Epidemiological studies have demonstrated an association between low birth weight and adult disease development with transmission to subsequent generations. The aim of this study was to examine the effect of intrauterine growth restriction in rats, induced by uteroplacental insufficiency, on cardiac structure, number, size, nuclearity and adult blood pressure in first (F1) and second (F2) generation male offspring. Uteroplacental insufficiency or sham surgery was induced in F0 WKY pregnant rats in late gestation giving rise to F1 Restricted and Control offspring, respectively. F1 Control and Restricted females were mated with normal males resulting in F2 Control and Restricted offspring, respectively. F1 Restricted male offspring were significantly lighter at birth (P<0.05), but there were no differences in birth weight of F2 offspring. Left ventricular weights and volumes were significantly increased (P<0.05) in F1 and F2 Restricted offspring at day 35. Left ventricular cardiomyocyte number was not different in F1 and F2 Restricted offspring. At 6 months of age, F1 and F2 Restricted offspring had elevated blood pressure (8-15mmHg, P<0.05). Our findings demonstrate the emergence of left ventricular hypertrophy and hypertension, with no change in cardiomyocyte number, in F1 Restricted male offspring and this was transmitted to the F2 offspring. The findings support transgenerational programming effects. This article is protected by copyright. All rights reserved.
A developmental insult that restricts growth in the first generation has the potential to program disease in subsequent generations. The aim of this study was to ascertain transgenerational growth and cardio-renal effects, via the maternal line, in a rat model of utero-placental insufficiency. Bilateral uterine vessel ligation or sham surgery (offspring termed first generation; F1 Restricted and Control, respectively) was performed in WKY rats. F1 Restricted and Control females were mated with normal males to produce second generation (F2) offspring (Restricted and Control) studied from fetal (embryonic Day 20) to adult (12 months) life. F2 Restricted male and female fetuses had reduced (P<0.05) nephron number (down 15-22%) but this deficit was not sustained postnatally and levels were similar to Controls at Day 35. F2 Restricted males, but not females, developed elevated (+16mmHg, P<0.05) systolic blood pressure at 6 months of age, which was sustained to 9 months. This was not explained by alterations to intra-renal or plasma components of the renin-angiotensin system. In a rat model of utero-placental insufficiency, we report alterations to F2 kidney development and sex-specific adult hypertension. This study demonstrates that low birthweight can have far-reaching effects that extend into the next generation.
Hepatic insulin resistance is a key contributor to the pathogenesis of obesity and type 2 diabetes (T2D). Paradoxically, the development of insulin resistance in the liver is not universal, but pathway selective, such that insulin fails to suppress gluconeogenesis but promotes lipogenesis, contributing to the hyperglycemia, steatosis, and hypertriglyceridemia that underpin the deteriorating glucose control and microvascular complications in T2D. The molecular basis for the pathway-specific insulin resistance remains unknown. Here we report that oxidative stress accompanying obesity inactivates protein-tyrosine phosphatases (PTPs) in the liver to activate select signaling pathways that exacerbate disease progression. In obese mice, hepatic PTPN2 (TCPTP) inactivation promoted lipogenesis and steatosis and insulin-STAT-5 signaling. The enhanced STAT-5 signaling increased hepatic IGF-1 production, which suppressed central growth hormone release and exacerbated the development of obesity and T2D. Our studies define a mechanism for the development of selective insulin resistance with wide-ranging implications for diseases characterized by oxidative stress.
