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Perinatal protein restriction with postnatal catch-up growth leads to elevated p66Shc and mitochondrial dysfunction in the adult rat liver.

ABSTRACT: Epidemiological data suggest an inverse relationship between birth weight and long-term metabolic deficits, which is exacerbated by postnatal catch-up growth. We have previously demonstrated that rat offspring subject to maternal protein restriction (MPR) followed by catch-up growth exhibit impaired hepatic function and ER stress. Given that mitochondrial dysfunction is associated with various metabolic pathologies, we hypothesized that altered expression of p66Shc, a gatekeeper of oxidative stress and mitochondrial function, contributes to the hepatic defects observed in MPR offspring. To test this hypothesis, pregnant Wistar rats were fed a control (20% protein) diet or an isocaloric low protein (8%; LP) diet throughout gestation. Offspring born to control dams received a control diet in postnatal life, while MPR offspring remained on a LP diet (LP1) or received a control diet post weaning (LP2) or at birth (LP3). At four months, LP2 offspring exhibited increased protein abundance of both p66Shc and the cis-trans isomerase PIN1. This was further associated with aberrant markers of oxidative stress (i.e. elevated 4-HNE, SOD1 and SOD2, decreased catalase) and aerobic metabolism (i.e., increased phospho-PDH and LDHa, decreased complex II, citrate synthase and TFAM). We further demonstrated that tunicamycin-induced ER stress in HepG2 cells led to increased p66Shc protein abundance, suggesting that ER stress may underlie the programmed effects observed in vivo. In summary, because these defects are exclusive to adult LP2 offspring, it is possible that a low protein diet during perinatal life, a period of liver plasticity, followed by catch-up growth is detrimental to long-term mitochondrial function.

SUBMITTER: Oke SL

PROVIDER: S-EPMC6933810 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Perinatal protein restriction with postnatal catch-up growth leads to elevated p66Shc and mitochondrial dysfunction in the adult rat liver.

Oke Shelby L SL Sohi Gurjeev G Hardy Daniel B DB

Reproduction (Cambridge, England) 20200101 1

Epidemiological data suggest an inverse relationship between birth weight and long-term metabolic deficits, which is exacerbated by postnatal catch-up growth. We have previously demonstrated that rat offspring subject to maternal protein restriction (MPR) followed by catch-up growth exhibit impaired hepatic function and ER stress. Given that mitochondrial dysfunction is associated with various metabolic pathologies, we hypothesized that altered expression of p66Shc, a gatekeeper of oxidative str ...[more]

PMID: 31689235

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Project description:BackgroundPostnatally, small-for-gestational-age (SGA; birthweight <10th centile) infants who are growth restricted due to uteroplacental insufficiency (UPI) demonstrate 'catch-up growth' to meet their genetically-predetermined size. Infants who demonstrate slowing growth during pregnancy are those that cross estimated fetal weight centiles at serial ultrasound examinations. These infants that slow in growth but are born appropriate-for-gestational-age (AGA; ≥10th centile), exhibit antenatal, intrapartum and postnatal indicators of UPI. Here, we examine if and when these infants (labelled as AGA-FGR) also demonstrate catch-up growth like SGA infants, when compared with AGA infants with normal antenatal growth velocity (AGA-NG).MethodsWe followed-up the infants of women who had previously undergone ultrasound assessment of fetal size at 28- and 36-weeks' gestation, enabling calculation of antenatal growth velocity. To assess postnatal growth, we asked parents to send their infant's growth measurements, up to two years post-birth, which are routinely collected through the state-wide Maternal-Child Health service. Infants with medical conditions affecting postnatal growth were excluded from the analysis. From the measurements obtained we calculated age-adjusted z-scores for postnatal weight, length and body mass index (BMI; weight(kg)/height(m2)) at birth and 4, 8, 12, 18 and 24 months. We used linear spline regression modelling to predict mean weight, length and BMI z-scores at intervals post birth. Predicted mean age-adjusted z-scores were then compared between three groups; SGA, AGA with low antenatal growth (AGA-FGR; loss of >20 customised estimated fetal weight centiles), and AGA-NG to determine if catch-up growth occurred. In addition, we compared the rates of catch-up growth (defined as an increase in weight age-adjusted z-score of ≥0.67 over 1 year) between the groups with Fisher's exact tests.ResultsOf 158 (46%) infant growth records received, 146 were AGA, with low antenatal growth velocity occurring in 34/146 (23.2%). Rates of gestational diabetes and SGA birthweight were higher in those lost to follow-up. Compared to AGA-NG infants, AGA-FGR infants had significantly lower predicted mean weight (p<0.001), length (p = 0.04) and BMI (p = 0.001) z-scores at birth. These significant differences were no longer evident at 4 months, suggesting that catch-up growth had occurred. As expected, the catch-up growth that occurred among the AGA-FGR was not as great in magnitude as that demonstrated by the SGA. When assessed categorically, there was no significant difference between the rate of catch-up growth among the AGA-FGR and the SGA. Catch-up growth was significantly more frequent among both the AGA-FGR and the SGA groups compared to the AGA-NG.ConclusionsAGA infants that have exhibited reduced antenatal fetal growth velocity also exhibit significant catch-up growth in the first 12 months of life. This finding represents further evidence that AGA fetuses that slow in growth during pregnancy do so due to UPI.

Project description:A number of studies have reported the occurrence of long-term metabolic disorders in mammals following intrauterine growth retardation (IUGR). However, the effects of dietary patterns during IUGR have not been fully elucidated. The present study aimed to evaluate the effects of different dietary patterns during critical growth windows on metabolic outcomes in the offspring of rats with IUGR. Male offspring rats from mothers fed either a normal or low-protein diet were randomly assigned to one of the following groups: Normal diet throughout pregnancy, lactation and after weaning (CON); normal diet throughout pregnancy and high-fat diet throughout lactation and after weaning (N + H + H); low-protein diet throughout pregnancy and high-fat diet throughout lactation and after weaning (IUGR + H + H); low-protein diet throughout pregnancy and lactation and high-fat diet after weaning (IUGR + L + H); and low-protein diet throughout pregnancy and normal diet throughout lactation and after weaning. During lactation, the male offspring in the N + H + H group exhibited the fastest growth rate, whereas the slowest rate was in the IUGR + L + H group. Following weaning, all IUGR groups demonstrated significant catch-up growth. Abnormal insulin tolerance were observed in the N + H + H, IUGR + H + H and IUGR + L + H groups and insulin sensitivity was decreased in IUGR + L + H group. The triglycerides/high-density lipoprotein ratio in the IUGR + L + H group was significantly higher compared with in the other groups. The abdominal circumference, Lee's index and adipocyte diameter of IUGR groups were significantly increased compared with the CON group. High levels of leptin and interleukin-6 in adipose tissues, and low adiponectin were observed in the IUGR + L + H group. Different dietary patterns during specific growth windows showed numerous impacts on glycolipid metabolism in IUGR offspring. The present study elucidated the mechanisms and potential options for IUGR treatment and prevention.

Dataset Information

Perinatal protein restriction with postnatal catch-up growth leads to elevated p66Shc and mitochondrial dysfunction in the adult rat liver.

Publications

Perinatal protein restriction with postnatal catch-up growth leads to elevated p66Shc and mitochondrial dysfunction in the adult rat liver.

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