Syndrome In Adult Offspring Research Articles

Dexamethasone exposure during pregnancy triggers metabolic syndrome in offspring via epigenetic alteration of IGF1

BackgroundPrevious research has reported that prenatal exposure to dexamethasone (PDE) results in organ dysplasia and increased disease susceptibility in offspring. This study aimed to investigate the epigenetic mechanism of metabolic syndrome induced by PDE in offspring.MethodsPregnant Wistar rats were administered dexamethasone, and their offspring’s serum and liver tissues were analyzed. The hepatocyte differentiation model was established to unveil the molecular mechanism. Neonatal cord blood samples were collected to validate the phenomenon and mechanism.ResultsThe findings demonstrated that PDE leads to insulin resistance and typical metabolic syndrome traits in adult offspring rats, which originated from fetal liver dysplasia. Additionally, PDE reduced serum corticosterone level and inhibited hepatic insulin-like growth factor 1 (IGF1) signaling in fetal rats. It further revealed that liver dysplasia and functional impairment induced by PDE persist after birth, driven by the continuous downregulation of serum corticosterone and hepatic IGF1 signaling. Both in vitro and in vivo experiments confirmed that low endogenous corticosterone reduces the histone 3 lysine 9 acetylation (H3K27ac) level of IGF1 and its expression by blocking glucocorticoid receptor α, special protein 1, and P300 into the nucleus, resulting in hepatocyte differentiation inhibition and liver dysplasia. Intriguingly, neonatal cord blood samples validated the link between reduced liver function in neonates induced by PDE and decreased serum cortisol and IGF1 levels.ConclusionsThis study demonstrated that low endogenous glucocorticoid level under PDE lead to liver dysplasia by downregulating the H3K27ac level of IGF1 and its expression, ultimately contributing to metabolic syndrome in adult offspring.

Alteration of the embryonic microenvironment and sex-specific responses of the preimplantation embryo related to a maternal high-fat diet in the rabbit model.

The maternal metabolic environment can be detrimental to the health of the offspring. In a previous work, we showed that maternal high-fat (HH) feeding in rabbit induced sex-dependent metabolic adaptation in the fetus and led to metabolic syndrome in adult offspring. As early development representing a critical window of susceptibility, in the present work we aimed to explore the effects of the HH diet on the oocyte, preimplantation embryo and its microenvironment. In oocytes from females on HH diet, transcriptomic analysis revealed a weak modification in the content of transcripts mainly involved in meiosis and translational control. The effect of maternal HH diet on the embryonic microenvironment was investigated by identifying the metabolite composition of uterine and embryonic fluids collected in vivo by biomicroscopy. Metabolomic analysis revealed differences in the HH uterine fluid surrounding the embryo, with increased pyruvate concentration. Within the blastocoelic fluid, metabolomic profiles showed decreased glucose and alanine concentrations. In addition, the blastocyst transcriptome showed under-expression of genes and pathways involved in lipid, glucose and amino acid transport and metabolism, most pronounced in female embryos. This work demonstrates that the maternal HH diet disrupts the in vivo composition of the embryonic microenvironment, where the presence of nutrients is increased. In contrast to this nutrient-rich environment, the embryo presents a decrease in nutrient sensing and metabolism suggesting a potential protective process. In addition, this work identifies a very early sex-specific response to the maternal HH diet, from the blastocyst stage.

Exercise intervention during pregnancy induces DNA methylation alterations in maternal blood and cord blood.

Exercise intervention during pregnancy induces DNA methylation alterations in maternal blood and cord blood.

Early-life dietary exposures mediate persistent shifts in the gut microbiome and visceral fat metabolism.

