Insulin Resistance 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 pregnancy diet quality, night eating, and offspring metabolic health: the GUSTO study.

We investigated the understudied influence of maternal diet quality, food timing, and their interactions during pregnancy on offspring metabolic health. Maternal diet at 26-28 weeks' gestation was assessed using a 24-h recall and adherence to the modified-healthy-eating-index (HEI-SGP) reflects diet quality. Predominant night-eating (PNE) was defined as consuming >50% of total daily energy intake from 19:00 to 06:59. Outcomes were offspring composite metabolic syndrome score and its components measured at age 6 years. Multivariable linear regressions adjusted for relevant maternal and child covariates assessed associations of diet quality and PNE with these outcomes. Up to 758 mother-child pairs were included. The mean(SD) maternal HEI-SGP score was 52.3(13.7) points (theoretical range: 0-100) and 15% of the mothers demonstrated PNE. Maternal diet quality showed inverse relationship with offspring HomeostaticModel AssessmentforInsulinResistance (HOMA-IR) [β(95% CI): -0.08(-0.15, -0.02) per-10-point HEI-SGP increment; P = 0.012]. Maternal PNE was associated with a higher offspring HOMA-IR [0.28(0.06, 0.50); P = 0.012], with similar estimates after adjustment for children's BMI and diet quality; the association was stronger for boys (P-interaction<0.001) and among mothers with lower diet quality (<median HEI-SGP) (P-interaction = 0.062). Maternal PNE and low dietary quality were associated with a higher level of insulin resistance in early childhood, especially among boys. We demonstrated that maternal predominant night-eating behavior and low-quality diet are associated with higher offspring insulin resistance. Maternal low-quality diet and predominant night-eating behavior synergistically interact to influence offspring insulin resistance, particularly among boys. While maternal diet quality and food timing impact the mother's health, their influence on offspring long-term health outcomes through developmental programming is not well understood. Our findings highlight the significance of maternal food timing and calls for further studies on its influence on child health through developmental programming. Targeting both dietary quality and food timing during pregnancy could be a promising intervention strategy.

Maternal DNA methylation signatures of arsenic exposure is associated with adult offspring insulin resistance in the Strong Heart Study

Exposure to low to moderate arsenic (As) levels has been associated with type 2 diabetes (T2D) and other chronic diseases in American Indian communities. Prenatal exposure to As may also increase the risk for T2D in adulthood, and maternal As has been associated with adult offspring metabolic health measurements. We hypothesized that T2D-related outcomes in adult offspring born to women exposed to low to moderate As can be evaluated utilizing a maternally-derived molecular biosignature of As exposure. Herein, we evaluated the association of maternal DNA methylation with incident T2D and insulin resistance (Homeostatic model assessment of insulin resistance [HOMA2-IR]) in adult offspring. For DNA methylation, we used 20 differentially methylated cytosine-guanine dinucleotides (CpG) previously associated with the sum of inorganic and methylated As species (ΣAs) in urine in the Strong Heart Study (SHS). Of these 20 CpGs, we found six CpGs nominally associated (p < 0.05) with HOMA2-IR in a fully adjusted model that included clinically relevant covariates and offspring adiposity measurements; a similar model that adjusted instead for maternal adiposity measurements found three CpGs nominally associated with HOMA2-IR, two of which overlapped the offspring adiposity model. After adjusting for multiple comparisons, cg03036214 remained associated with HOMA2-IR (q < 0.10) in the offspring adiposity model. The odds ratio of incident T2D increased with an increase in maternal DNA methylation at one HOMA2-IR associated CpG in the model adjusting for offspring adiposity, cg12116137, whereas adjusting for maternal adiposity had a minimal effect on the association. Our data suggests offspring adiposity, rather than maternal adiposity, potentially influences the effects of maternal DNAm signatures on offspring metabolic health parameters. Here, we have presented evidence supporting a role for epigenetic biosignatures of maternal As exposure as a potential biomarker for evaluating risk of T2D-related outcomes in offspring later in life.