Adverse conditions in utero can have transgenerational effects, in the absence of a subsequent insult. We aimed to investigate the contribution of the maternal pregnancy environment vs. germ line effects in mediating alterations to cardiorenal and metabolic physiology in offspring from mothers born small. Uteroplacental insufficiency was induced by bilateral uterine artery and vein ligation (Restricted group) or sham surgery (Control group) in Wistar-Kyoto rats. Restricted and control female offspring (F1) were mated with either breeder males (embryo donor) or vasectomized males (embryo recipient). Embryo transfer was performed at embryonic day (E) 1, whereby second-generation (F2) embryos gestated (donor-in-recipient) in either a control (Cont-in-Cont, Rest-in-Cont) or restricted (Cont-in-Rest, Rest-in-Rest) mother. In male and female offspring, glomerular number and size were measured at postnatal day (PN) 35, and systolic blood pressure, glucose control, insulin sensitivity, and pancreatic ?-cell mass were measured in separate sibling cohorts at 6 mo. Rest-in-Rest offspring were hypothesized to have similar characteristics (reduced growth, altered metabolic control, and hypertension) to non-embryo-transferred Rest, such that embryo transfer would not be a confounding experimental influence. However, embryo-transferred Rest-in-Rest offspring underwent accelerated growth during the peripubertal phase, followed by slowed growth between 2 and 3 mo of age compared with non-embryo-transferred Rest groups. Furthermore, renal function and insulin response to a glucose load were different to respective non-embryo-transferred groups. Our data demonstrate the long-term effects of in vitro embryo manipulation, which confounded the utility of this approach in delineating between the maternal pregnancy environment and germ line effects that drive transgenerational outcomes.
Suboptimal conditions in utero are associated with the development of adult-onset diseases in offspring. Uteroplacental insufficiency in rats is a well-established animal model used to mimic and study the effects of developmental insults relevant to countries of abundant nutrient supply. However, wide-ranging outcomes for the offspring are apparent between the different investigators that use this model and also between cohorts generated in our laboratory. We aimed to explore the reasons for variability in rat models of uteroplacental insufficiency between different investigators and also between our own animal cohorts. We suggest differences in growth and disease development reflect uniqueness in susceptibility and highlight the complexity of interactions between genetic potential and environmental exposures. The impact of adverse exposures in utero has been described as having far-reaching effects that extend well beyond the first, directly exposed generation. However, the resulting phenotypes are not consistent between generations. This suggests that programmed effects are established de novo in each generation and challenges the prediction of disease. Characterization of growth and disease in the numerous rat models has led to our understanding of the impact of early life experiences on adult health. In order to drive the development of preventative and/or treatment strategies, future studies should focus on identifying the initial cause(s) of uteroplacental insufficiency, including genetic origins and the influence of poor diets.
This study estimated unmet need for mental health services, identified population risk factors related to unmet need, and established baseline data to assess the impact of the Affordable Care Act (ACA) and the Mental Health Parity and Addiction Equity Act.
Intrauterine growth restriction increases adult metabolic disease risk with evidence to suggest that suboptimal conditions in utero can have transgenerational effects. We determined whether impaired glucose tolerance, reduced insulin secretion, and pancreatic deficits are evident in second-generation (F2) male and female offspring from growth-restricted mothers, in a rat model of uteroplacental insufficiency. Late gestation uteroplacental insufficiency was induced by bilateral uterine vessel ligation (restricted) or sham surgery (control) in Wistar-Kyoto rats. First-generation (F1) control and restricted females were mated with normal males and F2 offspring studied at postnatal day 35 and at 6 and 12 months. F2 glucose tolerance, insulin secretion, and sensitivity were assessed at 6 and 12 months and pancreatic morphology was quantified at all study ages. At 6 months, F2 restricted male offspring exhibited blunted first-phase insulin response (-35%), which was associated with reduced pancreatic ?-cell mass (-29%). By contrast, F2 restricted females had increased ?-cell mass despite reduced first-phase insulin response (-38%). This was not associated with any changes in plasma estradiol concentrations. Regardless of maternal birth weight, F2 control and restricted males had reduced homeostatic model assessment of insulin resistance and elevated plasma triglyceride concentrations at 6 months and reduced whole-body insulin sensitivity at 6 and 12 months compared with females. We report that low maternal birth weight is associated with reduced first-phase insulin response and gender-specific differences in pancreatic morphology in the F2. Further studies will define the mode(s) of disease transmission, including direct insults to developing gametes, adverse maternal responses to pregnancy, or inherited mechanisms.
