Glucose Metabolism 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.

Associations of Placental Inflammation and Oxidative Stress Biomarkers with Glucolipid Metabolism in Children: A Birth Cohort Study in China.

The maternal intrauterine immune environment may affect offspring long-term health. We aimed to investigate the association between the intrauterine placental immunological milieu and glycolipid metabolic health in children. This study enrolled 1803 mother-child pairs from the Ma'anshan birth cohort (2013-2014). Placental mRNA expression of inflammatory cytokines (interleukin-1β [IL-1β], IL-10, monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-4, IL-6, IL-8, C-reactive protein, and interferon-γ) and oxidative stress biomarkers (heme oxygenase-1, hypoxia-inducible factor-1alpha, and glucose-related protein 78) was quantified using real-time quantitative polymerase chain reaction. Fasting blood glucose, insulin, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol were assessed at 5 to 6 years old. Statistical analyses included multiple linear regression, binary logistic regression, restricted cubic spline model, and the Bayesian kernel machine regression model. Placental inflammatory cytokines (IL-1β, monocyte chemoattractant protein-1, C-reactive protein, IL-6, IL-8, IL-10) and oxidative stress biomarkers (heme oxygenase-1, hypoxia-inducible factor-1alpha, glucose-related protein 78) showed positive associations with children's fasting blood glucose levels. Heme oxygenase-1 and glucose-related protein 78 exhibited negative correlations with children's fasting insulin levels. Elevated IL-6, heme oxygenase-1, hypoxia-inducible factor-1alpha, and glucose-related protein 78 were associated with increased risk of prediabetes in children. Overall upregulation of placental proinflammatory cytokines and oxidative stress factors mRNA expression correlated with higher prediabetes risk in children. Bayesian kernel machine regression analysis indicated a joint positive effect of the 12 placental inflammation and oxidative stress mixtures on children's risk of high fasting blood glucose. This exploratory study underscores significant correlations between maternal intrauterine placental inflammation, oxidative stress markers, and offspring fasting blood glucose and insulin levels. These findings highlight the potential role of intrauterine holistic immunity in shaping offspring glucose metabolism health.

Intrauterine arsenic exposure induces glucose metabolism disorders in adult offspring by targeting TET2-mediated DNA hydroxymethylation reprogramming of HNF4α in developing livers, an effect alleviated by ascorbic acid

Exposure to arsenic during gestation has lasting health-related effects on the developing fetus, including an increase in the risk of metabolic disease later in life. Epigenetics is a potential mechanism involved in this process. Ten-eleven translocation 2 (TET2) has been widely considered as a transferase of 5-hydroxymethylcytosine (5hmC). Here, mice were exposed, via drinking water, to arsenic or arsenic combined with ascorbic acid (AA) during gestation. For adult offspring, intrauterine arsenic exposure exhibited disorders of glucose metabolism, which are associated with DNA hydroxymethylation reprogramming of hepatic nuclear factor 4 alpha (HNF4α). Further molecular structure analysis, by SEC-UV-DAD, SEC-ICP-MS, verified that arsenic binds to the cysteine domain of TET2. Mechanistically, arsenic reduces the stability of TET2 by binding to it, resulting in the decrease of 5hmC levels in Hnf4α and subsequently inhibiting its expression. This leads to the disorders of expression of its downstream key glucose metabolism genes. Supplementation with AA blocked the reduction of TET2 and normalized the 5hmC levels of Hnf4α, thus alleviating the glucose metabolism disorders. Our study provides targets and methods for the prevention of offspring glucose metabolism abnormalities caused by intrauterine arsenic exposure.

The Role of Gut Microbiota in Gestational Diabetes Mellitus Affecting Intergenerational Glucose Metabolism: Possible Mechanisms and Interventions

The incidence of type 2 diabetes is increasing every year and has become a serious public health problem. In addition to genetic factors, environmental factors in early life development are risk factors for diabetes. There is growing evidence that the gut microbiota plays an important role in glucose metabolism, and the gut microbiota of pregnant women with gestational diabetes mellitus (GDM) differs significantly from that of healthy pregnant women. This article reviews the role of maternal gut microbiota in offspring glucose metabolism. To explore the potential mechanisms by which the gut microbiota affects glucose metabolism in offspring, we summarize clinical studies and experimental animal models that support the hypothesis that the gut microbiota affects glucose metabolism in offspring from dams with GDM and discuss interventions that could improve glucose metabolism in offspring. Given that adverse pregnancy outcomes severely impact the quality of survival, reversing the deleterious effects of abnormal glucose metabolism in offspring through early intervention is important for both mothers and their offspring.