Effects of High-dose Folic Acid Supplementation on Maternal/Child Health Outcomes: Gestational Diabetes Mellitus in Pregnancy and Insulin Resistance in Offspring

ObjectivesThe purpose of this study was to evaluate the effects of maternal high folic acid (FA) supplementation during pregnancy on glucose intolerance in dams and insulin resistance in offspring. MethodsWistar female rats (n=18) were mated and randomly divided into 3 groups: a control group and 2 experimental groups. Three different feeding protocols were administered during pregnancy: control group, 2 mg/kg FA (recommended level FA supplementation); experimental 1 group, 5 mg/kg FA (tolerable upper intake level of FA supplementation [ULFolS]); and experimental 2 group, 40 mg/kg FA (high FA supplementation [HfolS]). All dams were fed the same FA content diet (2 mg/kg FA) during the lactation period. An oral glucose tolerance test was performed on day 16 of pregnancy. After the lactation period, body weight and food intake of 36 pups were monitored. Dams were euthanized at the end of the lactation period and half of the pups were euthanized at the end of week 7 and the others at the end of week 12. Serum FA, homocysteine, vitamin B12, insulin, glucose, interleukin-6, tumor necrosis factor-alpha, glycated hemoglobin (A1C), and adiponectin levels of mothers and pups were evaluated. The homeostatic model of insulin resistance (HOMA-IR) was used to determine insulin resistance in dams and offspring. ResultsAccording to glucose tolerance test results of dams, blood glucose values at minutes 0, 60, 90, and 120 for the HFolS group were significantly higher compared with the control group (p<0.05). The A1C level in HFolS dams was significantly higher than in the control group (p<0.05). The mean birthweight of the pups in the HFolS group was significantly higher than that of control pups (p<0.05). HOMA-IR values for control and HFolS offspring were similar at weeks 7 and 12 and higher than in ULFolS offspring (p>0.05). ConclusionsIt was determined that high doses of FA exposure during pregnancy might be effective in the development of glucose intolerance in dams and insulin resistance in offspring in this study.

The programming of kidney injury in offspring affected by maternal overweight and obesity: role of lipid accumulation, inflammation, oxidative stress, and fibrosis in the kidneys of offspring.

Maternal overweight and obesity are considered important factors affecting fetal development with many potential consequences for offspring after delivery, including the increased risk of obesity and diabetes mellitus. Maternal obesity promotes adiposity in the offspring by increasing fat deposition and expansion in the body of the offspring. The expansion of adipose tissue changes adipokine levels, including a decrease in adiponectin and an increase in leptin. In addition to changes in adipokine levels, there are also increases in pro-inflammatory cytokines, pro-fibrotic cytokines, and reactive oxygen species, leading to oxidative stress in the offspring. These contribute to the promotion of insulin resistance in offspring, which is associated with kidney injury. Interestingly, maternal obesity can also promote renal lipid accumulation, which could activate inflammatory processes and promote renal oxidative stress and renal fibrosis. These alterations in the kidneys of the offspring imply that a mother being overweight/obese can program the development of kidney disease in offspring. This review will discuss the effects of a mother being overweight or obese on their offspring and the consequences with regard to the kidneys of their offspring. With a focus on the molecular mechanisms, including renal inflammation, renal oxidative stress, renal fibrosis, and renal lipid metabolism in offspring born to overweight and obese mothers, the causative mechanisms and perspective of these conditions will be included.

Maternal DNA Methylation Signatures of Arsenic Exposure is Associated with Adult Offspring Insulin Resistance in the Strong Heart Study

Maternal DNA Methylation Signatures of Arsenic Exposure is Associated with Adult Offspring Insulin Resistance in the Strong Heart Study

Infant Mesenchymal Stem Cell Insulin Action Is Associated With Maternal Plasma Free Fatty Acids, Independent of Obesity Status: The Healthy Start Study.

