Children's Hospital Colorado

Maternal Western Diet Exposure Increases Periportal Fibrosis Beginning in Utero in Nonhuman Primate Offspring

Maternal and Fetal Medicine | June 22, 2022

For families

  • Maternal obesity and consumption of a high-fat diet can impact the long-term health of offspring, including a high risk for developing metabolic conditions.
  • Early onset of pediatric nonalcoholic fatty liver disease (NAFLD) is a particular concern for these children, increasing the risk for progressive liver disease.
  • Researchers found a link between maternal obesity from consuming a high-fat, high-sugar diet and an increased risk for pediatric NAFLD.
  • A focus on maternal nutrition to ease stress on the developing liver in a fetus could help lower the risk for early-onset metabolic disease.

For health professionals

  • Maternal obesity is a major risk factor for early-onset pediatric NAFLD and is different from adult disease patterns.
  • Pediatric NAFLD is the most common liver disease seen at Children’s Colorado’s Pediatric Liver Center.
  • The condition is characterized by excess liver fat and fibrosis that may progress to nonalcoholic steatohepatitis (NASH).
  • Offspring of obese macaque mothers fed a Western-style diet had increased periportal fibrosis, indicating that fibrogenesis begins in utero and persists for at least one year.
  • Researchers found that switching to a healthier diet or supplementing with antioxidants during pregnancy reduced liver scarring and oxidative stress on offsprings’ livers.
  • Notably, liver pathogenesis occurred in the absence of obesity in offspring, emphasizing the need for better surveillance and biomarkers.

Stats

  • ~1/3 of pregnant women in the U.S. have obesity
  • ~10% of all U.S. children have NAFLD

Background: maternal obesity and Western-style diet as potential risk factors

Nonalcoholic fatty liver disease (NAFLD) progresses more rapidly in children than in adults and can lead to cirrhosis, liver cancer and a need for liver transplantation by early adulthood. Despite advances in understanding adult-onset NAFLD, there are still gaps in the understanding of early-onset childhood NAFLD.

Children with NAFLD are more likely to have inflammation and fibrosis in the liver’s portal regions, associated with more severe liver disease. Few studies have assessed the degree of scarring and inflammation in the portal regions and how it progresses to pediatric nonalcoholic steatohepatitis (NASH).

The NASH Clinical Research Network multicenter, cross-sectional study of children with NAFLD, found children with high birth weights were at higher risk for NASH than children with low birth weight, even after controlling for childhood BMI.

In a study led by neonatology researchers at the University of Colorado School of Medicine in collaboration with researchers at the Oregon National Primate Research Center and University of Oklahoma Health Sciences Center, female macaques were fed a chronic Western-style diet (WSD) and studied during pregnancy to investigate:

  • Effect of WSD and maternal obesity on fetal liver tissue
  • Cellular mechanisms promoting liver fibrosis in utero
  • If increased liver fibrosis persisted until age 1
  • If maternal dietary interventions and resveratrol (a polyphenol antioxidant) could halt progression of fibrosis

Methods: comparison of markers for NAFLD

Adult female Japanese macaques were fed either a WSD or a control diet (CD) for two to nine years before conception and throughout pregnancy.

During the early third trimester of pregnancy, researchers collected data from both groups:

  • Body weight
  • Plasma insulin
  • Glucose measurements
  • Glucose tolerance test

CFCC_Maternal Western Diet Exposure graphics-1.jpg

Second harmonic generation (SHG) imaging technology and ribonucleic acid scope were used to detect and quantify collagen deposition in livers of offspring exposed to WSD and CD by measuring SHG signal intensity and area. Flow cytometry was used to characterize changes in immune cell populations.

To investigate whether dietary changes affected liver fibrosis:

  • Obese, WSD-diet fed macaques switched to CD two months before next pregnancy
  • Obese, WSD-fed, pregnant female macaques given resveratrol three months before and throughout pregnancy

To investigate whether in utero liver fibrosis persisted in 1-year-old offspring, those exposed to WSD or CD were switched to or continued CD at 6 months old.

Results: Western-style diet and maternal obesity increases periportal fibrosis in offspring

Key study findings include:

Overall, no difference between offspring exposed to a WSD and CD in:

  • Fetal body weights
  • Liver weight relative to body weight
  • Area of increased collagen deposition around central veins
  • Cellular markers for inflammation

When compared to fetuses exposed to CD, fetuses exposed to WSD had:

  • Increased hypoxemia, hepatic steatosis and triglycerides
  • 22% increase in SHG signal intensity
  • 43% increase in signal area around portal triads
  • 28% increase in SHG signal intensity around central veins
    • No increase in signal area
  • Increased phagocytosis-induced HSC and myofibroblast-derived markers of fibrosis
  • No systemic or liver inflammation
  • Increase in several markers for oxidative stress
    • Four-fold increase in thiobarbituric acid reactive substances (TBAR)
    • 20% increase in manganese superoxide dismutase (MnSOD)
    • Increase in acetylated MnSOD
  • Reduced protein expression of SIRT 3 (a deacetylase of MnSOD that promotes resolution of oxidative stress)

When compared to fetuses exposed to a CD throughout, 1-year-old offspring exposed to a WSD until 6 months old and weaned to a CD at 6 months old had decreased collagen deposition:

CFCC_Maternal Western Diet Exposure graphics-2.jpg

When compared to offspring exposed only to a WSD, offspring exposed to WSD and switched to a CD two months before conception had decreased collagen deposition and signs of oxidative stress:

  • 20% decrease in collagen (SHG) signal intensity
  • Decrease in SHG area
  • 76% decrease in TBAR
  • Decreased signs of oxidative stress
  • Lower fetal triglycerides

When compared to offspring exposed only to a WSD, offspring exposed to WSD whose mothers were fed resveratrol before and throughout pregnancy had decreased collagen deposition and signs of oxidative stress:

CFCC_Maternal Western Diet Exposure graphics-3.jpg

Discussion: periportal fibrosis indicates maternal obesity is a risk factor for early onset NAFLD

Key study findings:

  • Consuming a WSD increased:
    • Maternal obesity
    • Maternal insulin resistance
    • Fetal hypoxemia
    • Fetal hepatic steatosis
  • 1-year-old offspring of WSD-fed mothers showed persistent increases in periportal collagen deposition and no increases in inflammatory cytokines.
  • Collagen deposition, triglycerides, signs of oxidative stress were reduced by diet switching or resveratrol treatment.
  • Arterial percent oxygen inversely correlated with SHG areas, supporting the relationship between hypoxemia and fibrosis.
  • Collagen formation in discrete liver areas in utero, difficult to detect when analyzing whole-liver tissue, is increased by maternal WSD exposure.

Conclusion: Maternal obesity may explain early onset of severe NAFLD

This study suggests alleviating maternal obesity and insulin resistance caused by chronic WSD consumption may help reduce or prevent fetal liver steatosis and fibrosis, which are classic early changes associated with NAFLD. Further studies are underway to better understand the molecular changes unique to the progression of pediatric NAFLD.