# Fetal glucagon links fetal metabolism with uterine blood flow and placental nutrient transfer by inhibiting placental lactogen secretion

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $661,228

## Abstract

PROJECT ABSTRACT
Our goal is to establish a new framework for understanding the regulation of fetal growth. To do so,
we will demonstrate novel roles for fetal glucagon and maternal placental lactogen. Current dogma
holds that the mother's nutritional and hormonal status, uterine blood flow, and early events in
placental development regulate placental nutrient delivery and fetal growth. However, knowledge
gaps in this understanding have prevented progress towards successful treatment of disordered fetal
growth during complications of pregnancy. This proposal will show how fetal glucagon inhibits uterine
blood flow and placental nutrient delivery by inhibiting secretion of placental lactogen into the
maternal circulation. We have recently demonstrated that experimentally increasing fetal glucagon
concentrations with direct fetal glucagon infusions into late gestation fetal sheep lowers uterine blood,
placental uptake of nutrients and oxygen from the maternal circulation, placental delivery of amino
acids to the fetus, fetal plasma concentrations of amino acids, fetal plasma concentrations of the
anabolic growth factors insulin and IGF-1, and fetal protein accretion. These were associated with a
13% reduction in fetal weight after just a nine-day infusion. Additionally, we have demonstrated that
experimentally lowering placental lactogen in pregnant sheep results in lower uterine blood flow and
placental nutrient delivery independent of its classically described role in regulating maternal nutrient
metabolism. We have repeatedly shown that increasing fetal amino acids raises fetal glucagon
concentrations. Taken together, these data support our overarching hypothesis: fetal glucagon
matches placental nutrient delivery to fetal metabolic demand by inhibiting PL secretion. This
hypothesis will be tested in pregnant sheep, isolated human primary trophoblasts, and uterine and
myometrial arteries isolated from pregnant sheep and humans, respectively. In Aim #1 we will show
that the mechanism by which fetal glucagon inhibits fetal growth is by lowering placental amino acid
delivery and fetal amino acid concentrations. In Aim #2 we will demonstrate that the mechanism by
which fetal glucagon inhibits uterine blood flow and placental nutrient delivery is by lowering placental
lactogen secretion. In Aim #3 we will establish the mechanism by which glucagon inhibits placental
lactogen secretion. This proposal will be the first mechanistic physiological investigation into fetal
glucagon as an inhibitor of uterine blood flow, placental nutrient delivery, and fetal growth and
placental lactogen as a vasodilator in the uterine circulation. The impact will be to shift the paradigm
for our understanding of the regulation of fetal growth. This is required if we are to make new
advances into the management of disordered fetal growth in pregnancies complicated by placental
insufficiency, preeclampsia, diabetes, maternal obesity and other conditions.

## Key facts

- **NIH application ID:** 10636131
- **Project number:** 1R01HD111557-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Paul Joseph Rozance
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $661,228
- **Award type:** 1
- **Project period:** 2023-04-13 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10636131

## Citation

> US National Institutes of Health, RePORTER application 10636131, Fetal glucagon links fetal metabolism with uterine blood flow and placental nutrient transfer by inhibiting placental lactogen secretion (1R01HD111557-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10636131. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*