Preclinical rodent and nonhuman primate models investigating maternal obesity have highlighted the importance of the intrauterine environment in the development of insulin resistance in offspring; however, it remains unclear if these findings can be translated to humans. To investigate possible intrauterine effects in humans, we isolated mesenchymal stem cells (MSCs) from the umbilical cord tissue of infants born to mothers of normal weight or mothers with obesity. Insulin-stimulated glycogen storage was determined in MSCs undergoing myogenesis in vitro. There was no difference in insulin action based on maternal obesity. However, maternal free fatty acid (FFA) concentration, cord leptin, and intracellular triglyceride content were positively correlated with insulin action. Furthermore, MSCs from offspring born to mothers with elevated FFAs displayed elevated activation of the mTOR signaling pathway. Taken together, these data suggest that infants born to mothers with elevated lipid availability have greater insulin action in MSCs, which may indicate upregulation of growth and lipid storage pathways during periods of maternal overnutrition.

Maternal secretin ameliorates obesity by promoting white adipose tissue browning in offspring.

Our knowledge of the coordination of intergenerational inheritance and offspring metabolic reprogramming by gastrointestinal endocrine factors is largely unknown. Here, we showed that secretin (SCT), a brain-gut peptide, is downregulated by overnutrition in pregnant mice and women. More importantly, genetic loss of SCT in the maternal gut results in undesirable phenotypes developed in offspring including enhanced high-fat diet (HFD)-induced obesity and attenuated browning of inguinal white adipose tissue (iWAT). Mechanistically, loss of maternal SCT represses iWAT browning in offspring by a global change in genome methylation pattern through upregulation of DNMT1. SCT functions to facilitate ubiquitination and degradation of DNMT1 by activating AMPKα, which contributes to the observed alteration of DNMT1 in progeny. Lastly, we showed that SCT treatment during pregnancy can reduce the development of obesity and improve glucose tolerance and insulin resistance in offspring of HFD-fed females, suggesting that SCT may serve as a novel biomarker or a strategy for preventing metabolic diseases.

Maternal DNA Methylation Signatures of Arsenic Exposure is Associated with Adult Offspring Insulin Resistance in the Strong Heart Study

Maternal DNA Methylation Signatures of Arsenic Exposure is Associated with Adult Offspring Insulin Resistance in the Strong Heart Study

GABA administration improves liver function and insulin resistance in offspring of type 2 diabetic rats

This study investigated the role of GABA in attenuating liver insulin resistance (IR) in type 2 diabetes parents and reducing its risk in their descendants’ liver. Both sexes’ rats were divided into four groups of non-diabetic control, diabetic control (DC), GABA-treated (GABA), and insulin-treated (Ins). The study duration lasted for six months and the young animals followed for four months. Consequently, hyperinsulinemic-euglycemic clamp was performed for all animals. Apart from insulin tolerance test (ITT), serum and liver lipid profile were measured in all groups. Glycogen levels, expression of Foxo1, Irs2, Akt2, and Pepck genes in the liver were assessed for all groups. Overall, GABA improved ITT, increased liver glycogen levels and decreased lipid profile, blood glucose level, and HbA1c in parents and their offspring in compared to the DC group. GIR also increased in both parents and their offspring by GABA. Moreover, the expression of Foxo1, Irs2, Akt2, and Pepck genes improved in GABA-treated parents and their descendants in compared to DC group. Results indicated that GABA reduced liver IR in both parents and their offspring via affecting their liver insulin signaling and gluconeogenesis pathways.

Calcium-Deficiency during Pregnancy Affects Insulin Resistance in Offspring.

Prenatal malnutrition is known to affect the phenotype of the offspring through changes in epigenetic regulation. Growing evidence suggests that epigenetics is one of the mechanisms by which nutrients and minerals affect metabolic traits. Although the perinatal period is the time of highest phenotypic plasticity, which contributes largely to developmental programming, there is evidence of nutritional influence on epigenetic regulation during adulthood. Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Cortisol, the most important glucocorticoid, is considered to lead to insulin resistance and metabolic syndrome. 11β-hydroxysteroid dehydrogenase-1 is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. This brief review aims to identify the effects of Ca deficiency during pregnancy and/or lactation on insulin resistance in the offspring. Those findings demonstrate that maternal Ca deficiency during pregnancy may affect the epigenetic regulation of gene expression and thereby induce different metabolic phenotypes. We aim to address the need for Ca during pregnancy and propose the scaling-up of clinical and public health approaches that improved pregnancy outcomes.

Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome.

OBJECTIVEGestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure.RESEARCH DESIGN AND METHODSWe explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring.RESULTSWe did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10−2) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy.CONCLUSIONSOur study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.

Mechanisms Involved in Intrauterine Growth Restriction in Patients With Polycystic Ovary Syndrome: Primary and Secondary Prevention of Metabolic Syndrome and Cancer Risk in the Adult Life of Offspring

Polycystic ovary syndrome (PCOS) is one of the most common hormonal disorders that affects between 5- 10% of women of reproductive age. It is currently considered a complex and multifactorial disease with metabolic, cardiovascular implications and represents per se an increased cancer risk. PATIENTS with PCOS routinely have menstrual disorders, hyperandrogenism, infertility and reproductive complications such as recurrent abortions, gestational diabetes, intrauterine growth restriction, pregnancy induced hypertension that give rise to underweight newborns and condition metabolic diseases to adult life and increased risk of cancer, especially breast and endometrial cancer. Insulin resistance and hyperandrogenism are the most important etiopathogenic factors in PCOS. On the other hand, subjects exposed to an adverse microenvironment in the intrauterine stage develop compensating responses to survive, a process called fetal programming. Prenatal exposure to androgens and/or insulin resistance may act as fetal programming factors and cause restriction of intrauterine growth, obesity and insulin resistance in offspring. Newborn may have an increased risk of metabolic syndrome, increased incidence of hypertensive, type 2 diabetes, heart disease and cerebrovascular disease. Prevention of these complications will be achieved if women with Polycystic Ovary Syndrome are treated appropriately throughout their lives, but especially before and during their pregnancy. Only in this way can the risk of them be reduced, representing a better quality and greater life expectancy.

Paternal exercise protects against liver steatosis in the male offspring of mice submitted to high fat diet

Parental lifestyle has been related to alterations in the phenotype of their offspring. Obese sires can induce offspring insulin resistance as well as increase susceptibility to obesity. On the other hand, obese sires submitted to voluntary exercise ameliorate the deleterious metabolic effects on their offspring. However, there are no studies reporting the effect of programmed exercise training of lean sires on offspring metabolism. AimsThis study aimed to investigate the role of swimming training of sires for 6 weeks on the offspring metabolic phenotype. Main methodsMale C57BL/6 mice fed a control diet were divided into sedentary and swimming groups. After the exercise, they were mated with sedentary females, and body weight and molecular parameters of the offspring were subsequently monitored. Key findingsSwimming decreased the gene expression of Fasn and Acaca in the testes and increased the AMPK protein content in the testes and epididymis of the sires. The progeny presented a low weight at P1, which reached a normal level at P60 and at P90 the animals were challenged with HFD for 16 weeks. The male offspring of trained sires presented less body weight gain than the control group. The level of steatosis decreased in the male offspring from trained sires. The gene expression of Prkaa2, Ppar-1α and Cpt-1 was also increased in the liver of male offspring from trained sires. SignificanceTaken together, these findings suggest that paternal exercise training can improve the metabolic profile in the liver of the progeny, thereby ameliorating the effects of obesity.

Maternal overnutrition impairs offspring's insulin sensitivity: A systematic review and meta-analysis.