DNA methylation regulates pancreatic gene expression and links maternal high-fat diet to the offspring glucose metabolism

Maternal high-fat diet (HFD) is related to an increased risk of glucose metabolism disorders throughout the whole life of offspring. The pancreas is a glucose homeostasis regulator. Accumulating evidence has revealed that maternal HFD affects offspring pancreas structure and function. However, the potential mechanism remains unclear. In this study, the mouse dam was fed with HFD or control diet (CD) during prepregnancy, pregnancy and lactation. The pancreatic insulin secretion function and islet genome methylome of offspring were analyzed. Pancreatic islet specific gene methylation was detected by using MeDIP qPCR. The results showed that body weight, blood glucose after oral glucose loads, fasting serum insulin, and HOMA-IR index values were significantly higher in male 12-week-old offspring from HFD dams than in the offspring from CD dams. Maternal HFD induced insulin secretion defects in male offspring. Compared with that in maternal CD group, methylation of the Abcc8 and Kcnj11 genes was increased in maternal HFD group in male offspring pancreatic islets. Furthermore, the expression levels of Abcc8 and Kcnj11 were downregulated by intrauterine exposure to a maternal HFD. In summary, maternal HFD results in a long-term functional disorder of the pancreas that is involved in insulin secretion-related gene DNA hypermethylation.

Maternal consumption of l-malic acid enriched diets improves antioxidant capacity and glucose metabolism in offspring by regulating the gut microbiota

Maternal diets during pregnancy and lactation are key determinants that regulate the development of metabolic syndrome (MetS) in offspring. l-malic acid (MA) was previously reported to improve antioxidant capacity and aerobic metabolism. However, the effects of maternal MA consumption on the metabolic features of offspring remain largely unexplored. Herein, through pig models consuming MA-enriched diets during late pregnancy and lactation, we found that maternal MA consumption potentiated the anti-inflammatory and antioxidant capacity of sows, thereby improving their reproductive performance and the growth performance of piglets. Maternal MA consumption also induced a transition of slow-twitch to fast-twitch fibers in the early life of offspring. Along with muscle growth and fiber-type transition, insulin sensitivity and glucose metabolism, including aerobic metabolism and glycolysis, were improved in the skeletal muscle of offspring. An untargeted metabolomic analysis further revealed the contribution of modified amino acid metabolism to the improved aerobic metabolism. Mechanistically, maternal MA consumption remodeled colonic microbiota of their offspring. Briefly, the abundance of Colidextribacter, Romboutsia, and Family_XIII_AD3011_group increased, which were positively associated with the antioxidant capacity and glucose metabolism of skeletal muscles. A decreased abundance of Prevotella, Blautia, Prevotellaceae_NK3B31_group, and Collinsella was also detected, which were involved in less insulin sensitivity. Notably, milk metabolites, such as ascorbic acid (AA) and granisetron (GS), were found as key effectors regulating the gut microbiota composition of piglets. The properties of AA and GS in alleviating insulin resistance, inflammation, and oxidative stress were further verified through mice treated with high-fat diets. Overall, this study revealed that maternal MA consumption could modulate the inflammatory response, antioxidant capacity, and glucose metabolism by regulating the gut microbiota of offspring through the vertical transmission of milk metabolites. These findings suggest the potential of MA in the prevention and treatment of MetS in early life.

Maternal exercise and vitamin D feeding cooperatively regulate the offspring glucose metabolism

Maternal exercise and vitamin D feeding cooperatively regulate the offspring glucose metabolism

Maternal voluntary wheel running modulates glucose homeostasis, the gut microbiota and its derived fecal metabolites in offspring.

