, phosphatidylserine [PS (18:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z))], lysoPE (18:1(11Z)/0:0), and PS (14:0/20:4(5Z,8Z,11Z,14Z)) were significantly correlated with phospholipid metabolism disorders. Correlation analysis indicated the DEGs, including FA binding protein (Fabp4), spermine oxidase (Smox), Fabp2, acyl-CoA thioesterase 5 (Acot5), sarcosine dehydrogenase (Sardh), and amine oxidase, copper-containing 3 (Aoc3) that significantly enriched in xenobiotic metabolism by cytochrome P450 and glycine, serine, and threonine metabolism signaling pathways were highly related to the differential metabolite pantetheine 4’−phosphate. Pantetheine 4′-phosphate was significantly negatively associated with non-high-density lipoprotein (non-HDL) and TC levels. Collectively, our study indicated that maternal PFBS exposure at a relatively low level could alter gene expression and metabolic molecules in lipid metabolism-related pathway series in rat offspring, although the effects on metabolic phenotypes were not significant within the limited observational period, using group-wise and trend analyses.

Maternal exercise shifts adiposity distribution in offspring towards energy burning brown fat

Human epidemiological and animal studies show the maternal in utero environment significantly impacts offspring development. This includes sedentary lifestyle, which is linked to developmental programming of metabolic dysfunction. The aim of this study was to investigate metabolic outcomes in offspring of sedentary mice versus mice that exercised in pregnancy. C57BL/6J female mice were placed on control diet and allocated to sedentary (SED) versus voluntary running wheel exercise (EX) cages. Voluntary wheel running was allowed 2 weeks prior to breeding and throughout weaning. Offspring underwent body composition measurement and insulin and glucose tolerance tests at 6 and 12 weeks of age, were placed in an indirect calorimetry system to assess energy balance at 14 weeks, and were euthanized for collection of adipose depots at 16 weeks. Outcomes were analyzed by two-way ANOVA to assess effects of exercise, sex, and their interaction. We studied metabolic function in 11 male SED, 13 female SED, 15 male EX, and 13 female EX offspring. While body mass and adiposity were similar among groups, EX mice had less subcutaneous white adipose (% body mass: 1.26±0.09 male SED vs. 0.87±0.06 male EX vs. 1.15±0.11 female SED vs. 0.95 ±0.04 female EX; PSex=0.871, PEX=0.001, PInt=0.237) and more brown adipose (% body mass: 0.31±0.03 male SED vs. 0.47±0.05 male EX vs. 0.27±0.02 female SED vs. 0.48 ±0.05 female EX; PSex=0.704, PEX=0.001, PInt=0.527). There were no differences in fasting glucose and insulin levels, insulin sensitivity, glucose tolerance, or measures of energy balance (e.g., food intake, energy expenditure) among groups. These data suggest that despite no change in overall body mass or body composition, maternal exercise shifts adiposity distribution of offspring away from energy storing white fat towards energy burning brown fat. This change may impact energy metabolism over the lifespan given increasing evidence for advantageous metabolic adaptations with increased brown fat.

A meta-analysis of pre-pregnancy maternal body mass index and placental DNA methylation identifies 27 CpG sites with implications for mother-child health

Higher maternal pre-pregnancy body mass index (ppBMI) is associated with increased neonatal morbidity, as well as with pregnancy complications and metabolic outcomes in offspring later in life. The placenta is a key organ in fetal development and has been proposed to act as a mediator between the mother and different health outcomes in children. The overall aim of the present work is to investigate the association of ppBMI with epigenome-wide placental DNA methylation (DNAm) in 10 studies from the PACE consortium, amounting to 2631 mother-child pairs. We identify 27 CpG sites at which we observe placental DNAm variations of up to 2.0% per 10 ppBMI-unit. The CpGs that are differentially methylated in placenta do not overlap with CpGs identified in previous studies in cord blood DNAm related to ppBMI. Many of the identified CpGs are located in open sea regions, are often close to obesity-related genes such as GPX1 and LGR4 and altogether, are enriched in cancer and oxidative stress pathways. Our findings suggest that placental DNAm could be one of the mechanisms by which maternal obesity is associated with metabolic health outcomes in newborns and children, although further studies will be needed in order to corroborate these findings.

Associations of maternal glucose markers in pregnancy with cord blood glucocorticoids and child hair cortisol levels.