This systematic review and meta‐analysis aimed to investigate the association between maternal overnutrition and offspring's insulin sensitivity—following the Preferred Reporting Items for Systematic Reviews and Meta‐analyses statement. Studies published in English before April 22, 2019, were identified through searches of four medical databases. After selection, 15 studies aiming to explore the association between prepregnancy body mass index (ppBMI) or gestational weight gain (GWG) of non‐diabetic mothers and their offspring's insulin sensitivity (fasting insulin or glucose level and Homeostatic Measurement Assessment for Insulin Resistance [HOMA‐IR]) were included in the meta‐analysis. Associations of ppBMI and GWG with offspring's insulin sensitivity were analysed by pooling regression coefficients or standardized differences in means with 95% confidence intervals (CIs). Maternal ppBMI showed significant positive correlations with the level of both fasting insulin and HOMA‐IR in offspring (standardized regression coefficient for fasting insulin: 0.107, CI [0.053, 0.160], p < 0.001 and that for HOMA‐IR: 0.063, CI [0.006, 0.121], p = 0.031). However, the result of the analysis on coefficients adjusted for offspring's actual anthropometry (BMI and adiposity) was not significant. Independent from ppBMI, GWG tended to show a positive correlation with insulin level, but not after adjustment for offspring's anthropometry. Offspring of mothers with excessive GWG showed significantly higher HOMA‐IR than those of mothers with optimal GWG (p = 0.004). Our results demonstrate that both higher ppBMI and GWG increase the risk of offspring's insulin resistance, but the effect of ppBMI on insulin sensitivity in offspring may develop as consequence of their adiposity.

Antioxidant Effects of N-Acetylcysteine Prevent Programmed Metabolic Disease in Mice

An adverse maternal in utero and lactation environment can program offspring for increased risk for metabolic disease. The aim of this study was to determine whether N-acetylcysteine (NAC), an anti-inflammatory antioxidant, attenuates programmed susceptibility to obesity and insulin resistance in offspring of mothers on a high-fat diet (HFD) during pregnancy. CD1 female mice were acutely fed a standard breeding chow or HFD. NAC was added to the drinking water (1 g/kg) of the treatment cohorts from embryonic day 0.5 until the end of lactation. NAC treatment normalized HFD-induced maternal weight gain and oxidative stress, improved the maternal lipidome, and prevented maternal leptin resistance. These favorable changes in the in utero environment normalized postnatal growth, decreased white adipose tissue (WAT) and hepatic fat, improved glucose and insulin tolerance and antioxidant capacity, reduced leptin and insulin, and increased adiponectin in HFD offspring. The lifelong metabolic improvements in the offspring were accompanied by reductions in proinflammatory gene expression in liver and WAT and increased thermogenic gene expression in brown adipose tissue. These results, for the first time, provide a mechanistic rationale for how NAC can prevent the onset of metabolic disease in the offspring of mothers who consume a typical Western HFD.

Dietary Protein Intake during Pregnancy Is Not Associated with Offspring Insulin Sensitivity during the First Two Years of Life

Literature describing a relationship between dietary protein intake during pregnancy and offspring insulin resistance are equivocal perhaps because of the lapse between maternal and offspring measurements (~9–40 years). Thus, we evaluated protein intake in healthy women [n = 182, mean ± SD; body mass index (BMI): 26.2 ± 4.2 kg/m2] in early pregnancy (8.4 ± 1.6 weeks, EP), late pregnancy (30.1 ± 0.4 weeks, LP), and averaged throughout pregnancy, and determined the relationship between protein intake and offspring homeostatic model assessment of insulin resistance (HOMA2-IR) at 12 (12mo) and 24 (24mo) months. EP protein (g·kg−1·day−1) did not associate with HOMA2-IR at 12mo (β = 0.153, p = 0.429) or 24mo (β = −0.349, p = 0.098). LP protein did not associate with HOMA2-IR at 12mo (β = 0.023, p = 0.916) or 24mo (β = −0.442, p = 0.085). Finally, average protein did not associate with HOMA2-IR at 12mo (β = 0.711, p = 0.05) or 24mo (β = −0.445, p = 0.294). Results remained unchanged after adjusting for plant protein intake quartiles during pregnancy, maternal BMI, and offspring sex and body fat percentage. Additionally, these relationships did not change after quartile analysis of average protein intake, even after considering offspring fasting time and HOMA2-IR outliers, and maternal under-reporters of energy intake. Protein intake during pregnancy is not associated with indirect measurements of insulin sensitivity in offspring during the first two years of life.

