# Placental adiponectin signaling and fetal programming in maternal obesity

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $437,255

## Abstract

Over 60% of American women now enter pregnancy either overweight or obese, which increases the risk for
the infant to develop obesity, diabetes and cardiovascular disease in childhood and later in life. However, the
mechanisms linking the in utero environment in maternal obesity to programming of the fetus for later disease
remain poorly understood, which constitutes a major roadblock for the development of specific intervention
strategies. Circulating levels of adiponectin are decreased in obese pregnant women and in our mouse model
of maternal obesity. We have previously reported that adiponectin, in contrast to its well-known insulin-
sensitizing effects in skeletal muscle and liver, inhibits placental insulin and mTOR signaling and amino acid
transport. This effect is mediated by activation of trophoblast PPARsignaling, which increases ceramide
synthesis resulting in inhibition of IRS-1. Remarkably, in our novel model of maternal obesity, which shows
extensive similarities with the human condition (elevated levels of maternal leptin, glucose intolerance,
activation of placental insulin and mTOR signaling, increased placental nutrient transport and fetal overgrowth),
restoration of normal circulating levels of adiponectin completely prevented placental dysfunction, fetal
hyperglycemia and overgrowth. Our findings demonstrate that low circulating adiponectin in maternal obesity is
mechanistically linked to increased placental nutrient transport and fetal growth. However, whether
normalization of maternal adiponectin levels in pregnancy attenuates the long-term adverse metabolic and
cardiovascular consequences of intrauterine exposure to maternal obesity in the offspring is unknown. Our
central hypothesis is that adiponectin supplementation in late pregnancy prevents the development of
metabolic and cardiovascular disease in the offspring in response to maternal obesity and that this effect is
mediated by adiponectin receptor 2 (AdipoR2) in the placenta. This hypothesis is supported by compelling
preliminary data including the demonstration that 3-month old male offspring of obese dams (1) develop
obesity, glucose intolerance, hypertriglyceridemia and fatty liver; (2) have up-regulation of fetal cardiac genes,
activation of cardiac insulin and mTOR signaling and left ventricular diastolic dysfunction and (3) these
developmentally programmed changes are prevented by maternal adiponectin supplementation in pregnancy.
Using mini-osmotic pumps, we will supplement adiponectin the last four days of pregnancy to lean and obese
dams, with or without trophoblast-specific knock down of AdipoR2, and study male and female offspring at 3
and 6 months of age to address our hypothesis in three specific aims: Determine the effect of adiponectin
supplementation in obese dams on offspring metabolism (Aim 1) and cardiovascular function (Aim 2) and to
determine the mechanistic role of placental adiponectin receptors in fetal programming in maternal obesity
(Aim 3...

## Key facts

- **NIH application ID:** 9930108
- **Project number:** 5R01HD065007-09
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Thomas Jansson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,255
- **Award type:** 5
- **Project period:** 2010-12-25 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930108

## Citation

> US National Institutes of Health, RePORTER application 9930108, Placental adiponectin signaling and fetal programming in maternal obesity (5R01HD065007-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9930108. Licensed CC0.

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