# Mechanisms of metabolic dysfunction in the offspring of maternal obesity: role of inflammation

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $186,020

## Abstract

Obesity in pregnancy predisposes the offspring to obesity, thus initiating a vicious cycle of obesity and its
health-related consequences in subsequent generations. Over the past two decades, the search for a potential
unifying mechanism behind obesity and its related diseases has revealed a close relationship between nutrient
excess and dysfunction in immunity and inflammation. Obesity is considered a state of chronic, low-grade
inflammation. The activation of pathological inflammation in obese pregnant women has been characterized,
but the role of inflammation in the developmental programming of maternal obesity remains unclear. Dipeptyl
peptidase 4 (DPP4) is an adipokine that is released from adipocytes, hepatocytes, and immune cells and
promotes obesity by activating innate inflammation and increasing caloric intake. DPP4 expression is
substantially elevated in the visceral fat of obese subjects, and serum DPP4 correlates with all parameters of
metabolic syndrome. Pharmacological inhibitors of DPP4 have been effective in the prevention of insulin
resistance and cardiovascular diseases. In ongoing experiments, we found that modulation of maternal
immune system precedes obesity and metabolic dysfunction, suggesting that maternal inflammation and not
obesity per se is the major culprit in developmental programming. We have established a mouse model of a
maternal high-fat diet (HFD) and were able to recapitulate the metabolic dysfunction seen in the human
offspring of obese mothers. Our preliminary data show that: 1). Three-week-old offspring of HFD-fed mothers
have increased infiltrations of CD4+, CD8+, and memory T cells in the liver and visceral adipose tissue and
increased body fat percentage when compared to the offspring of a regular diet (RD)-fed mothers. 2). At 8
weeks of age, mice that were born to HFD-fed mothers show increased adiposity, impaired glucose tolerance,
and perivascular fibrosis despite eating a regular diet. 3). At 11 months of age, the offspring of HFD-fed
mothers are obese and insulin-resistant. 4). Adoptive transfer of dendritic cells collected from the offspring of
HFD- but not RD-fed mothers to naïve mice caused accumulation of adipose tissue and dysregulation of
glucose metabolism. 5. DPP4 activity is increased in the plasma and cord blood from obese mothers carrying
male fetuses, and in the liver of male offspring of HFD-fed mice, suggesting that DPP4 is regulated in a sex-
dependent manner. The overarching hypothesis of this proposal is that maternal obesity induces hepatic and
adipose tissue inflammation in offspring, thereby increasing the production of Dpp4 and the activation of
inflammatory pathways leading to metabolic dysfunction. Aim 1 will test the hypothesis that T cells play a
critical role in metabolic dysfunction in the offspring of HFD fed mothers. Aim 2 will test the hypothesis that
DPP4 inhibition attenuates the programming effect of maternal obesity by reducing caloric intake, improving
glucose tole...

## Key facts

- **NIH application ID:** 10006018
- **Project number:** 5R21HD099367-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Alina Maloyan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $186,020
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006018

## Citation

> US National Institutes of Health, RePORTER application 10006018, Mechanisms of metabolic dysfunction in the offspring of maternal obesity: role of inflammation (5R21HD099367-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10006018. Licensed CC0.

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