Maternal overnutrition can dramatically increase the susceptibility of offspring to metabolic diseases, whereas maternal exercise may improve glucose metabolism in offspring. However, the underlying mechanism programming the intergenerational effects of maternal exercise on the benefits of glucose metabolism has not been fully elaborated. C57BL/6 female mice were randomly assigned to four subgroups according to a diet and exercise paradigm before and during pregnancy as follows: NC (fed with normal chow diet and sedentary), NCEx (fed with normal chow diet and running), HF (fed with high-fat diet and sedentary), and HFEx (fed with high-fat diet and running). Integrative 16S rDNA sequencing and mass spectrometry-based metabolite profiling were synchronously performed to characterize the effects of maternal exercise on the gut microbiota composition and metabolite alterations in offspring. Maternal exercise, acting as a natural pharmaceutical intervention, prevented deleterious effects on glucose metabolism in offspring. 16S rDNA sequencing revealed remarkable changes in the gut microbiota composition in offspring. Metabolic profiling indicated multiple altered metabolites, which were enriched in butanoate metabolism signaling in offspring. We further found that maternal exercise could mediate gene expression related to intestinal gluconeogenesis in offspring. In conclusion, our study indicated that maternal running significantly improved glucose metabolism in offspring and counteracted the detrimental effects of maternal high-fat feeding before and during pregnancy. We further demonstrated that maternal voluntary wheel running could integratively program the gut microbiota composition and fecal metabolite changes and then regulate butanoate metabolism and mediate intestinal gluconeogenesis in offspring.

Like father, like daughter:Paternal cadmium exposure causes hepatic glucose metabolic disorder and phospholipids accumulation in adult female offspring

Cadmium (Cd), is a well-known reproductive toxicant. The impacts of paternal Cd exposure on offspring glucose and lipid metabolism remain unclear, despite the abundance of adverse reports following early exposure from the mother. Here, we assessed paternally acquired metabolic derailment using a mouse model. LC-MS/MS, transcriptomics and molecular experimental techniques were subsequently applied in this study to explore the potential mechanism. We found that paternal Cd exposure caused glucose intolerance, lower insulin sensitivity and abnormal hepatic glycogen storage in adult female offspring, but not in males. LC-MS/MS data showed that hepatic phospholipids accumulation was also only observed in adult female offspring after paternal Cd exposure. Gene expression data showed that the level of insulin signaling and lipid transport-related genes was decreased in Cd-treated adult female offspring livers. Meanwhile, AHR, a transcription factor that combines with phospholipids to promote insulin resistance, was increased in Cd-treated adult female offspring livers. In addition, the escalation of the afore-mentioned lipid metabolites in the liver occurred as early as fetal stages in the female pups following paternal Cd exposure, suggesting the potential for these lipid species to be selected as early markers of disease for metabolic derailment later in life. Altogether, paternal Cd exposure causes offspring glucose metabolism disorder and phospholipids accumulation in a sex-dependent manner. This study provides a theoretical framework for future understanding of paternal-originated metabolic diseases.

Early emergence of sexual dimorphism in offspring leukocyte telomere length was associated with maternal and children’s glucose metabolism—a longitudinal study

BackgroundLeukocyte telomere length (LTL) is suggested to be a biomarker of biological age and reported to be associated with metabolic diseases such as type 2 diabetes. Glucose metabolic traits including glucose and insulin levels have been reported to be associated with LTL in adulthood. However, there is relatively little research focusing on children’s LTL and the association with prenatal exposures. This study investigates the relationship between maternal and offspring glucose metabolism with offspring LTL in early life.MethodsThis study included 882 mother-child pairs from the HAPO Hong Kong Field Centre, with children evaluated at age 7.0 ± 0.4 (mean ± SD) years. Glucose metabolic traits including maternal post-load glucose during pregnancy, children’s glucose and insulin levels, and their derived indices at follow-up were measured or calculated. Offspring LTL was assessed using real-time polymerase chain reaction.ResultsSex- and age-adjusted children’s LTL was found to be associated with children’s HOMA-IR (β=−0.046 ± 0.016, p=0.005). Interestingly, both children’s and maternal post-load glucose levels were positively associated with children’s LTL. However, negative associations were observed between children’s LTL and children’s OGTT insulin levels. In addition, the LTL in females was more strongly associated with pancreatic beta-cell function whilst LTL in males was more strongly associated with OGTT glucose levels.ConclusionsOur findings suggest a close association between maternal and offspring glucose metabolic traits with early life LTL, with the offspring sex as an important modifier of the disparate relationships in insulin production and response.