Exposure to maternal hyperglycemia in utero has been associated with adverse metabolic outcomes in offspring. However, few studies have investigated the relationship between maternal hyperglycemia and offspring cortisol levels. We assessed associations of gestational diabetes mellitus (GDM) with cortisol biomarkers in two longitudinal prebirth cohorts: Project Viva included 928 mother-child pairs and Gen3G included 313 mother-child pairs. In Project Viva, GDM was diagnosed in N = 48 (5.2%) women using a two-step procedure (50 g glucose challenge test, if abnormal followed by 100 g oral glucose tolerance test [OGTT]), and in N = 29 (9.3%) women participating in Gen3G using one-step 75 g OGTT. In Project Viva, we measured cord blood glucocorticoids and child hair cortisol levels during mid-childhood (mean (SD) age: 7.8 (0.8) years) and early adolescence (mean (SD) age: 13.2 (0.9) years). In Gen3G, we measured hair cortisol at 5.4 (0.3) years. We used multivariable linear regression to examine associations of GDM with offspring cortisol, adjusting for child age and sex, maternal prepregnancy body mass index, education, and socioeconomic status. We additionally adjusted for child race/ethnicity in the cord blood analyses. In both Project Viva and Gen3G, we observed null associations of GDM and maternal glucose markers in pregnancy with cortisol biomarkers in cord blood at birth (β = 16.6 nmol/L, 95% CI -60.7, 94.0 in Project Viva) and in hair samples during childhood (β = -0.56 pg/mg, 95% CI -1.16, 0.04 in Project Viva; β = 0.09 pg/mg, 95% CI -0.38, 0.57 in Gen3G). Our findings do not support the hypothesis that maternal hyperglycemia is related to hypothalamic-pituitary-adrenal axis activity.

Maternal Exercise May Improve Metabolic Outcomes in Offspring in Mice

ObjectiveIt is well recognized in both human epidemiological and animal studies that the maternal in utero environment has significant effects on development of offspring. This includes sedentary lifestyle, which has been linked to developmental programming of metabolic dysfunction. The aim of this study is to investigate metabolic outcomes in offspring of sedentary mice versus mice that exercised in pregnancy.Study DesignC57BL/6J female mice were placed on a control diet and allocated to sedentary versus exercise cages at 17 weeks of age. Exercise cages included a voluntary running wheel, with daily exercise measured via activity trackers. Mice were allowed to exercise for 2 weeks prior to breeding and throughout weaning. Offspring underwent body composition measurement and insulin and glucose tolerance tests at 6 weeks of age. At 14‐16 weeks of age, body composition was reassessed and mice were euthanized for tissue collection. Outcomes were analyzed between sedentary (SED) and exercise (EX) offspring using an unpaired t‐test, with p&lt;0.05 considered significant.ResultsWe studied metabolic function in 10 SED and 9 EX offspring. Insulin sensitivity, measured as the area under the curve for the decrease in glucose over time in response to insulin, tended to be improved in EX versus SED offspring (‐188 vs. 2991; p=0.062), with no difference in fasting glucose levels or glucose tolerance. While body mass was similar at end of study (23.4 EX vs. 23.1 SED; p=0.83), the percentage of subcutaneous white adipose tissue tended to be lower (0.94 EX vs. 1.67 SED; p=0.054) and brown adipose tissue was higher (0.57 EX vs. vs 0.30 SED; p&lt;0.001) in EX offspring.ConclusionsThese data suggest that maternal exercise may improve insulin sensitivity in offspring even under normal diet conditions. Further, despite similar body mass, offspring from mice that exercised during pregnancy had a shift in adipose depot composition with lower white adipose and higher brown adipose tissue. This change in body composition may have important implications for energy metabolism and is an important area of future study.

Gestational Diabetes Mellitus Is Associated with Altered Abundance of Exosomal MicroRNAs in Human Milk