Intrauterine growth restriction caused by uteroplacental insufficiency increases risk of cardiovascular and metabolic disease in offspring. Cardio-renal and metabolic responses to pregnancy are critical determinants of immediate and long-term maternal health. However, no studies to date have investigated the renal and metabolic adaptations in growth restricted offspring when they in turn become pregnant. We hypothesised that the physiological challenge of pregnancy in growth restricted females exacerbates disease outcome and compromises next generation fetal growth. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham surgery (Control) on day 18 of gestation in WKY rats and F1 female offspring birth and postnatal body weights were recorded. F1 Control and Restricted females were mated at 4 months and blood pressure, renal and metabolic parameters were measured in late pregnancy and F2 fetal and placental weights recorded. Age-matched non-pregnant Control and Restricted F1 females were also studied. F1 Restricted females were born 10-15% lighter than Controls. Basal insulin secretion and pancreatic ?-cell mass were reduced in non-pregnant Restricted females but restored in pregnancy. Pregnant Restricted females, however, showed impaired glucose tolerance and compensatory glomerular hypertrophy, with a nephron deficit but normal renal function and blood pressure. F2 fetuses from Restricted mothers exposed to physiological measures during pregnancy were lighter than Controls highlighting additive adverse effects when mothers born small experience stress during pregnancy. Female rats born small exhibit mostly normal cardio-renal adaptations but altered glucose control during late pregnancy making them vulnerable to lifestyle challenges.
There is a strong inverse relationship between a females own birth weight and her subsequent risk for gestational diabetes with increased risk of developing diabetes later in life. We have shown that growth restricted females develop loss of glucose tolerance during late pregnancy with normal pancreatic function. The aim of this study was to determine whether growth restricted females develop long-term impairment of metabolic control after an adverse pregnancy adaptation. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham surgery (Control) in late pregnancy (E18) in F0 female rats. F1 Control and Restricted female offspring were mated with normal males and allowed to deliver (termed Ex-Pregnant). Age-matched Control and Restricted Virgins were also studied and glucose tolerance and insulin secretion were determined. Pancreatic morphology and hepatic glycogen and triacylglycerol content were quantified respectively. Restricted females were born lighter than Control and remained lighter at all time points studied (p<0.05). Glucose tolerance, first phase insulin secretion and liver glycogen and triacylglycerol content were not different across groups, with no changes in ?-cell mass. Second phase insulin secretion was reduced in Restricted Virgins (-34%, p<0.05) compared to Control Virgins, suggestive of enhanced peripheral insulin sensitivity but this was lost after pregnancy. Growth restriction was associated with enhanced basal hepatic insulin sensitivity, which may provide compensatory benefits to prevent adverse metabolic outcomes often associated with being born small. A prior pregnancy was associated with reduced hepatic insulin sensitivity with effects more pronounced in Controls than Restricted. Our data suggests that pregnancy ameliorates the enhanced peripheral insulin sensitivity in growth restricted females and has deleterious effects for hepatic insulin sensitivity, regardless of maternal birth weight.
Uteroplacental insufficiency is associated with adult cardiorenal and metabolic diseases, particularly in males. Pregnancy is the greatest physiological challenge facing women, and those born small are at increased risk of gestational hypertension and diabetes and delivering smaller babies. Increased maternal age is associated with exacerbated pregnancy complications. We hypothesized that pregnancy in aged, growth-restricted females unmasks an underlying predisposition to cardiorenal and metabolic dysfunction and compromises fetal growth. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (restricted group) or sham surgery (control group) on d 18 of gestation in Wistar Kyoto rats. At 12 mo, growth-restricted F1 female offspring were mated with a normal male. F1 restricted females had elevated systolic blood pressure, before and during pregnancy (+10 mmHg) but normal renal and metabolic pregnancy adaptations. F2 fetal weight was not different between groups. In control and restricted females, advanced maternal age (12 vs. 4 mo) was associated with a reduction in the hypoglycemic response to pregnancy and reduced F2 fetal litter size and body weight. Aged rats born small exhibited mostly normal pregnancy adaptations, although they had elevated blood pressure. Advanced maternal age was associated with poorer fetal outcomes that were not exacerbated by low maternal birth weight.