Vertical transmission of the gut microbiota influences glucose metabolism in offspring of mice with hyperglycaemia in pregnancy

BackgroundHyperglycaemia in pregnancy (HIP) is a common metabolic disorder that not only poses risks to maternal health but also associates with an increased risk of diabetes among offspring. Vertical transmission of microbiota may influence the offspring microbiome and subsequent glucose metabolism. However, the mechanism by which maternal gut microbiota may influence glucose metabolism of the offspring remains unclear and whether intervening microbiota vertical transmission could be used as a strategy to prevent diabetes in the offspring of mothers with HIP has not been investigated. So we blocked vertical transmission to investigate its effect on glucose metabolism in the offspring.ResultsWe established a murine HIP model with a high-fat diet (HFD) and investigated the importance of vertical transmission of gut microbiota on the glucose metabolism of offspring via birth and nursing by blocking these events through caesarean section (C-section) and cross-fostering. After weaning, all offspring were fed a normal diet. Based on multi-omics analysis, biochemical and transcriptional assays, we found that the glucometabolic deficits in the mothers were subsequently ‘transmitted’ to the offspring. Meanwhile, the partial change in mothers’ gut microbial community induced by HIP could be transmitted to offspring, supported by the closed clustering of the microbial structure and composition between the offspring and their mothers. Further study showed that the microbiota vertical transmission was blocked by C-section and cross-fostering, which resulted in improved insulin sensitivity and islet function of the offspring of the mothers with HIP. These effects were correlated with changes in the relative abundances of specific bacteria and their metabolites, such as increased relative abundances of Bifidobacterium and short-chain fatty acids. In particular, gut microbial communities of offspring were closely related to those of their foster mothers but not their biological mothers, and the effect of cross-fostering on the offspring’s gut microbiota was more profound than that of C-section.ConclusionOur study demonstrates that the gut microbiota transmitted via birth and nursing are important contributors to the glucose metabolism phenotype in offspring.56mzRGmxnTDVmmEec8EWAWVideo

Maternal Exercise-Induced SOD3 Reverses the Deleterious Effects of Maternal High-Fat Diet on Offspring Metabolism Through Stabilization of H3K4me3 and Protection Against WDR82 Carbonylation.

Preclinical studies reveal maternal exercise as a promising intervention to reduce the transmission of multigenerational metabolic dysfunction caused by maternal obesity. The benefits of maternal exercise on offspring health may arise from multiple factors and have recently been shown to involve DNA demethylation of critical hepatic genes leading to enhanced glucose metabolism in offspring. Histone modification is another epigenetic regulator, yet the effects of maternal obesity and exercise on histone methylation in offspring are not known. Here, we find that maternal high-fat diet (HFD; 60% kcal from fat) induced dysregulation of offspring liver glucose metabolism in C57BL/6 mice through a mechanism involving increased reactive oxygen species, WD repeat-containing 82 (WDR82) carbonylation, and inactivation of histone H3 lysine 4 (H3K4) methyltransferase leading to decreased H3K4me3 at the promoters of glucose metabolic genes. Remarkably, the entire signal was restored if the HFD-fed dams had exercised during pregnancy. WDR82 overexpression in hepatoblasts mimicked the effects of maternal exercise on H3K4me3 levels. Placental superoxide dismutase 3 (SOD3), but not antioxidant treatment with N-acetylcysteine was necessary for the regulation of H3K4me3, gene expression, and glucose metabolism. Maternal exercise regulates a multicomponent epigenetic system in the fetal liver resulting in the transmission of the benefits of exercise to offspring.

The Effect and Potential Mechanism of Maternal Micronutrient Intake on Offspring Glucose Metabolism: An Emerging Field.

Diabetes has become the most common metabolic disease around the world. In addition to genetic and environmental factors in adulthood, the early life environment is critical to the progression of diabetes in adults, especially the environment during the fetal period; this concept is called “fetal programming.” Substantial evidence has illustrated the key role of early life macronutrient in programming metabolic diseases. Recently, the effect of maternal micronutrient intake on offspring glucose metabolism during later life has become an emerging field. This review focuses on updated human and animal evidence about the effect of maternal micronutrient status on offspring glucose metabolism and the underlying mechanism.

Maternal and fetal metabolomic alterations in maternal lipopolysaccharide exposure-induced male offspring glucose metabolism disorders.