Nonnutritive sweetener consumption during pregnancy, adiposity, and adipocyte differentiation in offspring: evidence from humans, mice, and cells

Obesity often originates in early life, and is linked to excess sugar intake. Nonnutritive sweeteners (NNS) are widely consumed as "healthier" alternatives to sugar, yet recent evidence suggests NNS may adversely influence weight gain and metabolic health. The impact of NNS during critical periods of early development has rarely been studied. We investigated the effect of prenatal NNS exposure on postnatal adiposity and adipocyte development. In the CHILD birth cohort (N = 2298), we assessed maternal NNS beverage intake during pregnancy and child body composition at 3 years, controlling for maternal BMI and other potential confounders. To investigate causal mechanisms, we fed NNS to pregnant C57BL6J mice at doses relevant to human consumption (42 mg/kg/day aspartame or 6.3 mg/kg/day sucralose), and assessed offspring until 12 weeks of age for: body weight, adiposity, adipose tissue morphology and gene expression, glucose and insulin tolerance. We also studied the effect of sucralose on lipid accumulation and gene expression in cultured 3T3-L1 pre-adipocyte cells. In the CHILD cohort, children born to mothers who regularly consumed NNS beverages had elevated body mass index (mean z-score difference +0.23, 95% CI 0.05-0.42 for daily vs. no consumption, adjusted for maternal BMI). In mice, maternal NNS caused elevated body weight, adiposity, and insulin resistance in offspring, especially in males (e.g., 47% and 15% increase in body fat for aspartame and sucralose vs. controls, p < 0.001). In cultured adipocytes, sucralose exposure at early stages of differentiation caused increased lipid accumulation and expression of adipocyte differentiation genes (e.g., C/EBP-α, FABP4, and FASN). These genes were also upregulated in adipose tissue of male mouse offspring born to sucralose-fed dams. By triangulating evidence from humans, mice, and cultured adipocytes, this study provides new evidence that maternal NNS consumption during pregnancy may program obesity risk in offspring through effects on adiposity and adipocyte differentiation.

Acute alcohol exposure in early gestation programmes sex-specific insulin resistance in offspring: a shifting tide in prenatal alcohol exposure models.

Acute alcohol exposure in early gestation programmes sex-specific insulin resistance in offspring: a shifting tide in prenatal alcohol exposure models.

Gestational diabetes impacts fetal precursor cell responses with potential consequences for offspring.

Fetal programming has been proposed as a key mechanism underlying the association between intrauterine exposure to maternal diabetes and negative health outcomes in offspring. To determine whether gestational diabetes mellitus (GDM) might leave an imprint in fetal precursors of the amniotic membrane and whether it might be related to adverse outcomes in offspring, a prospective case‐control study was conducted, in which amniotic mesenchymal stem cells (AMSCs) and resident macrophages were isolated from pregnant patients, with either GDM or normal glucose tolerance, scheduled for cesarean section. After characterization, functional characteristics of AMSCs were analyzed and correlated with anthropometrical and clinical variables from both mother and offspring. GDM‐derived AMSCs displayed an impaired proliferation and osteogenic potential when compared with control cells, accompanied by superior invasive and chemotactic capacity. The expression of genes involved in the inflammatory response (TNFα, MCP‐1, CD40, and CTSS) was upregulated in GDM‐derived AMSCs, whereas anti‐inflammatory IL‐33 was downregulated. Macrophages isolated from the amniotic membrane of GDM mothers consistently showed higher expression of MCP‐1 as well. In vitro studies in which AMSCs from healthy control women were exposed to hyperglycemia, hyperinsulinemia, and palmitic acid confirmed these results. Finally, genes involved in the inflammatory response were associated with maternal insulin sensitivity and prepregnancy body mass index, as well as with fetal metabolic parameters. These results suggest that the GDM environment could program stem cells and subsequently favor metabolic dysfunction later in life. Fetal adaptive programming in the setting of GDM might have a direct negative impact on insulin resistance of offspring.