# Maternal Obesity and Pediatric NAFLD: Fetal Origins and Long-term outcomes in Non Human Primates

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $536,924

## Abstract

PROJECT SUMMARY
 The prevalence of maternal overweight and obesity continues to increase in the U.S. and spans the
spectrum of age, race and ethnicity, and socioeconomic status. Alarmingly, 1 in 10 infants and toddlers are
obese, and 1 in 5 youth are both obese and at-risk for pediatric Non-alcoholic fatty liver disease (NAFLD).
NAFLD can begin in utero with longitudinal studies showing an increased risk of NAFLD in adolescents born to
obese mothers. Some features of NAFLD are similar in children and adults, yet portal fibrosis and inflammation
are more common in pediatric NASH patients than adult patients, and portends a rapid progression to end-stage
liver disease in early adulthood for reasons that remain poorly understood. Our group has spent the past decade
developing and characterizing a sophisticated nonhuman primate (NHP) model of high fat/calorically dense
maternal diet consumption that has critically important developmental and physiological similarities to humans.
 Data from our well-characterized NHP model demonstrate that maternal Western-style diet (MWSD) triggers
fetal hepatic collagen deposition in the portal triad and stellate cell activation that persists in 3-year-old (3YO)
juvenile animals, despite switching to a healthy chow diet at weaning. Notably, 2 miRNAs with critical roles in
liver metabolism and inflammatory responses were significantly increased (miR-122) or decreased (miR-34a) in
fetal liver and partially normalized when obese mothers were switched to a healthy chow diet. Our results suggest
these miRNAs are diet-sensitive and candidate targets for epigenetic priming of NAFLD early in life. Our
preliminary data in 3YO NHP offspring also show that MWSD reprograms hematopoietic stem cell progenitors
(HSPC)s and bone marrow derived macrophages (BMDM) to a glycolytic phenotype and a blunted response to
IL-4, suggesting decreased anti-inflammatory capacity and impaired Mφ ability to assume a reparative
phenotype. Given the importance of M2-like Mφ for healing liver injury,our overall hypothesis is that MWSD alters
miRNAs in liver in parallel with epigenetically reprogrammed HSPC and liver Mφ before birth. This leads to
ongoing production of hyper-inflammatory Mφ and the inability to resolve liver injury across the lifespan. The
overarching goal of this proposal is to understand the mechanistic basis by which MWSD drives epigenetic
remodeling and the pathogenesis for NAFLD beginning in utero. In this revised application, our Aims are to: 1)
Test the hypothesis that MWSD alters binding of fetal miR-34a, and miR-122 to specific targets in fetal liver, and
identify macrophage sub-sets in Juvenile livers using single cell RNAseq; 2) Test the hypothesis that MWSD
drives pro-inflammatory functions in isolated fetal and 3YO HSPC and liver Mφ through distinct transcriptional
and epigenetic mechanisms. 3) Test the hypothesis that MWSD disrupts BA signaling and HNF4α in MWSD
hepatocytes and preferentially affects periportal hepatocy...

## Key facts

- **NIH application ID:** 10875459
- **Project number:** 5R01DK128416-04
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** JACOB E FRIEDMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $536,924
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875459

## Citation

> US National Institutes of Health, RePORTER application 10875459, Maternal Obesity and Pediatric NAFLD: Fetal Origins and Long-term outcomes in Non Human Primates (5R01DK128416-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10875459. Licensed CC0.

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