Maternal lipopolysaccharide (LPS) exposure during pregnancy induces metabolic abnormalities in male offspring, but the underlying mechanisms remain unclear. The purpose of this study was to investigate the effects of maternal LPS exposure during pregnancy on metabolic profiling of maternal serum and male fetal liver using Liquid Chromatograph Mass Spectrometer techniques. From day 15 to day 17 of gestation, pregnant mice were administered intraperitoneal LPS (experimental group) (50 μg/kg/d) or saline (control group). On day 18 of gestation, maternal serum and male fetal liver were collected. After LPS exposure, levels of 38 and 75 metabolites, mainly glycerophospholipid and fatty acid metabolites, were altered in maternal serum and male fetal liver, respectively. It was found that in maternal serum and male fetal livers, the glycerophospholipids containing saturated fatty acids (SFAs) and the SFAs were upregulated, while the glycerophospholipids containing polyunsaturated fatty acids (PUFAs) and the PUFAs were downregulated. This concordance between maternal and fetal alterations in glycerophospholipid and fatty acid metabolites may be a metabolomic signature of the early intrauterine period and may provide insight into the mechanisms by which maternal LPS exposure induces disorders of glucose metabolism in male offspring.

Environmental cadmium exposure during pregnancy causes diabetes-like phenotypes in mouse offspring: Association with oxidative stress in the fetal liver.

Cadmium (Cd), a noxious heavy metal, is widespread in the living environment. Gestational exposure to Cd at environmental dose has been shown to cause fetal growth restriction (FGR). However, the long-term effects and the mechanisms underlying environmental Cd exposure on glucose metabolism in offspring remain unclear. Here, we established a murine model to study the impacts of gestational exposure to environmental Cd on glucose metabolism at different life stages of offspring. Results demonstrated that the offspring mice developed hyperglycemia in puberty and impaired glucose tolerance in adulthood following maternal Cd exposure during gestation. Further mechanistic investigation showed that Cd exposure upregulated the expression of key proteins in hepatic gluconeogenesis, including p-CREB, PGC-1α and G6PC, in pubertal and adult offspring. In addition, we demonstrated that Cd exposure during pregnancy markedly elevated the level of oxidative stress-related proteins, including NOX2, NOX4 and HO-1, in the fetal liver. The effects of gestational exposure to N-acetylcysteine (NAC), a free-radical scavenging antioxidant, presented that NAC supplementation alleviated hepatic oxidative stress in fetuses, and thereby reversed hyperglycemia and glucose intolerance in mouse offspring. Collectively, our data suggested that gestational exposure to environmental Cd caused diabetes-like phenotypes via enhancing hepatic gluconeogenesis, which is associated with oxidative stress in fetal livers. This work provides new insights into the protective effects of antioxidants on fetal-originated diabetes triggered by environmental toxicants.

Maternal sitagliptin treatment attenuates offspring glucose metabolism and intestinal proinflammatory cytokines IL-6 and TNF-α expression in male rats.

Increasing evidence shows that maternal overnutrition may increase the risk of diabetes in offspring. We hypothesized that maternal sitagliptin intervention may improve glucose intolerance through gut targeting. Female Sprague-Dawley (SD) rats were fed a normal diet (ND) or a high-fat diet (HFD) for 4 weeks before mating. ND pregnant rats were divided into two subgroups: ND group (ND alone) and the ND-sitagliptin group (ND combined with 10 mg/kg/day sitagliptin treatment). HFD pregnant rats were randomized to one of two groups: HFD group (HFD alone) and the HFD-sitagliptin group (HFD combined with 10 mg/kg/day sitagliptin treatment) during pregnancy and lactation. Glucose metabolism was assessed in offspring at weaning. Intestinal gene expression levels were investigated. Maternal sitagliptin intervention moderated glucose intolerance and insulin resistance in male pups. Moreover, maternal sitagliptin treatment inhibited offspring disordered intestinal expression of proinflammatory markers, including interleukin-6 (Il6), ll1b, and tumor necrosis factor (Tnf), at weaning and reduced intestinal IL-6, TNF-α expression by immunohistochemical staining and serum IL-6, TNF-α levels. However, maternal sitagliptin intervention did not affect offspring serum anti-inflammatory cytokine IL-10 level. Our results are the first to show that maternal sitagliptin intervention moderated glucose metabolism in male offspring. It may be involved with moderating intestinal IL-6 and TNF-α expression in male rat offspring.

Autism-like behaviors and abnormality of glucose metabolism in offspring derived from aging males with epigenetically modified sperm.