In utero dietary exposures are linked to the development of metabolic syndrome in adult offspring. These dietary exposures can potentially impact gut microbial composition and offspring metabolic health. Female BALB/c mice were administered a lard, lard + flaxseed oil, high sugar, or control diet 4 wk before mating, throughout mating, pregnancy, and lactation. Female offspring were offered low-fat control diet at weaning. Fecal 16S sequencing was performed. Untargeted metabolomics was performed on visceral adipose tissue (VAT) of adult female offspring. Immunohistochemistry was used to determine adipocyte size, VAT collagen deposition, and macrophage content. Hippurate was administered via weekly intraperitoneal injections to low-fat and high-fat diet-fed female mice and VAT fibrosis and collagen 1A (COL1A) were assessed by immunohistochemistry. Lard diet exposure was associated with elevated body and VAT weight and dysregulated glucose metabolism. Lard + flaxseed oil attenuated these effects. Lard diet exposures were associated with increased adipocyte diameter and VAT macrophage count. Lard + flaxseed oil reduced adipocyte diameter and fibrosis compared with the lard diet. Hippurate-associated bacteria were influenced by lard versus lard + flax exposures that persisted to adulthood. VAT hippurate was increased in lard + flaxseed oil compared with lard diet. Hippurate supplementation mitigated VAT fibrosis pathology. Maternal high-fat lard diet consumption resulted in long-term metabolic and gut microbiome programming in offspring, impacting VAT inflammation and fibrosis, and was associated with reduced VAT hippurate content. These traits were not observed in maternal high-fat lard + flaxseed oil diet-exposed offspring. Hippurate supplementation reduced VAT fibrosis. These data suggest that detrimental effects of early-life high-fat lard diet exposure can be attenuated by dietary omega-3 polyunsaturated fatty acid supplementation.

The Impact of Gut Microbiome on Maternal Fructose Intake-Induced Developmental Programming of Adult Disease.

Excessive or insufficient maternal nutrition can influence fetal development and the susceptibility of offspring to adult disease. As eating a fructose-rich diet is becoming more common, the effects of maternal fructose intake on offspring health is of increasing relevance. The gut is required to process fructose, and a high-fructose diet can alter the gut microbiome, resulting in gut dysbiosis and metabolic disorders. Current evidence from animal models has revealed that maternal fructose consumption causes various components of metabolic syndrome in adult offspring, while little is known about how gut microbiome is implicated in fructose-induced developmental programming and the consequential risks for developing chronic disease in offspring. This review will first summarize the current evidence supporting the link between fructose and developmental programming of adult diseases. This will be followed by presenting how gut microbiota links to common mechanisms underlying fructose-induced developmental programming. We also provide an overview of the reprogramming effects of gut microbiota-targeted therapy on fructose-induced developmental programming and how this approach may prevent adult-onset disease. Using gut microbiota-targeted therapy to prevent maternal fructose diet-induced developmental programming, we have the potential to mitigate the global burden of fructose-related disorders.

Maternal high-fructose intake during pregnancy and lactation induces metabolic syndrome in adult offspring.

BACKGROUND/OBJECTIVESNutritional status and food intake during pregnancy and lactation can affect fetal programming. In the current metabolic syndrome epidemic, high-fructose diets have been strongly implicated. This study investigated the effect of maternal high-fructose intake during pregnancy and lactation on the development of metabolic syndrome in adult offspring.SUBJECTS/METHODSDrinking water with or without 20% fructose was administered to female C57BL/6J mice over the course of their pregnancy and lactation periods. After weaning, pups ate regular chow. Accu-Chek Performa was used to measure glucose levels, and a tail-cuff method was used to examine systolic blood pressure. Animals were sacrificed at 7 months, their livers were excised, and sections were stained with Oil Red O and hematoxylin and eosin (H&E) staining. Kidneys were collected for gene expression analysis using quantitative real-time Polymerase chain reaction.RESULTSAdult offspring exposed to maternal high-fructose intake during pregnancy and lactation presented with heavier body weights, fattier livers, and broader areas under the curve in glucose tolerance test values than control offspring. Serum levels of alanine aminotransferase, aspartate aminotransferase, glucose, triglycerides, and total cholesterol and systolic blood pressure in the maternal high-fructose group were higher than that in controls. However, there were no significant differences in mRNA expressions of renin-angiotensin-aldosterone system genes and sodium transporter genes.CONCLUSIONSThese results suggest that maternal high-fructose intake during pregnancy and lactation induces metabolic syndrome with hyperglycemia, hypertension, and dyslipidemia in adult offspring.

Epigenetic Programming and Fetal Metabolic Programming.

Fetal metabolic programming caused by the adverse intrauterine environment can induce metabolic syndrome in adult offspring. Adverse intrauterine environment introduces fetal long-term relatively irreversible changes in organs and metabolism, and thus causes fetal metabolic programming leading metabolic syndrome in adult offspring. Fetal metabolic programming of obesity and insulin resistance plays a key role in this process. The mechanism of fetal metabolic programming is still not very clear. It is suggested that epigenetic programming, also induced by the adverse intrauterine environment, is a critical underlying mechanism of fetal metabolic programming. Fetal epigenetic programming affects gene expression changes and cellular function through epigenetic modifications without DNA nucleotide sequence changes. Epigenetic modifications can be relatively stably retained and transmitted through mitosis and generations, and thereby induce the development of metabolic syndrome in adult offspring. This manuscript provides an overview of the critical role of epigenetic programming in fetal metabolic programming.

