# Maternal obesity and neonatal innate immunity

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2022 · $503,067

## Abstract

The developing fetal immune system is exquisitely sensitive to signals from the maternal
environment. Maternal pre-pregnancy (pregravid) obesity has emerged as one of the most
consequential regulators of fetal health. Data from clinical and animal model studies
demonstrated increased susceptibility to microbial infection as well as a higher incidence of
inflammatory disorders and auto-immune diseases with maternal obesity. This dichotomy is
illustrated by splenocytes generating dampened inflammatory responses to LPS stimulation while
gut resident immune cells generate exaggerated ones. Similarly, pregravid obesity resulted in
lower expression of inflammatory genes in umbilical cord blood monocytes at rest, but following
differentiation into macrophages, expression of inflammatory genes was significantly increased.
These observations strongly suggest that pregravid obesity disrupts the development and
maturation of the fetal immune system and differentially impacts circulating monocytes
and tissue resident macrophages (TRMs). However, the molecular underpinnings of this
dysregulation by maternal obesity remain poorly understood due to the difficulty of obtaining term
fetal tissues and of controlling for multiple maternal variables that modulate fetal immunity. Thus,
in this application, we will leverage the rhesus macaque model to interrogate multiple fetal
compartments within the same subject to address this knowledge gap. Immune ontogeny occurs
via 3 different waves starting with yolk sac, transitioning to fetal liver, and finally the bone marrow.
TRMs are derived primarily from yolk sac and fetal liver while circulating monocytes are derived
from bone marrow. We recently reported that pregravid obesity is associated with low grade
inflammation that is further compounded by pregnancy. Thus, we postulate that exposure to low
grade maternal inflammation leads to “training” of TRMs while heightened maternal inflammatory
environment in late gestation leads to “tolerance” of bone marrow derived monocytes. Therefore,
this application will test the central hypothesis that pregravid obesity results in differential
rewiring of TRMs and circulating monocytes wherein TRMs are poised to generate a
heightened inflammatory response while circulating monocytes display a stunted
response. The novelty of this application lies in the systems biology approach integrating
maternal clinical metadata with genomic and functional readouts obtained in multiple immune
compartments in the same animal. Completion of the proposed experiments will reveal the
molecular mechanisms that result in altered fetal macrophage and monocyte functions thus
informing the potential development of early interventions.

## Key facts

- **NIH application ID:** 10534915
- **Project number:** 2R01AI142841-05
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Ilhem Messaoudi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $503,067
- **Award type:** 2
- **Project period:** 2018-09-24 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534915

## Citation

> US National Institutes of Health, RePORTER application 10534915, Maternal obesity and neonatal innate immunity (2R01AI142841-05). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10534915. Licensed CC0.

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