# Role of the Macrophage in Developmentally Programmed NAFLD

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $607,942

## Abstract

PROJECT SUMMARY
Strong evidence across species suggests that exposure to maternal western-style diets (WD) creates a long-
lasting metabolic signature on the offspring liver, its innate immune system, and the microbiota. We have found
that maternal WD reprograms development of offspring macrophages (Mφ) toward a non-reparative,
inflammatory phenotype that accelerates nonalcoholic fatty liver disease (NAFLD) risk in response to WD later
in life. Our findings suggest that exposure to WD has both immediate and long-term effects on offspring
hematopoiesis, Mϕ function, pro-inflammatory liver gene expression and fibrogenesis that are not resolved
despite switching to a healthy diet. How maternal WD during pregnancy or lactation imparts lasting effects on
offspring whole body physiology and Mϕ function through distinct metabolic and/or transcriptional mechanisms
is unknown. Our preliminary data show that gut bacteria-derived indoles, mediators of the aryl hydrocarbon
receptor (AHR)-driven immune response, are decreased in WD-fed dams and their offspring concomitant with
an increase in metabolic reprogramming of myeloid cells. Moreover, dietary treatment of WD-fed pregnant dams
with a novel antioxidant (pyrroloquinoline quinone [PQQ]), found in high concentrations in breast milk, decreases
offspring NAFLD and liver fibrosis, attenuates inflammatory Mφ polarization, improves gut microbial function and
activates AHR signaling. These findings suggest activating AHR may hold promise for prevention of NAFLD.
The goal of this proposal is to establish the mechanisms through which changes in maternal diet impact
Mφ remodeling to increase risk for NAFLD development in later life. We hypothesize that indole-producing
bacteria control NAFLD risk through reprogramming of liver Mφ progenitors in a time- and AHR-dependent
manner. We will target gestation (embryonic d 14.5) and lactation (post-natal d 14) as critical windows of WD
exposure leading to persistent effects in adulthood (16 wks of age). In Aim 1, we will pair functional assays in
isolated Mϕ from liver- and bone marrow-derived cells with single cell analyses in the liver to investigate distinct
transcriptional mechanisms by which maternal WD during pregnancy or lactation disrupts normal development
and function of offspring innate immune cells to affect physiology. In Aim 2, we will use germ-free mice and
myeloid-specific knockout of AHR to determine how bacterial indole metabolism and AHR signaling drive
remodeling of naive Mφ to a pro-inflammatory phenotype. Metagenomic sequencing of dam and offspring
microbiota will identify microbial functions altered by maternal WD exposure. Metabolomics in serum will identify
deficient metabolites, such as indoles, which we will test in gain-of-function experiments. In Aim 3, we will
determine how dietary PQQ promotes metabolism of indoles during pregnancy or lactation to preserve Mφ
function in offspring exposed to maternal WD in vivo and in vitro. Completion of the...

## Key facts

- **NIH application ID:** 10051944
- **Project number:** 1R01DK121951-01A1
- **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:** 2020
- **Award amount:** $607,942
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051944

## Citation

> US National Institutes of Health, RePORTER application 10051944, Role of the Macrophage in Developmentally Programmed NAFLD (1R01DK121951-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10051944. Licensed CC0.

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