Intrauterine growth restriction is associated with increased risk of adult cardiorenal diseases. Small birth weight females are more likely to experience complications during their own pregnancy, including pregnancy-induced hypertension, preeclampsia, and gestational diabetes. We determined whether the physiological demand of pregnancy predisposes growth-restricted females to cardiovascular and renal dysfunction later in life. Late gestation bilateral uterine vessel ligation was performed in Wistar-Kyoto rats. At 4 months, restricted and control female offspring were mated with normal males and delivered naturally (ex-pregnant). Regardless of maternal birth weight, at 13 months, ex-pregnant females developed elevated mean arterial pressure (indwelling tail-artery catheter; +6 mm Hg), reduced effective renal blood flow ((14)C-PAH clearance; -23%), and increased renal vascular resistance (+27%) compared with age-matched virgins. Glomerular filtration rate ((3)H-inulin clearance) was not different across groups. This adverse cardiorenal phenotype in ex-pregnant females was associated with elevated systemic (+57%) and altered intrarenal components of the renin-angiotensin system. After pregnancy at 13 months, coronary flow (Langendorff preparation) was halved in restricted females compared with controls, and together with reduced NO excretion, this may increase susceptibility to additional lifestyle challenges. Our results have implications for aging females who have been pregnant, suggesting long-term cardiovascular and renal alterations, with additional consequences for females who were small at birth.
Adverse exposures in utero have long been linked with an increased susceptibility to adult cardio-renal and metabolic diseases. Clear gender differences exist, whereby growth-restricted females, although exhibiting some phenotypic modifications, are often protected from overt disease outcomes. One of the greatest physiological challenges facing the female gender, however, is that of pregnancy; yet little research has focused on the outcomes associated with this, as a potential second-hit for those who were small at birth. We review the limited evidence suggesting that pregnancy may unmask cardio-renal and metabolic disease states and the consequences for long-term maternal health in females who were born small. Additionally, a growing area of research in this programming field is in the transgenerational transmission of low birth weight and disease susceptibility. Pathways for transmission might include an abnormal adaptation to pregnancy by the growth-restricted mother and/or inheritance via the parental germline. Strategies to optimise the pregnancy environment and/or prevent the consequences of inheritance of programmed deficits and dysfunction are of critical importance for future generations.
Aims: Reactive oxygen species (ROS) such as H2O2 can promote signalling through the inactivation of protein tyrosine phosphatases (PTPs). However in obesity the generation of ROS exceeds the antioxidant reserve and can contribute to the promotion of insulin resistance. Glutathione peroxidase 1 (Gpx1) is an antioxidant enzyme that eliminates H2O2. Here we have used Gpx1-/- mice to assess the impact of oxidative stress on glucose homeostasis in the context of obesity. Results: Gpx1-/- mice fed an obesogenic high fat diet for 12 weeks exhibited systemic oxidative stress and hyperglycemia, but had unaltered whole-body insulin sensitivity, improved hepatic insulin signalling and decreased whole-body glucose production. High fat fed Gpx1-/- mice also exhibited decreased hepatic steatosis and liver damage accompanied by decreased plasma insulin and decreased glucose-induced insulin secretion. The decreased insulin secretion was associated with reduced islet ? cell Pdx1 and insulin content, elevated pancreatic PTP oxidation (including PTPN2 oxidation) and elevated STAT1 Y701 phosphorylation. Innovation and conclusion: Taken together these results are consistent with H2O2 inactivating pancreatic PTPs (such as the STAT1 phosphatase PTPN2) for the promotion of STAT-1 signalling to suppress Pdx1 expression and differentiation and consequently reduce ? cell insulin secretion. We propose that the decreased insulin secretion in turn results in decreased hepatic lipogenesis and steatosis, attenuates liver damage and improves hepatic insulin signalling to suppress hepatic glucose production. Limiting insulin secretion may help combat the development of hepatic steatosis and liver damage in diet-induced obesity.
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