Accumulating evidence from epidemiological studies of humans and genetic models in rodents has shown that offspring from males of advanced paternal age (APA) are susceptible to metabolic and neurological disorders. However, knowledge of molecular mechanism(s) underlying these metabolic and behavioral changes at the intergeneration and trans-generation levels from APA is limited. Here, we characterized changes on glucose and cholesterol metabolism, and also autism spectrum disorders (ASD)-like behaviors in 1st and 2nd generations from 12- and 18-month-old male mice, respectively. Whole Genome Bisulfite Sequencing (WGBS) of sperm from APA mice identified differentially methylated regions (DMRs) within the whole genome, and DMRs within promoter regions, suggesting that specific genes and relevant pathways might be associated with autism and aberrant glucose metabolism in the offspring from APA males. These results strongly suggest that epigenetic reprogramming induced by aging in male sperm may lead to high risks of aberrant glucose metabolism and the development of ASD behaviors in intergenerational and transgenerational offspring.

Prenatal High-Salt Diet-Induced Metabolic Disorders via Decreasing Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1α in Adult Male Rat Offspring.

Although prenatal high-salt (HS) intake leads to physiological complications in the offspring, little is known regarding its effects on the offspring's glucose metabolism. Therefore, the objectives of this study are to determine the consequences of prenatal HS diet on the offspring's metabolism and to test a potential therapy. Pregnant rats are fed either a normal-salt (1% NaCl) or high-salt (8% NaCl) diet during the whole pregnancy. Experiments are conducted in five-month-old male offspring. It is found that the prenatal HS diet reduced the glucose tolerance and insulin sensitivity of the offspring. Additionally, there is down-regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Ppargc1a/PPARGC1A) at the transcript and protein level, which leads to decreased mitochondrial biogenesis and oxidative respiration in skeletal muscle. Moreover, the down-regulation of Ppargc1a is accompanied by decreases in the expression of glucose transporter type 4 (Glut4). With endurance exercise training, these changes are mitigated, which ultimately resulted in improved insulin resistance. These findings suggest that prenatal HS intake induces metabolic disorders via the decreased expression of Ppargc1a in the skeletal muscle of adult offspring, providing novel information concerning the mechanisms and early prevention of metabolic diseases of fetal origins.

Maternal exercise and its beneficial effects on glucose metabolism in offspring.

It shows that detrimental exposures and conditions in mothers can lead to the development of obesity and type 2 diabetes in offspring. This can lead to a vicious cycle of metabolic dysfunction, where rising rates of obesity, pre-diabetes, and diabetes in individuals of reproductive age, propagating risks to subsequent generations. It is well established that regular exercise has important health benefits for people with obesity and type 2 diabetes. Recently, increasing studies aim to examine the effects of maternal exercise on metabolic health in offspring. This review aims to demonstrate the evidence linking maternal exercise during critical periods of development and its implications for glucose metabolism in offspring, including intervention timing, sexual dimorphism, different exercise type, and intensity. Then we further examine the potential role of epigenetic modifications in this process.

Maternal Inulin Supplementation Alters Hepatic DNA Methylation Profile and Improves Glucose Metabolism in Offspring Mice.

ScopeAs a prebiotic, inulin may have a protective effect on glucose metabolism. However, the mechanism of inulin treatment on glucose intolerance in offspring exposed to a maternal high-fat (HF) diet is still not clear. Here, we examined the hepatic DNA methylation profile to determine how maternal inulin supplementation modified glucose metabolism in offspring mice.ProceduresFemale mice were fed a HF diet, control diet (CON), or a HF diet with inulin supplementation (HF-inulin) during gestation and lactation. Upon weaning, pup livers were obtained. A hepatic genome DNA methylation array was performed.ResultsPups exposed to a maternal HF diet exhibited glucose intolerance and insulin resistance. Maternal inulin treatment moderated glucose metabolism. A DNA methylation array identified differentially methylated regions associated with 970 annotated genes from pups exposed to a HF diet in response to maternal inulin treatment. In particular, the wingless-type MMTV integration site family member 5A (Wnt5a) gene was hypermethylated, and the phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (Pik3c2a), phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (Pik3c2b), and phosphoinositide-3-kinase regulatory subunit 2 (Pik3r2) genes were hypomethylated in inulin-treated pups. Consistently, hepatic Wnt5a gene expression was reduced and Pik3c2a, Pik3c2b, and Pik3r2 gene expression were increased in the inulin group.ConclusionMaternal inulin treatment improved glucose intolerance by changing DNA methylation and gene expression of Wnt5a and Pi3k in mice exposed to a maternal HF diet.