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Published on: November 20, 2015
Perinatal protein restriction with postnatal catch-up growth leads to elevated p66Shc and mitochondrial dysfunction
Shelby L Oke1,2,3,4,5, Gurjeev Sohi4,5, Daniel B Hardy1,2,3,4,5
1The Children's Health Research Institute, London, Ontario, Canada.
Insights
Maternal protein restriction followed by catch-up growth in rats impairs liver mitochondrial function by altering p66Shc expression and increasing oxidative stress, leading to long-term metabolic deficits.
Area of Science:
- Metabolic research
- Mitochondrial biology
- Developmental programming
Background:
- Epidemiological studies link low birth weight and catch-up growth to metabolic deficits.
- Maternal protein restriction (MPR) in rats causes hepatic dysfunction and ER stress in offspring.
- Mitochondrial dysfunction is implicated in metabolic diseases.
Purpose of the Study:
- To investigate the role of p66Shc, a regulator of oxidative stress and mitochondrial function, in hepatic defects of MPR offspring.
- To determine if altered p66Shc expression contributes to metabolic impairments in offspring exposed to maternal low protein diets and subsequent catch-up growth.
Main Methods:
- Wistar rats were fed control (20% protein) or low protein (8%) diets during gestation.
- Offspring were assigned to control diet, continuous low protein (LP1), or low protein followed by control diet post-weaning (LP2).
- Hepatic p66Shc, oxidative stress markers, and mitochondrial enzymes were assessed at four months; HepG2 cells were used to study ER stress effects.
Main Results:
- LP2 offspring (MPR with catch-up growth) showed increased p66Shc and PIN1 protein levels.
- Aberrant oxidative stress markers (elevated 4-HNE, SOD1/2; decreased catalase) and impaired aerobic metabolism (altered PDH, LDHa, Complex II, citrate synthase, TFAM) were observed in LP2 offspring.
- Tunicamycin-induced ER stress in HepG2 cells increased p66Shc, suggesting a link between ER stress and p66Shc upregulation.
Conclusions:
- Postnatal catch-up growth following perinatal low protein exposure detrimentally impacts long-term hepatic mitochondrial function in rats.
- Altered p66Shc expression, driven by ER stress, is a key mechanism contributing to these programmed metabolic deficits.
- Perinatal nutrition and postnatal growth dynamics significantly influence offspring metabolic health trajectory.
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.