PurposeHuman milk (HM) is a unique biological fluid that is enriched with a variety of factors, including microRNAs (miRNAs) that potentially provide both short- and long-term benefits to the infants. miRNAs are packaged within exosomes, making them bioavailable to infants. Gestational diabetes mellitus (GDM) may affect the abundance of exosomal miRNAs in HM, providing a mechanism for growth and adiposity variation in infants of mothers with GDM in early life. Therefore, the purposes of this study were to examine the impact of GDM on select miRNAs (miRNA-148a, miRNA-30b, miRNA-let-7a, and miRNA-let-7d) involved in metabolism and to examine the association of these miRNAs with measures of infant body composition in the first 6 months of life. MethodsMilk samples were collected from a cohort of 94 mothers (62 mothers without GDM and 32 mothers with GDM) matched on body mass index strata at 1 month post partum. miRNA abundance was measured by real-time polymerase chain reaction. Linear regression models were used to examine potential differences in miRNA abundance in women with and without GDM, testing associations between miRNA abundance and infant growth and body composition measures from 1 to 6 months. FindingsThe abundances of miRNA-148a, miRNA-30b, miRNA-let-7a, and miRNA-let-7d were reduced in milk from mothers with GDM. Independent of GDM status, higher maternal diet quality was associated with increased abundance of each of the measured miRNAs. miRNA-148a was negatively associated with infant weight, percentage of body fat, and fat mass, whereas miRNA-30b was positively associated with infant weight and fat mass at 1 month of age. There was no association of milk miRNA-148a and miRNA-30b with infant weight at 1 month of age or with body composition measures at 3 months of age; however, miRNA-148a was negatively associated with infant weight at 6 months of age. ImplicationsIf supported by randomized dietary supplementation or other intervention trials, HM miRNAs may be a therapeutic target to mitigate risk of metabolic outcomes in offspring of women with GDM.

Maternal Transmission of Human OGG1 Protects Mice Against Genetically- and Diet-Induced Obesity Through Increased Tissue Mitochondrial Content

Obesity and related metabolic disorders are pressing public health concerns, raising the risk for a multitude of chronic diseases. Obesity is multi-factorial disease, with both diet and lifestyle, as well as genetic and developmental factors leading to alterations in energy balance. In this regard, a novel role for DNA repair glycosylases in modulating risk for obesity has been previously established. Global deletion of either of two different glycosylases with varying substrate specificities, Nei-like endonuclease 1 (NEIL1) or 8-oxoguanine DNA glycosylase-1 (OGG1), both predispose mice to diet-induced obesity (DIO). Conversely, enhanced expression of the human OGG1 gene renders mice resistant to obesity and adiposity. This resistance to DIO is mediated through increases in whole body energy expenditure and increased respiration in adipose tissue. Here, we report that hOGG1 expression also confers resistance to genetically-induced obesity. While Agouti obese (Ay/a) mice are hyperphagic and consequently develop obesity on a chow diet, hOGG1 expression in Ay/a mice (Ay/aTg) prevents increased body weight, without reducing food intake. Instead, obesity resistance in Ay/aTg mice is accompanied by increased whole body energy expenditure and tissue mitochondrial content. We also report for the first time that OGG1-mediated obesity resistance in both the Ay/a model and DIO model requires maternal transmission of the hOGG1 transgene. Maternal, but not paternal, transmission of the hOGG1 transgene is associated with obesity resistance and increased mitochondrial content in adipose tissue. These data demonstrate a critical role for OGG1 in modulating energy balance through changes in adipose tissue function. They also demonstrate the importance of OGG1 in modulating developmental programming of mitochondrial content and quality, thereby determining metabolic outcomes in offspring.

Early Embryo Exposure to Assisted Reproductive Manipulation Induced Subtle Changes in Liver Epigenetics with No Apparent Negative Health Consequences in Rabbit.

Embryo manipulation is a requisite step in assisted reproductive technology (ART). Therefore, it is of great necessity to appraise the safety of ART and investigate the long-term effect, including lipid metabolism, on ART-conceived offspring. Augmenting our ART rabbit model to investigate lipid metabolic outcomes in offspring longitudinally, we detected variations in hepatic DNA methylation ART offspring in the F3 generation for embryonic exposure (multiple ovulation, vitrification and embryo transfer). Through adult liver metabolomics and proteomics, we identified changes mainly related to lipid metabolism (e.g., polyunsaturated fatty acids, steroids, steroid hormone). We also found that DNA methylation analysis was linked to changes in lipid metabolism and apoptosis genes. Nevertheless, these differences did not apparently alter the general health status. Thus, our findings suggest that ART is likely to be a player in embryo epigenetic events related to hepatic homeostasis alteration in adulthood.

Paternal high protein diet modulates body composition, insulin sensitivity, epigenetics, and gut microbiota intergenerationally in rats.