Maternal High-Fructose Intake Induces Multigenerational Activation of the Renin-Angiotensin-Aldosterone System.

Although maternal high-fructose intake induces cardiometabolic syndrome in adult offspring, whether it induces hypertension in successive multiple generations has not yet been studied. We hypothesized that maternal high-fructose intake induces multigenerational activation of the renin-angiotensin-aldosterone system. Pregnant mice were offered 20% fructose in drinking water, of which subsequent first to fourth generation offspring were raised without being offered fructose. Blood pressure was measured via the tail-cuff method, mRNA expression was determined using the quantitative polymerase chain reaction, and fibrosis was evaluated using trichrome staining. Maternal high-fructose intake statistically significantly increased blood pressure in the first and second, but not the third and fourth, generation offspring as compared to the control group, with maximal increases in serum renin, angiotensin II, and aldosterone in the third generation offspring. It increased the mRNA expression of renin-angiotensin-aldosterone system genes as well as the expression of renin in the kidneys in the first to third generation offspring, with the exception of the vasodilatory Mas1 gene, the mRNA expression of which was the lowest in the second generation offspring. Moreover, it maximally increased fibrosis and the mRNA expression of inflammatory cytokines in the second generation offspring and increased the mRNA expression of oxidative factors in the first to third generation offspring, but maximally decreased the mRNA expression of antioxidant-encoding Sod1 in the second generation offspring. Maternal high-fructose intake induces multigenerational activation of renin-angiotensin-aldosterone system, and the results of this study implicate that it epigenetically induces cardiometabolic syndrome in multiple generations of offspring.

3: Pregnancy high fructose diet: pathways involved in fetal programming of metabolic syndrome in adult offspring

We, as well as others, have shown that maternal intake of high fructose has been shown to lead to sex- specific fetal programming of adult obesity, hypertension and metabolic dysfunction in mice. Our objective was to test the hypothesis that these outcomes are related to altered fructose metabolism, lipid accumulation and inflammation in the liver of adult offspring. Pregnant C57BL/6J dams were randomly allocated to fructose solution (10% W/V; n=10) as only drinking liquid or water (n=10), starting at ED 1 and until birth. After weaning, pups were then started on regular chow. Offspring were sacrificed when they reached adult stage (1 year of life) and their liver harvested. Protein and mRNA levels of ketohexokinase (KHK; a crucial enzyme in fructose metabolism that promotes insulin resistance and hepatic inflammation through toll like receptor-4: TLR-4), of transcription factors that lead to hepatic lipid accumulation (CHREBP: carbohydrate responsive element-binding protein; SREBP-1c: sterol regulatory element-binding protein-1c; PPAR-g: peroxisome proliferator-activated receptors-gamma), and of an enzyme responsible for tissue fat entrapment (CD36: fatty acid translocase) were assayed using Western blotting and PCR techniques. Normality was tested using Kurtosis. T-test or Mann-Whitney rank sum were used for statistical analysis. P< 0.05 was considered significant.Data are reported as mean ± SEM or median [IQR]. Female adult mice born to dams in the fructose group had significantly higher liver CHREBP, SREBP-1c & KHK protein levels compared to controls (Figure 1A). No significant differences were noted in the male counterparts (Figure 1B). Despite lack of significant changes in liver protein levels of CD36 and PPAR-g, exposure to fructose was associated with upregulation of CD36, KHK & TLR-4 mRNA in females (Figure 2 A, B & C), and PPAR-g mRNA in males (Figure 2 D). Exposure to high fructose diet in utero leads to gender-specific activation of molecular pathways responsible for insulin resistance, liver inflammation and liver steatosis in adults. High fructose enriched diets in pregnancy can have significant adverse long-term impact on health. Understanding the pathways involved can guide development of preventive and therapeutic approaches.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Obesity in mares promotes uterine inflammation and alters embryo lipid fingerprints and homeostasis.

