Maternal high-fat diet consumption programs male offspring to mitigate complications in liver regeneration

Abstract

In the last decades, obesity and nonalcoholic fatty liver disease (NAFLD) have become increasingly prevalent in wide world. Fatty liver can be detrimental to liver regeneration (LR) and offspring of obese dams (HFD-O) are susceptible to NAFLD development. Here we evaluated LR capacity in HFD-O after partial hepatectomy (PHx). HFD-O re-exposed or not to HFD in later life were evaluated for metabolic parameters, inflammation, proliferation, tissue repair markers and survival rate after PHx. Increasing adiposity and fatty liver were observed in HFD-O. Despite lower IL-6 levels, Ki67 labeling, cells in S phase and Ciclin D1/PCNA protein content, a lower impact on survival rate was found after PHx, even when re-exposed to HFD. However, no difference was observed between offspring of control dams (SC-O) and HFD-O after surgery. Although LR impairment is dependent of steatosis development, offspring of obese dams are programmed to be protected from the damage promoted by HFD.

Hepatic Epigenetic Reprogramming After Liver Resection in Offspring Alleviates the Effects of Maternal Obesity

“…Although Nf2 gene expression dysregulation could be involved in NAFLD pathogenesis and progression to HCC ( Ardestani et al, 2018 ), the reduction in the transcript levels in the HF-O group 48h after PHx, compared to baseline, may be an indication that the pathway that controls cell repair is more permissive in this group after mechanical injury, similar to the CT-O. This result is supported by the findings of cyclin D1 content in the same model in our previous work ( Fante et al, 2021 ). Xiao et al (2005) suggested that the product of the Nf2 gene inhibits cell cycle progression through Cyclin D1 suppression since Nf2 gene silencing results in upregulation of cyclin D1 and S-phase entry.…”

“… Xiao et al (2005) suggested that the product of the Nf2 gene inhibits cell cycle progression through Cyclin D1 suppression since Nf2 gene silencing results in upregulation of cyclin D1 and S-phase entry. We have shown that despite cyclin D1 showing a tendency to decrease in the HF-O group 48hs after PHx, the protein content still increases greatly in comparison to the baseline, being similar to the CT-O group and allowing the cell to enter the S-phase of the cycle, even with some delay ( Fante et al, 2021 ).…”

“…The liver has a unique ability to regenerate ( Mao et al, 2014 ), though the excessive presence of ectopic fat is a limiting factor for liver regeneration ( Truant et al, 2013 ; Amini et al, 2016 ). Notably, our recent study showed that the offspring of obese dams have delayed regenerative process after partial hepatectomy; however, they seem to be programmed by maternal overnutrition to overlap the metabolic damage and promote cellular proliferation to ensure survival ( Fante et al, 2021 ). However, this previous study did not assess the epigenetic modulation in the offspring of obese dams and the role of miRNAs in liver regeneration.…”

“…The females were randomly separated into two groups: the standard chow-fed group (CT, NUVILAB ® Cr-1; Nuvital; 3.5 kcal/g, 9.5% of energy from fat) and a high-fat diet-fed group (HF for growth; AIN-93G; 4.6 kcal/g, 45% of energy from fat) both ad libitum during the adaptation period (4 weeks before mating), gestation, and lactation. The HF diet was prepared according to previous studies ( Simino et al, 2017 ), and only obesity-prone females were included in the HF group (80% belonging to the cohort described by Fante et al, 2021 ). All mice had free access to water and were maintained in individual polypropylene micro-isolators at 22 ± 1°C with lights on from 06:00 to 18:00 h. Swiss males from the same age fed CT diet were used for mating (2 females:1 male).…”

“…We have recently shown that mice offspring programmed by maternal obesity during gestation and lactation have delayed regenerative response after PHx since they present lower IL-6 levels, Ki67 labeling, cells in S-phase, and Cyclin D1 content as compared to the offspring of control dams. However, even when rechallenged to HFD in adult life, PHx had lower impact on the survival rate of the offspring of obese dams, since they reach successful liver regeneration as the offspring of control dams ( Fante et al, 2021 ).…”