Mounting evidence demonstrates that paternal diet programs offspring metabolism. However, the contribution of a pre-conception paternal high protein (HP) diet to offspring metabolism, gut microbiota, and epigenetic changes remains unclear. Here we show that paternal HP intake in Sprague Dawley rats programs protective metabolic outcomes in offspring. Compared to paternal high fat/sucrose (HF/S), HP diet improved body composition and insulin sensitivity and improved circulating satiety hormones and cecal short-chain fatty acids compared to HF/S and control diet (P<.05). Further, using 16S rRNA gene sequencing to assess gut microbial composition, we observed increased alpha diversity, distinct bacterial clustering, and increased abundance of Bifidobacterium, Akkermansia, Bacteroides, and Marvinbryantia in HP fathers and/or male and female adult offspring. At the epigenetic level, DNMT1and 3b expression was altered intergenerationally. Our study identifies paternal HP diet as a modulator of gut microbial composition, epigenetic markers, and metabolic function intergenerationally.

Sex-specific effects of in vitro fertilization on adult metabolic outcomes and hepatic transcriptome and proteome in mouse.

Although in vitro fertilization (IVF) is associated with adverse perinatal outcomes, there is increasing concern about the long-term and sex-specific health implications. Augmenting our IVF mouse model to longitudinally investigate metabolic outcomes in offspring from optimal neonatal litter sizes, we found sex-specific metabolic outcomes in IVF offspring. IVF-conceived females had higher body weight and cholesterol levels compared to naturally conceived females, whereas IVF-conceived males had higher levels of triglycerides and insulin, and increased body fat composition. Through adult liver transcriptomics and proteomics, we identified sexually dimorphic dysregulation of the sterol regulatory element-binding protein (SREBP) pathways that are associated with the sex-specific phenotypes. We also found that global loss of DNA methylation in placenta was linked to higher cholesterol levels in IVF-conceived females. Our findings indicate that IVF procedures have long-lasting sex-specific effects on metabolic health of offspring and lay the foundation to utilize the placenta as a predictor of long-term outcomes.

The postnatal window is critical for the development of sex-specific metabolic and gut microbiota outcomes in offspring

ABSTRACT The Developmental Origins of Health and Disease (DOHaD) concept has been proposed to explain the influence of environmental conditions during critical developmental stages on the risk of diseases in adulthood. The aim of this study was to compare the impact of the prenatal vs. postnatal environment on the gut microbiota in dams during the preconception, gestation and lactation periods and their consequences on metabolic outcomes in offspring. Here we used the cross-fostering technique, e.g. the exchange of pups following birth to a foster dam, to decipher the metabolic effects of the intrauterine versus postnatal environmental exposures to a polyphenol-rich cranberry extract (CE). CE administration to high-fat high-sucrose (HFHS)-fed dams improved glucose homeostasis and reduced liver steatosis in association with a shift in the maternal gut microbiota composition. Unexpectedly, we observed that the postnatal environment contributed to metabolic outcomes in female offspring, as revealed by adverse effects on adiposity and glucose metabolism, while no effect was observed in male offspring. In addition to the strong sexual dimorphism, we found a significant influence of the nursing mother on the community structure of the gut microbiota based on α-diversity and β-diversity indices in offspring. Gut microbiota transplantation (GMT) experiments partly reproduced the observed phenotype in female offspring. Our data support the concept that the postnatal environment represents a critical window to influence future sex-dependent metabolic outcomes in offspring that are causally but partly linked with gut microbiome alterations.

Metabolic and behavioural effects in offspring exposed to maternal sucrose consumption: a systematic review and meta-analysis of data from rodent models.

Consumption of sugar-sweetened beverages (SSBs) during pregnancy has been associated with childhood obesity. Research in which rodent dams have been given high-fat/high-sugar diets has consistently found metabolic alterations in their offspring. However, what remains unclear is the potential impact on the developing fetus of giving sugar in isolation at concentrations similar to SSBs to the mothers. Therefore, we conducted a systematic review and meta-analysis (Protocol No: 127115 on Prospero) to identify potential relationships between maternal sucrose consumption and metabolic outcomes in offspring of rodent (rat or mouse) models. We analysed studies that provided rodent mothers dams with access to sucrose solutions (8-20% w/v) prior to conception, during pregnancy and/or lactation and that reported offspring outcomes of body weight (BW), body composition and glycaemic control. Following a systematic search of four databases (PubMed, EMBASE, Web of Science and Scopus) performed on 15 January 2019, maternal and offspring data from 15 papers were identified for inclusion. Only rat studies were identified. Meta-analyses were performed on standardised mean differences for maternal and offspring BW and fasting glucose levels, with subgroup analyses of strain, sucrose concentration, exposure period and sex of offspring. A bias towards the inclusion of only data from male offspring was identified and this limited interpretation of potential sexually dimorphic outcomes. Maternal sucrose exposure was associated with an increased risk of obesity and poor glucose disposal in adult and aged offspring.