Maternal body composition can be an important determinant for development of obesity and metabolic syndrome in adult offspring. Obesity-related outcomes in offspring may include epigenetic alterations; however, mechanisms of fetal programming remain to be fully elucidated. This study was conducted to determine the impact of maternal obesity in the absence of a high fat diet on equine endometrium and preimplantation embryos. Embryos were collected from normal and obese mares at 8 and 16 days and a uterine biopsy at 16 days (0 day=ovulation). With the exception of 8 day embryos, each sample was divided into two pieces. One piece was analyzed for gene expression markers related to carbohydrate metabolism, lipid homeostasis, inflammation, endoplasmic reticulum stress, oxidative stress, mitochondrial stress, and components of the insulin-like growth factor (IGF) system. The second piece was analyzed for lipid content using matrix-assisted laser desorption/ionization mass spectrometry. Obese mares had elevated concentrations of insulin, leptin, and total cholesterol, and they tended to have increased triglycerides and decreased insulin sensitivity. Embryos from obese mares had altered transcript abundance in genes for inflammation and lipid homeostasis, as well as endoplasmic reticulum, oxidative and mitochondrial stress and altered lipid fingerprints. Endometrium from obese mares had increased expression of inflammatory cytokines, lipid homeostasis regulation, mitochondrial stress, and the IGF2 system. This study demonstrates that increased adiposity in mares alters the uterine environment, transcript abundance of genes for cellular functions, and lipid profiles of embryos. These alterations could affect prenatal programming, with potential long-term effects in offspring.

Brain inflammation and oxidative stress in the developmental programming of metabolic syndrome in adult offspring to maternal nutrition insult

Early life exposure to adverse environments can lead to a variety of adult diseases by a process referred to as developmental origin of adult health and disease (DOHaD) or developmental programming. Maternal high fructose diet (HFD) promotes programmed hypertension in adult offspring, although the underlying mechanism is not fully understood. Brain inflammation and oxidative stress have been reported to play pivotal roles in neural mechanism of hypertension. We tested in this study the hypothesis that brain inflammation and oxidative stress contribute to the programmed hypertension in adult offspring to maternal HFD. In normotensive Sprague‐Dawley rats, maternal HFD during gestation and lactation led to insulin resistance, hypertriglyceride, increased sympathetic activity and hypertension in the 3‐month‐old young offspring. The increase in blood pressure was associated with the augmented neurogenic sympathetic vasomotor tone, increase in plasma norepinephrine level, production of proinflammatory cytokines and high tissue levels of reactive oxygen species (ROS) at the brain stem. Maternal melatonin treatment or minocycline treatment beginning at the age of two months significantly ameliorated neuroinflammation and oxidative stress in the brain stem; alongside the delay in the programming of hypertension in adult offspring. At the same time, intracisternal infusion with a superoxide scavenger, tempol, abrogated sympathetic overexcitation and prevented the development of programmed hypertension in the 3‐month‐old offspring to maternal HFD. Together, these results suggest that brain inflammation and stem oxidative stress may contribute to sympathoexcitation and the programmed hypertension in offspring to maternal HFD.Support or Funding InformationThis study was supported by grant (CMRPG8C0051‐053) from Kaohsiung Chang Gung Memorial Hospital.

Sex-specific increase in susceptibility to metabolic syndrome in adult offspring after prenatal ethanol exposure with post-weaning high-fat diet.

Prenatal ethanol exposure (PEE) is an established risk factor for intrauterine growth retardation. The present study was designed to determine whether PEE can increase the susceptibility of high-fat diet (HFD)-induced metabolic syndrome (MS) in adult offspring in a sex-specific manner, based on a generalized linear model analysis. Pregnant Wistar rats were administered ethanol (4 g/kg.d) from gestational day 11 until term delivery. All offspring were fed either a normal diet or a HFD after weaning and were sacrificed at postnatal week 20, and blood samples were collected. Results showed that PEE reduced serum adrenocorticotropic hormone (ACTH) and corticosterone levels but enhanced serum glucose, insulin, insulin resistant index (IRI), triglyceride and total cholesterol (TC) concentrations. Moreover, the analysis showed interactions among PEE, HFD and sex. In the PEE offspring, HFD aggravated the decrease in ACTH and corticosterone levels and further increased serum glucose, insulin, triglyceride and TC levels. The changes of serum ACTH, glucose and IRI levels in the female HFD rats were greater than those in the male HFD rats. Our findings suggest that PEE enhances the susceptibility to MS induced by HFD in a sex-specific manner, which might be primarily associated with the neuroendocrine metabolic programming by PEE.

Sexual dimorphism of the feto-placental phenotype in response to a high fat and control maternal diets in a rabbit model.

