Maternal Calorie Restriction Induces a Transcriptional Cytoprotective Response in Embryonic Liver Partially Dependent on Nrf2

Abstract

Background: Calorie restriction is known to enhance Nrf2 signaling and longevity in adult mice, partially by reducing reactive oxygen species, but calorie restriction during pregnancy leads to intrauterine growth retardation. The latter is associated with fetal reprogramming leading to increased incidence of obesity, metabolic syndrome and diabetes in adult life. Transcription factor Nrf2 is a central regulator of the antioxidant response and its crosstalk with metabolic pathways is emerging. We hypothesized that the Nrf2 pathway is induced in embryos during calorie restriction in pregnant mothers. Methods: From gestational day 10 up to day 16, 50% of the necessary mouse diet was provided to Nrf2 heterozygous pregnant females with fathers being of the same genotype. Embryos were harvested at the end of gestational day 16 and fetal liver was used for qRT-PCR and assessment of oxidative stress (OS). Results: Intrauterine calorie restriction led to upregulation of mRNA expression of antioxidant genes (Nqo1, Gsta1, Gsta4) and of genes related to integrated stress response (Chac1, Ddit3) in WT embryos. The expression of a key gluconeogenic (G6pase) and two lipogenic genes (Acacb, Fasn) was repressed in calorie-restricted embryos. In Nrf2 knockout embryos, the induction of Nqo1 and Gsta1 genes was abrogated while that of Gsta4 was preserved, indicating an at least partially Nrf2-dependent induction of antioxidant genes after in utero calorie restriction. Measures of OS showed no difference (superoxide radical and malondialdehyde) or a small decrease (thiobarbituric reactive substances) in calorie-restricted WT embryos. Conclusions: Calorie restriction during pregnancy elicits the transcriptional induction of cytoprotective/antioxidant genes in the fetal liver, which is at least partially Nrf2-dependent, with a physiological significance that warrants further investigation.

Sheep litter size heredity basis using genome‐wide selective analysis

“…Furthermore, GSTA1 regulates the body's antioxidant capacity, and its expression level is positively correlated with oocyte quality (Habeos et al., 2022). Large follicular granulosa cells, with a notable developmental advantage, exhibit significantly higher GSTA1 expression compared to small follicular granulosa cells.…”

“…In particular, TCF4 has been demonstrated to play a crucial role in oocyte maturation, and it serves as a pivotal gene influencing litter size traits in goats (Shi et al, 2019;Sun et al, 2023). Furthermore, GSTA1 regulates the body's antioxidant capacity, and its expression level is positively correlated with oocyte quality (Habeos et al, 2022). Large follicular granulosa cells, with a notable developmental advantage, exhibit significantly higher GSTA1 expression compared to small follicular granulosa cells.…”

Maternal obesity induced metabolic disorders in offspring and myeloid reprogramming by epigenetic regulation

“…George I. Habeos et al demonstrated that calories restricted by the mother increased the expression of genes involved in the integrative reaction to stress as well as the fetal liver's antioxidant and cytoprotective enzymes. These changes are particularly significant as they may be how adult mice respond to various stimuli, including toxins, excessive nutrient intake, and food shortage (41). The identified alterations in metabolic and antioxidant/cytoprotective genes offer insights into the potential mechanisms that the impact of maternal calorie restriction throughout the long term on the offspring's response to environmental challenges, nutrient imbalances, and limited food availability.…”

Piezo1 in Digestive System Function and Dysfunction

“…Contrary to hypothetical cellular effect of Piezo1 activation, antioxidation induced by Piezo1 activation has also been discovered in hepatocytes. Nrf2 is an important antioxidant and anti-inflammatory regulator promoting the expression of glutathione-S-transferases (Gst) and NAD(P)H: quinone oxidoreductase 1 (Nqo1) [ 105 , 106 ]. Piezo1 activation in hepatocyte increases the level of Nrf2 and Nqo1/Gsta1 genes to reduce cell death and mitochondrial oxidative stress [ 67 ].…”