# The role of stress in the fetal origin of obesity and metabolic dysfunction

> **NIH NIH P20** · UNIVERSITY OF NEBRASKA LINCOLN · 2020 · $306,528

## Abstract

PROJECT SUMMARY / ABSTRACT
 Intrauterine growth-restriction (IUGR) due to stress causes fetal metabolic dysfunction in late
gestation, which persists after birth and worsens as the individual ages. Our long-term goal is to
identify molecular mechanisms that can be modified with maternally-delivered bioactive
compounds to improve glucose homeostasis and metabolic function in the IUGR fetus. We have
observed impaired glucose-stimulated insulin secretion and muscle glucose oxidation in IUGR
fetal and neonatal sheep. We also recently identified enhanced TNFR1 and TLR4 pathways in
IUGR fetal tissues, which we hypothesize are underlying mechanisms that disrupt glucose
oxidation, insulin secretion, and metabolic homeostasis. Thus, the overarching objective for
this study is to determine the extent to which mitigating the heightened activity of TNFR1 and
TLR4 pathways improves these deficits. The study will be performed using the hyperthermic
pregnant ewe model, which is a well-established biomedical model that mimics the human
IUGR phenotype. TNFR1 and TLR4 activity will be moderated by infusing catheterized IUGR
fetuses daily with eicosapentaenoic acid and docosahexaenoic acid, as these ω-3 fatty acids
are known to reduce the activity of both pathways. In Specific Aim 1, we will perform in vivo and
ex vivo studies to measure fetal whole-body and muscle-centric glucose metabolism. This will
allow us to determine the role that heightened TNFR1 and TLR4 activity plays in the glucose
metabolism deficits previously observed in the IUGR fetus. In Specific Aim 2, we will assess
fetal glucose-stimulated insulin secretion and islet morphology to determine the role of
heightened TNFR1 and TLR4 activity in β cell dysfunction and impaired islet development. In
addition, we will measure indicators of fat homeostasis and assess the total transcriptomes of
fetal muscle and islet tissues. This will provide a more comprehensive understanding of the
wider mechanistic changes that occur in these tissues in response to intrauterine stress,
including additional regulatory pathways that may be involved in the IUGR metabolic phenotype.
Currently, there are no treatment options for improving metabolic health status in IUGR-born
children and adults due to the gap in our understanding of the underlying adaptive mechanisms.
However, the findings of this study are expected to reveal that heightened TNFR1 and TLR4
activity has a key role in impaired muscle glucose oxidation and β cell dysfunction and thus are
appropriate mechanistic targets to moderate metabolic programming effects. This would fill a
need by establishing the basis for prenatal prevention of the metabolic dysfunction that places
IUGR-born babies at greater risk for metabolic disorders.

## Key facts

- **NIH application ID:** 10153201
- **Project number:** 3P20GM104320-07S1
- **Recipient organization:** UNIVERSITY OF NEBRASKA LINCOLN
- **Principal Investigator:** JANOS ZEMPLENI
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $306,528
- **Award type:** 3
- **Project period:** 2014-08-05 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153201

## Citation

> US National Institutes of Health, RePORTER application 10153201, The role of stress in the fetal origin of obesity and metabolic dysfunction (3P20GM104320-07S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10153201. Licensed CC0.

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