Normalizing adiponectin levels in obese pregnant mice prevents adverse metabolic outcomes in offspring.

Infants of obese mothers have an increased risk of developing obesity, insulin resistance, and type 2 diabetes. The underlying mechanisms remain elusive, and no effective interventions to limit the transmission of metabolic disease from the obese mother to her infant are currently available. Obese pregnant women have decreased circulating levels of adiponectin, which is associated with increased placental nutrient transport and fetal overgrowth. We have reported that normalization of adiponectin levels during late gestation reversed placental dysfunction and fetal overgrowth in a mouse model of maternal obesity in pregnancy. In the current study, we hypothesized that adiponectin supplementation during pregnancy in obese mice attenuates the adverse metabolic outcomes in adult offspring. Adult male offspring of obese mice developed obesity, fatty liver, and insulin resistance, with adult female offspring of obese mice having a less pronounced metabolic phenotype. These metabolic abnormalities in offspring born to obese mice were largely prevented by normalization of maternal adiponectin levels in late pregnancy. We provide evidence that low circulating maternal adiponectin is a critical mechanistic link between maternal obesity and the development of metabolic disease in offspring. Strategies aimed at improving maternal adiponectin levels may prevent long-term metabolic dysfunction in offspring of obese mothers.-Paulsen, M. E., Rosario, F. J., Wesolowski, S. R., Powell, T. L., Jansson, T. Normalizing adiponectin levels in obese pregnant mice prevents adverse metabolic outcomes in offspring.

Associations of maternal BMI and insulin resistance with the maternal metabolome and newborn outcomes.

Maternal obesity increases the risk for large-for-gestational-age birth and excess newborn adiposity, which are associated with adverse long-term metabolic outcomes in offspring, probably due to effects mediated through the intrauterine environment. We aimed to characterise the maternal metabolic milieu associated with maternal BMI and its relationship to newborn birthweight and adiposity. Fasting and 1h serum samples were collected from 400 European-ancestry mothers in the Hyperglycaemia and Adverse Pregnancy Outcome Study who underwent an OGTT at ∼28weeks gestation and whose offspring had anthropometric measurements at birth. Metabolomics assays were performed using biochemical analyses of conventional clinical metabolites, targeted MS-based measurement of amino acids and acylcarnitines and non-targeted GC/MS. Per-metabolite analyses demonstrated broad associations with maternal BMI at fasting and 1h for lipids, amino acids and their metabolites together with carbohydrates and organic acids. Similar metabolite classes were associated with insulin resistance with unique associations including branched-chain amino acids. Pathway analyses indicated overlapping and unique associations with maternal BMI and insulin resistance. Network analyses demonstrated collective associations of maternal metabolite subnetworks with maternal BMI and newborn size and adiposity, including communities of acylcarnitines, lipids and related metabolites, and carbohydrates and organic acids. Random forest analyses demonstrated contribution of lipids and lipid-related metabolites to the association of maternal BMI with newborn outcomes. Higher maternal BMI and insulin resistance are associated with broad-based changes in maternal metabolites, with lipids and lipid-related metabolites accounting, in part, for the association of maternal BMI with newborn size at birth.

Sex-Specific Metabolic Outcomes in Offspring of Female Rats Born Small or Exposed to Stress During Pregnancy.