Maternal environment during early developmental stages plays a seminal role in the establishment of adult phenotype. Using a rabbit model, we previously showed that feeding dams with a diet supplemented with 8% fat and 0.2% cholesterol (HH diet) from the prepubertal period and throughout gestation induced metabolic syndrome in adult offspring. Here, we examined the effects of the HH diet on feto-placental phenotype at 28 days post-coïtum (term = 31days) in relation to earlier effects in the blastocyst (Day 6). At 28 days, both male and female HH fetuses were intrauterine growth retarded and dyslipidemic, with males more affected than females. Lipid droplets accumulated in the HH placentas’ trophoblast, consistent with the increased concentrations in cholesteryl esters (3.2-fold), triacylglycerol (2.5-fold) and stored FA (2.12-fold). Stored FA concentrations were significantly higher in female compared to male HH placentas (2.18-fold, p<0.01), whereas triacylglycerol was increased only in HH males. Trophoblastic lipid droplet accumulation was also observed at the blastocyst stage. The expression of numerous genes involved in lipid pathways differed significantly according to diet both in term placenta and at the blastocyst stage. Among them, the expression of LXR-α in HH placentas was reduced in HH males but not females. These data demonstrate that maternal HH diet affects the blastocyst and induces sex-dependent metabolic adaptations in the placenta, which appears to protect female fetuses from developing severe dyslipidemia.

Does physical activity during pregnancy adversely influence markers of the metabolic syndrome in adult offspring? A prospective study over two decades

BackgroundIt is unknown whether physical activity during pregnancy (PA) has long-term impact on the metabolic profile of the offspring. We investigated associations of PA with markers of the metabolic syndrome...

Developmental programming of cardiovascular disease by prenatal hypoxia.

It is now recognized that the quality of the fetal environment during early development is important in programming cardiovascular health and disease in later life. Fetal hypoxia is one of the most common consequences of complicated pregnancies worldwide. However, in contrast to the extensive research effort on pregnancy affected by maternal nutrition or maternal stress, the contribution of pregnancy affected by fetal chronic hypoxia to developmental programming is only recently becoming delineated and established. This review discusses the increasing body of evidence supporting the programming of cardiac susceptibility to ischaemia and reperfusion (I/R) injury, of endothelial dysfunction in peripheral resistance circulations, and of indices of the metabolic syndrome in adult offspring of hypoxic pregnancy. An additional focus of the review is the identification of plausible mechanisms and the implementation of maternal and early life interventions to protect against adverse programming.

Maternal Diabetes in Pregnancy: Early and Long-Term Outcomes on the Offspring and the Concept of “Metabolic Memory”

The adverse outcomes on the offspring from maternal diabetes in pregnancy are substantially documented. In this paper, we report main knowledge on impacts of maternal diabetes on early and long-term health of the offspring, with specific comments on maternal obesity. The main adverse outcome on progenies from pregnancy complicated with maternal diabetes appears to be macrosomia, as it is commonly known that intrauterine exposure to hyperglycemia increases the risk and programs the offspring to develop diabetes and/or obesity at adulthood. This “fetal programming”, due to intrauterine diabetic milieu, is termed as “metabolic memory”. In gestational diabetes as well as in macrosomia, the complications include metabolic abnormalities, degraded antioxidant status, disrupted immune system and potential metabolic syndrome in adult offspring. Furthermore, there is evidence that maternal obesity may also increase the risk of obesity and diabetes in offspring. However, women with GDM possibly exhibit greater macrosomia than obese women. Obesity and diabetes in pregnancy have independent and additive effects on obstetric complications, and both require proper management. Management of gestational diabetes mellitus and maternal obesity is essential for maternal and offspring's good health. Increasing physical activity, preventing gestational weight gain, and having some qualitative nutritional habits may be beneficial during both the pregnancy and offspring's future life.

Overweight and the Metabolic Syndrome in Adult Offspring of Women with Diet-Treated Gestational Diabetes Mellitus or Type 1 Diabetes

