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 nave 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 tolerance, and suppressing immune activation. The proposed studies will provide fetal sex-specific, mechanistic data linking maternal inflammation and metabolic function in the offspring.

Public Health Relevance

Pregnancies with maternal obesity predispose the offspring to cardiovascular and metabolic diseases in adult life. We propose that changes in the offspring?s immune systems constitute an important mechanism of this phenomenon. This proposal is highly relevant to public health because it will identify potential therapeutic targets to alleviate cardiovascular and metabolic diseases in the offspring of pregnancies complicated by maternal obesity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD099367-02
Application #
10006018
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Bremer, Andrew
Project Start
2019-09-01
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239