Low birth weight increases adult metabolic disease risk in both the first (F1) and second (F2) generation. Physiological stress during pregnancy in F1 females that were born small induces F2 fetal growth restriction, but the long-term metabolic health of these F2 offspring is unknown. Uteroplacental insufficiency (restricted) or sham (control) surgery was performed in F0 rats. F1 females (control, restricted) were allocated to unstressed or stressed pregnancies. F2 offspring exposed to maternal stress in utero had reduced birth weight. At 6 months, F2 stressed males had elevated fasting glucose. In contrast, F2 restricted males had reduced pancreatic β-cell mass. Interestingly, these metabolic deficits were not present at 12 month. F2 males had increased adrenal mRNA expression of steroidogenic acute regulatory protein and IGF-1 receptor when their mothers were born small or exposed to stress during pregnancy. Stressed control F2 males had increased expression of adrenal genes that regulate androgen signaling at 6 months, whereas expression increased in restricted male and female offspring at 12 months. F2 females from stressed mothers had lower area under the glucose curve during glucose tolerance testing at 12 months compared with unstressed females but were otherwise unaffected. If F1 mothers were either born small or exposed to stress during her pregnancy, F2 offspring had impaired physiological outcomes in a sex- and age-specific manner. Importantly, stress during pregnancy did not exacerbate disease risk in F2 offspring of mothers born small, suggesting that they independently program disease in offspring through different mechanisms.

Perinatal exposure to germinated brown rice and its gamma amino-butyric acid-rich extract prevents high fat diet-induced insulin resistance in first generation rat offspring

BackgroundEvidence suggests perinatal environments influence the risk of developing insulin resistance.ObjectiveThe present study was aimed at determining the effects of intrauterine exposure to germinated brown rice (GBR) and GBR-derived gamma (γ) aminobutyric acid (GABA) extract on epigenetically mediated high fat diet–induced insulin resistance.DesignPregnant Sprague Dawley rats were fed high-fat diet (HFD), HFD+GBR, or HFD+GABA throughout pregnancy until 4 weeks postdelivery. The pups were weighed weekly and maintained on normal pellet until 8 weeks postdelivery. After sacrifice, biochemical markers of obesity and insulin resistance including oral glucose tolerance test, adiponectin, leptin, and retinol binding protein-4 (RBP4) were measured. Hepatic gene expression changes and the global methylation and histone acetylation levels were also evaluated.ResultsDetailed analyses revealed that mothers given GBR and GABA extract, and their offspring had increased adiponectin levels and reduced insulin, homeostasis model assessment of insulin resistance, leptin, oxidative stress, and RBP4 levels, while their hepatic mRNA levels of GLUT2 and IPF1 were increased. Furthermore, GBR and GABA extract lowered global DNA methylation levels and modulated H3 and H4 acetylation levels.ConclusionsThese results showed that intrauterine exposure to GBR-influenced metabolic outcomes in offspring of rats with underlying epigenetic changes and transcriptional implications that led to improved glucose homeostasis.

Ethnic Differences in Effects of Maternal Pre-Pregnancy and Pregnancy Adiposity on Offspring Size and Adiposity.

Maternal adiposity and overnutrition, both before and during pregnancy, plays a key role in the subsequent development of obesity and metabolic outcomes in offspring. We explored the hypothesis that maternal adiposity (pre-pregnancy and at 26-28 weeks' gestation) and mid-pregnancy gestational weight gain (GWG) are independently associated with offspring size and adiposity in early childhood, and determined whether these effects are ethnicity dependent. In a prospective mother-offspring cohort study (N = 976, 56% Chinese, 26% Malay, and 18% Indian), we assessed the associations of offspring size (weight, length) and adiposity (subscapular and triceps skinfolds), measured at birth and age 6, 12, 18, and 24 mo, with maternal pre-pregnancy body mass index (ppBMI), mid-pregnancy GWG, and mid-pregnancy four-site skinfold thicknesses (triceps, biceps, subscapular, suprailiac). ppBMI and mid-pregnancy GWG were independently associated with postnatal weight up to 2 y and skinfold thickness at birth. Weight and subscapular and triceps skinfolds at birth increased by 2.56% (95% confidence interval, 1.68-3.45%), 3.85% (2.16-5.57%), and 2.14% (0.54-3.75%), respectively for every SD increase in ppBMI. Similarly, a one-SD increase in GWG increased weight and subscapular and triceps skinfolds at birth by 2.44% (1.66-3.23%), 3.28% (1.75-4.84%), and 3.23% (1.65-4.84%), respectively. ppBMI and mid-pregnancy suprailiac skinfold independently predicted postnatal skinfold adiposity up to 2 years of age, whereas only GWG predicted postnatal length. The associations of GWG with postnatal weight and length were present only among Chinese and Indians, but not Malays (P < .05 for interaction). ppBMI and GWG are independent modifiable factors for child size and adiposity up to 2 years of age. The associations are ethnic-dependent, and underscore the importance of ethnic specific studies before generalizing the applicability of risk factors reported in other populations.