In animal studies, exposure to intrauterine hyperglycemia increases the risk of cardiovascular disease through only partly understood epigenetic mechanisms. Human long-term follow-up studies on the same topic are few. The aim was to study the risk of overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus (GDM) or type 1 diabetes, and additionally to study associations between estimates of maternal hyperglycemia and outcome in the offspring. We conducted a follow-up study of 1066 primarily Caucasian women aged 18-27 yr in the Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark. Offspring of women with diet-treated GDM (n = 168) and an unexposed reference group (n = 141) participated, as well as offspring of women with type 1 diabetes (n = 160) and offspring from the background population representing an unexposed reference group (n = 128). The follow-up rate was 56% (597 of 1066). Women with body mass index of at least 25 kg/m(2) were considered overweight. The metabolic syndrome was determined by the International Diabetes Federation 2006 criteria. The risk of overweight was doubled in offspring of women with diet-treated GDM or type 1 diabetes compared with offspring from the background population, whereas the risk of the metabolic syndrome was 4- and 2.5-fold increased, respectively. Offspring risk of the metabolic syndrome increased significantly with increasing maternal fasting blood glucose as well as 2-h blood glucose (during oral glucose tolerance test). Adult offspring of women with diet-treated GDM or type 1 diabetes are risk groups for overweight and the metabolic syndrome. Intrauterine hyperglycemia may in addition to genetics and other factors contribute to the pathogenesis of overweight and the metabolic syndrome.

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Relationships of maternal and paternal birthweights to features of the metabolic syndrome in adult offspring: an inter-generational study in South India.

The association between lower birthweight and metabolic syndrome may result from fetal undernutrition (fetal programming hypothesis) and/or genes causing both low birthweight and insulin resistance (fetal insulin hypothesis). We studied associations between the birthweight of parents and metabolic syndrome in the offspring. We identified men and women (aged 35-68 years), who had been born in Holdsworth Memorial Hospital, Mysore, India. We also identified the offspring (20-46 years) of these men and women. In total, 283 offspring of 193 mothers and 223 offspring of 144 fathers were studied. Investigations included anthropometry, oral glucose tolerance, plasma insulin and lipid concentrations and blood pressure. The metabolic syndrome was defined using WHO criteria. Among the offspring, lower birthweight was associated with an increased risk of glucose intolerance (impaired glucose tolerance, impaired fasting glucose or type 2 diabetes) and higher cholesterol and triacylglycerol concentrations (p < 0.05 for all adjusted for sex and age). Most outcomes in the offspring, including most individual components of the metabolic syndrome, were unrelated to parental birthweight. However, both maternal and paternal birthweight were inversely related to offspring metabolic syndrome (odds ratio [OR] 0.36 [95% CI: 0.13-1.01] per kg, p = 0.053 for mother-offspring pairs; OR 0.26 [0.07-0.93], p = 0.04 for father-offspring pairs, adjusted for offspring age, sex, BMI and socioeconomic status). Maternal birthweight was inversely related to offspring systolic blood pressure (beta = -2.5 mmHg [-5.00 to 0.03] per kg maternal birthweight; p = 0.052). Factors in both parents may influence the risk of metabolic syndrome in their offspring. There are several possible explanations, but the findings are consistent with the fetal insulin (genetic) hypothesis.

A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring.

Epidemiological and animal studies suggest that diet-induced epigenetic modifications in early life can contribute to development of the metabolic syndrome in adulthood. We previously reported features of the metabolic syndrome in adult offspring of rats fed a diet rich in animal fat during pregnancy and suckling. We now report a study to compare the relative effects of high-fat feeding during 1) pregnancy and 2) the suckling period in the development of these disorders. As observed previously, 6-mo-old female offspring of fat-fed dams suckled by the same fat-fed dams (OHF) demonstrated raised blood pressure, despite being fed a balanced diet from weaning. Female offspring of fat-fed dams "cross fostered" to dams consuming a control diet during suckling (OHF/C) demonstrated raised blood pressure compared with controls (OC) [systolic blood pressure (SBP; mmHg) means +/- SE: OHF/C, 132.5 +/- 3.0, n = 6 vs. OC, 119.0 +/- 3.8, n = 7, P < 0.05]. Female offspring of controls cross fostered to dams consuming the fat diet (OC/HF) were also hypertensive [SBP (mmHg) 131.0 +/- 2.5 mmHg, n = 6 vs. OC, P < 0.05]. Endothelium-dependent relaxation (EDR) of male and female OHF and OHF/C mesenteric small arteries was similar and blunted compared with OC (P < 0.001). OC/HF arteries showed profoundly impaired EDR (OC/HF vs. OHF, P < 0.001). OHF/C and OC/HF demonstrated hyperinsulinemia and increased adiposity. Features of the metabolic syndrome in adult offspring of fat-fed rats can be acquired both antenatally and during suckling. However, exposure during pregnancy confers adaptive protection against endothelial dysfunction induced by maternal fat feeding during suckling.